Conditions: Anaplastic Large-Cell Lymphoma Non-Hodgkin Lymphoma T-Cell Lymphoma
Keywords: Antibodies, Monoclonal Antibody-Drug Conjugate Antigens, CD30 Drug Therapy Hematologic Diseases Lymphoma Monomethyl auristatin E Lymphoma, T-Cell Lymphoma, Non-Hodgkin Lymphoma, Large-Cell, Anaplastic
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 452
Healthy volunteers: no

Brief summary:
This is a double-blind, randomized, multicenter, phase 3 clinical trial to compare the efficacy and safety of brentuximab vedotin in combination with CHP with the standard-of-care CHOP in patients with CD30-positive mature T-cell lymphomas.

Detailed description:

Arms:
arm 1: cyclophosphamide, doxorubicin, vincristine, and prednisone arm 2: brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone

Interventions: intervention 1: brentuximab vedotin intervention 2: doxorubicin intervention 3: prednisone intervention 4: vincristine intervention 5: cyclophosphamide
Intervention descriptions: intervention 1: 1.8 mg/kg every 3 weeks by IV infusion for 6-8 cycles intervention 2: 50 mg/m2 every 3 weeks by IV infusion for 6-8 cycles intervention 3: 100 mg on Days 1 to 5 of each 3-week cycle, orally for 6-8 cycles intervention 4: 1.4 mg/m2 (maximum 2 mg) every 3 weeks by IV infusion for 6-8 cycles intervention 5: 750 mg/m2 every 3 weeks by IV infusion for 6-8 cycles

Protocol document:
Prot_000.pdf: 


Study SGN35-014  
Clinical Protocol  
 Amendment 5; 12-December-2018 
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PROTOCOL SYNOPSIS 
Protocol Number 
SGN35-014 
Version 
Amendment 5 
Phase 
3 
Product Name 
Brentuximab vedotin 
Sponsor 
Seattle Genetics, Inc. 
21823 30th Drive SE 
Bothell, WA 98021, USA 
Protocol Title 
A randomized, double-blind, placebo-controlled, phase 3 study of brentuximab vedotin and CHP (A+CHP) 
versus CHOP in the frontline treatment of patients with CD30-positive mature T-cell lymphomas 
Study Objectives 
Primary: 
● To compare the progression-free survival (PFS) as determined by an independent review facility (IRF) 
between the 2 treatment arms 
Secondary: 
● To compare the PFS per IRF between the 2 treatment arms for patients with systemic anaplastic large cell 
lymphoma (sALCL) 
● To compare the remission rates per IRF following the completion of study treatment between the 
2 treatment arms 
● To compare overall survival (OS) between the 2 treatment arms 
● To evaluate the safety and tolerability of the 2 treatment arms 
Additional: 
● To evaluate medical resource utilization (MRU) and calculate utility values 
● To characterize the incidence of antitherapeutic antibodies (ATA) to brentuximab vedotin 
Study Population 
Inclusion Criteria 
1. Patients with newly diagnosed, CD30-positive mature T-cell lymphomas per the Revised European-
American Lymphoma World Health Organization (WHO) 2008 classification by local assessment. Eligible 
histologies are limited to the following: 
● ALK-positive sALCL with an International Prognostic Index (IPI) score greater than or equal to 2 
● ALK-negative sALCL 
● Peripheral T-cell lymphoma – not otherwise specified (PTCL-NOS) 
● Angioimmunoblastic T-cell lymphoma (AITL) 
● Adult T-cell leukemia/lymphoma (ATLL; acute and lymphoma types only, must be positive for human 
T-cell leukemia virus 1) 
● Enteropathy-associated T-cell lymphoma (EATL) 
● Hepatosplenic T-cell lymphoma 
2. Fluorodeoxyglucose (FDG)-avid disease by PET and measurable disease of at least 1.5 cm by CT, as 
assessed by the site radiologist. 
3. Age greater than or equal to 18 years. 
4. An Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2. 
5. The following required baseline laboratory data: 


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● bilirubin ≤1.5X upper limit of normal (ULN) or ≤3X ULN for patients with Gilbert’s disease or 
documented hepatic involvement with lymphoma 
● alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3X ULN or ≤5X ULN for 
patients with document hepatic involvement with lymphoma 
● serum creatinine ≤2X ULN 
● absolute neutrophil count (ANC) ≥1000/µL (unless documented bone marrow involvement with 
lymphoma) 
● platelet count ≥50,000/µL (unless documented bone marrow involvement with lymphoma) 
6. Females of childbearing potential must have a negative serum or urine beta human chorionic gonadotrophin 
(β-hCG) pregnancy test result within 7 days prior to the first dose of study treatment and must agree to use 
an effective contraception method during the study and for at least 6 months following the last dose of study 
drug. Females of non-childbearing potential are those who are postmenopausal greater than 1 year or who 
have had a bilateral tubal ligation or hysterectomy. 
7. Males who have partners of childbearing potential must agree to use an effective contraceptive method 
during the study and for 6 months following the last dose of study drug. 
8. Patients or their legally authorized representative must provide written informed consent. 
Exclusion Criteria 
1. History of another primary invasive cancer, hematologic malignancy, or myelodysplastic syndrome that has 
not been in remission for at least 3 years. 
2. Current diagnosis of any of the following: 
● Primary cutaneous CD30-positive T-cell lymphoproliferative disorders and lymphomas. Cutaneous 
ALCL with extracutaneous tumor spread beyond locoregional lymph nodes is eligible (previous single-
agent treatment to address cutaneous and locoregional disease is permissible). 
● Mycosis fungoides (MF), including transformed MF 
3. History of progressive multifocal leukoencephalopathy (PML). 
4. Cerebral/meningeal disease related to the underlying malignancy. 
5. Prior treatment with brentuximab vedotin. 
6. Baseline peripheral neuropathy ≥ Grade 2 (per the NCI CTCAE, Version 4.03) or patients with the 
demyelinating form of Charcot-Marie-Tooth syndrome. 
7. Left ventricular ejection fraction less than 45% or symptomatic cardiac disease (including symptomatic 
ventricular dysfunction, symptomatic coronary artery disease, and symptomatic arrhythmias), or myocardial 
infarction within the past 6 months, or previous treatment with complete cumulative doses of doxorubicin or 
other anthracyclines. 
8. Any active Grade 3 (per the NCI CTCAE, Version 4.03) or higher viral, bacterial, or fungal infection within 
2 weeks prior to the first dose of study treatment; any known human immunodeficiency virus (HIV) 
infection, hepatitis B surface antigen-positive status, or known or suspected active hepatitis C infection. 
9. Current therapy with other systemic anti-neoplastic or investigational agents. 
10. 
Females who are pregnant or breastfeeding. 
11. 
Patients with a known hypersensitivity to any excipient contained in the drug formulation. 
12. 
Patients with known urinary outflow obstruction. 
Number of Planned Patients 
Approximately 450 patients (approximately 225 patients per treatment arm) will be randomized in this study. 
Study Design 
This is a randomized, double-blind, placebo-controlled, multicenter, phase 3 clinical trial designed to evaluate 
the efficacy and safety of including brentuximab vedotin in the treatment of newly diagnosed, CD30-positive 
mature T-cell lymphomas. The standard of care in this patient population consists of 6-8 cycles of CHOP 
chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone). Patients will be randomized in a 


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1:1 manner to receive 21-day cycles of treatment, either: 6-8 cycles of CHOP or 6-8 cycles of brentuximab 
vedotin plus CHP (A+CHP). A target of 8 cycles of study treatment will be administered, per investigator 
decision, based on patient-specific characteristics, including stage of disease and IPI risk score. 
Brentuximab vedotin or vincristine will be dispensed as a placebo-controlled double-dummy and administered 
to patients in a blinded manner. Placebo replacements for brentuximab vedotin/vincristine will be prepared by 
the pharmacist at each study site and a pharmacy blind will be enforced. 
Safety will be monitored over the course of the study by an Independent Data Monitoring Committee (IDMC). 
Test Product, Dose, and Mode of Administration 
Patients will be randomized 1:1 to receive 6-8 cycles of study treatment (number of cycles per investigator 
decision), either: 
Standard-of-care arm: Cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m
2, blinded vincristine 1.4 mg/m
2 
(dose capped at 2 mg) administered IV on Day 1 of each cycle; prednisone 100 mg daily administered orally on 
Days 1−5 of each cycle. Placebo replacement for brentuximab vedotin will also be administered IV in a blinded 
manner on Day 1 of each cycle. 
Experimental arm: Blinded brentuximab vedotin 1.8 mg/kg, cyclophosphamide 750 mg/m2, doxorubicin 
50 mg/m2, administered IV on Day 1 of each cycle; prednisone 100 mg daily administered orally on Days 1−5 
of each cycle. Placebo replacement for vincristine will also be administered IV in a blinded manner on Day 1 of 
each cycle. 
Duration of Treatment 
Study treatment consists of 6-8 cycles of multiagent chemotherapy. The maximum total duration of therapy is 
8 cycles, or approximately 6 months. 
Efficacy Assessments 
Lymphoma response and progression will be assessed using the Revised Response Criteria for Malignant 
Lymphoma (Cheson 2007). Radiographic disease evaluations, including CT scans of neck, chest, abdomen and 
pelvis, will be assessed at baseline, after Cycle 4 of treatment, after the completion of study treatment, at 9, 12, 
15, 18, 21 and 24 months after initiation of study treatment, and every 6 months thereafter until disease 
progression, patient death, or analysis of the primary endpoint, whichever comes first. A CT scan will also be 
performed at the time of suspected clinical progression. A PET scan is required at baseline, after Cycle 4, and 
after the completion of study treatment. Subsequent restage assessments (CT scans only) will be performed 
according to the calendar, relative to the first dose of study treatment, to ensure that tumor progression is 
uniformly assessed between the treatment arms. 
Pharmacokinetic/Pharmacodynamic/Immunogenicity Assessments 
Serum concentrations of brentuximab vedotin, antitherapeutic antibodies (ATA) to brentuximab vedotin, and 
free drug (monomethyl auristatin E; MMAE) will be measured. Pharmacodynamic assessments include the 
measurement of soluble CD30. 
Safety Assessments 
Safety assessments will consist of the surveillance and recording of adverse events (AEs) and measurements of 
physical examination findings and laboratory tests. 
Statistical Methods 
 
 
 
 
 
 


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Interim Analysis 
 The IDMC will provide recommendations to the sponsor as to appropriate study 
direction. 
Safety Analysis 
An IDMC will review safety data on an ongoing basis. 
Endpoints 
The primary efficacy endpoint of this study is PFS by IRF. 
Secondary endpoints are: 
● PFS per IRF for patients with sALCL 
● Complete remission (CR) rate per IRF following the completion of study treatment 
● OS 
● Objective response rate (ORR) per IRF following the completion of study treatment 
● Type, incidence, severity, seriousness, and relatedness of adverse events 
● Laboratory abnormalities 
 
Additional endpoints are: 
● Incidence of ATA to brentuximab vedotin 
● MRU based on the number of medical care encounters 
● Quality of life measured by the European Organisation for Research and Treatment of Cancer (EORTC) core 
quality of life questionnaire (QLQ-C30) and European Quality of Life 5-Dimensional (EQ-5D) 
Analysis Methods 
For the primary efficacy analysis, the stratified log-rank test will be used to compare the difference of PFS 
between the 2 treatment groups. Estimation of the hazard ratio will be based upon the stratified Cox regression 
model. PFS will also be summarized using the Kaplan-Meier method. Similar methods will be used for the 
secondary efficacy endpoints of OS and PFS in patients with sALCL. For the primary analysis, PFS will not be 
censored for post treatment radiotherapy, post treatment chemotherapy for the purpose of mobilizing peripheral 
blood stem cells, or consolidative autologous or allogeneic SCT because these interventions are not 
administered to treat progressive disease. 
 
 


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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ....................................................................................................................................... 2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ......................................................................... 9 
1 
INTRODUCTION ......................................................................................................................................... 11 
1.1 
CD30-Positive Mature T-Cell Lymphomas ........................................................................................ 11 
1.2 
Frontline Therapy for Mature T-cell Lymphomas .............................................................................. 12 
1.3 
Clinical Experience with Brentuximab Vedotin ................................................................................. 12 
1.4 
Rationale for Brentuximab Vedotin in Combination with CHP ......................................................... 13 
2 
OBJECTIVES ............................................................................................................................................... 14 
2.1 
Primary Objective ............................................................................................................................... 14 
2.2 
Secondary Objectives ......................................................................................................................... 14 
2.3 
Additional Objectives ......................................................................................................................... 14 
2.4 
Endpoints ............................................................................................................................................ 14 
2.4.1 
Primary Endpoint ................................................................................................................. 14 
2.4.2 
Secondary Endpoints ............................................................................................................ 15 
2.4.3 
Additional Endpoints ............................................................................................................ 15 
3 
INVESTIGATIONAL PLAN ....................................................................................................................... 15 
3.1 
Summary of Study Design .................................................................................................................. 15 
3.2 
Discussion and Rationale for Study Design........................................................................................ 16 
3.2.1 
Method of Assigning Patients to Treatment Groups ............................................................ 17 
3.2.2 
Rationale for Selection of Doses .......................................................................................... 17 
3.2.3 
Blinding ................................................................................................................................ 17 
4 
STUDY POPULATION................................................................................................................................ 18 
4.1 
Inclusion Criteria ................................................................................................................................ 18 
4.2 
Exclusion Criteria ............................................................................................................................... 19 
4.3 
Removal of Patients From Therapy or Assessment ............................................................................ 20 
4.3.1 
Discontinuation of Study Drug ............................................................................................. 20 
4.3.2 
Patient Withdrawal From Study ........................................................................................... 21 
5 
TREATMENTS ............................................................................................................................................ 21 
5.1 
Treatments Administered.................................................................................................................... 21 
5.2 
Investigational Study Drug ................................................................................................................. 21 
5.2.1 
Description ........................................................................................................................... 21 
5.2.2 
Method of Procurement ........................................................................................................ 21 
5.2.3 
Dose and Administration ...................................................................................................... 22 
5.2.4 
Required Premedication and Postmedication ....................................................................... 22 
5.2.5 
Management of Infusion Reactions ...................................................................................... 22 
5.2.6 
Management of Suspected PML .......................................................................................... 23 
5.2.7 
Storage and Handling ........................................................................................................... 23 
5.2.8 
Packaging and Labeling ....................................................................................................... 23 
5.2.9 
Preparation ........................................................................................................................... 23 
5.3 
Vincristine .......................................................................................................................................... 24 
5.3.1 
Description ........................................................................................................................... 24 
5.3.2 
Method of Procurement ........................................................................................................ 24 
5.3.3 
Dose and Administration ...................................................................................................... 24 
5.3.4 
Required Premedication and Postmedication ....................................................................... 24 
5.3.5 
Storage and Handling ........................................................................................................... 24 
5.3.6 
Packaging and Labeling ....................................................................................................... 25 
5.3.7 
Preparation ........................................................................................................................... 25 
5.4 
Cyclophosphamide, Doxorubicin, and Prednisone ............................................................................. 25 
5.4.1 
Description ........................................................................................................................... 25 
5.4.2 
Method of Procurement ........................................................................................................ 25 
5.4.3 
Dose and Administration ...................................................................................................... 25 
5.4.4 
Required Premedication and Postmedication ....................................................................... 25 


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5.4.5 
Packaging and Labeling ....................................................................................................... 26 
5.4.6 
Preparation ........................................................................................................................... 26 
5.4.7 
Storage and Handling ........................................................................................................... 26 
5.5 
Dose Modifications............................................................................................................................. 26 
5.6 
Concomitant Therapy ......................................................................................................................... 27 
5.6.1 
Required Concomitant Therapy ........................................................................................... 27 
5.6.2 
Allowed Concomitant Therapy ............................................................................................ 27 
5.6.3 
Prohibited Concomitant Therapy ......................................................................................... 27 
5.7 
Treatment Compliance ....................................................................................................................... 27 
6 
STUDY ACTIVITIES ................................................................................................................................... 27 
6.1 
Schedule of Events ............................................................................................................................. 27 
6.2 
Screening Visit (Day -28 to 1) ............................................................................................................ 28 
6.2.1 
Baseline Visit (Day -7 to Day 1) .......................................................................................... 28 
6.3 
Treatment Period (21-day cycles) ....................................................................................................... 28 
6.3.1 
Every Cycle: Day 1 .............................................................................................................. 28 
6.3.2 
Cycles 1 and 2 Only: Day 3 .................................................................................................. 29 
6.3.3 
Cycle 4 Only: Day 15-21...................................................................................................... 29 
6.3.4 
Last Planned Cycle of Treatment: Day 15-21 ...................................................................... 29 
6.4 
End-of-Treatment Visit (30-37 days after last dose of study drug) .................................................... 29 
6.5 
Follow-up ........................................................................................................................................... 30 
6.6 
End of Study/End of Follow-up .......................................................................................................... 31 
7 
STUDY ASSESSMENTS ............................................................................................................................. 31 
7.1 
Screening/Baseline Assessments ........................................................................................................ 31 
7.1.1 
CD30 Expression and Histologic Subtype ........................................................................... 31 
7.2 
Response/Efficacy Assessments ......................................................................................................... 32 
7.3 
Pharmacokinetic, Pharmacodynamic, and Immunogenicity Assessments .......................................... 33 
7.3.1 
Biopsy Tissue for Exploratory Correlative Studies .............................................................. 33 
7.3.2 
Biospecimen Samples for Future Research .......................................................................... 34 
7.4 
Medical Resource Utilization Data Collection ................................................................................... 34 
7.5 
Patient-Reported Outcomes ................................................................................................................ 34 
7.5.1 
EQ-5D – Utility Measurement ............................................................................................. 34 
7.5.2 
FACT/GOG-NTX ................................................................................................................ 34 
7.5.3 
QLQ-C30 .............................................................................................................................. 35 
7.6 
Safety Assessments............................................................................................................................. 35 
7.6.1 
Adverse Events ..................................................................................................................... 35 
7.6.2 
Clinical Laboratory Tests ..................................................................................................... 40 
7.6.3 
ECOG Performance Status ................................................................................................... 40 
7.6.4 
TNSn .................................................................................................................................... 40 
7.6.5 
Monitoring of Patients with Hepatitis .................................................................................. 40 
7.7 
Appropriateness of Measurements...................................................................................................... 40 
8 
DATA QUALITY CONTROL AND QUALITY ASSURANCE ................................................................ 41 
8.1 
Site Training and Monitoring Procedures ........................................................................................... 41 
8.2 
Data Management Procedures ............................................................................................................ 42 
8.3 
Access to Source Data ........................................................................................................................ 42 
8.4 
Accuracy and Reliability of Data........................................................................................................ 43 
8.5 
Quality Assurance Procedures ............................................................................................................ 43 
8.6 
Data Handling and Record Keeping ................................................................................................... 43 
8.6.1 
Data Handling ...................................................................................................................... 43 
8.6.2 
Investigator Record Retention .............................................................................................. 43 
9 
DATA ANALYSIS METHODS ................................................................................................................... 44 
9.1 
Determination of Sample Size ............................................................................................................ 44 
9.2 
Study Endpoint Definitions ................................................................................................................ 44 
9.2.1 
Primary Endpoint: PFS per IRF ........................................................................................... 44 
9.2.2 
Secondary Efficacy Endpoints ............................................................................................. 45 


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9.2.3 
Additional Endpoints ............................................................................................................ 45 
9.3 
Statistical and Analytical Plans .......................................................................................................... 46 
9.3.1 
General Considerations ........................................................................................................ 46 
9.3.2 
Patient Disposition ............................................................................................................... 48 
9.3.3 
Patient Characteristics .......................................................................................................... 48 
9.3.4 
Treatment Compliance ......................................................................................................... 48 
9.3.5 
Efficacy Analyses ................................................................................................................. 48 
9.3.6 
Pharmacokinetic and Pharmacodynamic Analyses .............................................................. 49 
9.3.7 
Health Outcomes Analyses .................................................................................................. 49 
9.3.8 
Safety Analyses .................................................................................................................... 49 
9.3.9 
Interim Analysis ................................................................................................................... 50 
10 INFORMED CONSENT, ETHICAL REVIEW, AND REGULATORY CONSIDERATIONS ................. 50 
10.1 Informed Consent ............................................................................................................................... 50 
10.2 Ethical Review .................................................................................................................................... 50 
10.3 Regulatory Considerations.................................................................................................................. 51 
10.3.1 
Investigator Information ....................................................................................................... 51 
10.3.2 
Protocol Amendments and Study Termination .................................................................... 51 
10.4 Study Documentation, Privacy and Records Retention ...................................................................... 51 
10.5 Clinical Trial Agreement .................................................................................................................... 52 
11 REFERENCES .............................................................................................................................................. 53 
APPENDIX A: STUDY SCHEDULE ................................................................................................................. 55 
APPENDIX B: ECOG PERFORMANCE STATUS ........................................................................................... 56 
APPENDIX C: INTERNATIONAL PROGNOSTIC INDEX FOR NHL ........................................................... 57 
APPENDIX D: INVESTIGATOR SIGNATURE PAGE .................................................................................... 58 
APPENDIX E: DOCUMENT HISTORY ............................................................................................................ 59 
 
LIST OF IN-TEXT TABLES 
Table 1: 
Study treatment by study arm ........................................................................................................ 21 
Table 2: 
Recommended dose modifications for treatment-associated neuropathy ...................................... 26 
Table 3: 
Pharmacokinetic, pharmacodynamic, and immunogenicity sampling time points ........................ 33 
 
LIST OF IN-TEXT FIGURES 
Figure 1: Study design .......................................................................................................................................... 16 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
A+CHP 
brentuximab vedotin (ADCETRIS®), cyclophosphamide, doxorubicin, and prednisone 
ADC 
antibody drug conjugate 
AE 
adverse event 
AITL 
angioimmunoblastic T-cell lymphoma 
ALK 
anaplastic lymphoma kinase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
ATA 
antitherapeutic antibodies 
ATLL 
adult T-cell leukemia/lymphoma 
AUC 
area under the concentration-time curve 
β-hCG 
beta human chorionic gonadotrophin 
CBC 
complete blood count 
Ceoi 
concentration at the end of infusion 
CFR 
Code of Federal Regulations 
CHOP 
cyclophosphamide, doxorubicin, vincristine, and prednisone 
CHOP-21 
cyclophosphamide, doxorubicin, vincristine, and prednisone administered every 21 days 
CHP 
cyclophosphamide, doxorubicin, and prednisone 
Cmax 
maximum concentration 
CNS 
central nervous system 
CR 
complete remission 
CRF 
case report form 
CT 
computed tomography 
Ctrough 
trough concentration 
EATL 
enteropathy-associated T-cell lymphoma 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EFS 
event-free survival 
EMA 
European Medicines Agency 
EOT 
end of treatment 
EQ-5D 
European Quality of Life 5-Dimensional 
FACT/GOG-NTX 
Functional Assessment of Cancer Therapy/Gynecologic Oncology Group – Neurotoxicity 
FDA 
Food and Drug Administration 
FDG 
fluorodeoxyglucose 
GCP 
Good Clinical Practice 
HEENT 
head, eyes, ears, nose, and throat 
HIPAA 
Health Information Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HR 
hazard ratio 
HRA 
Health Regulatory Authority 
HTLV-1 
human T-cell leukemia virus-1 
ICH 
International Conference on Harmonisation  
IV 
intravenous 
IDMC 
Independent Data Monitoring Committee 
IPI 
International Prognostic Index 
IEC 
Independent Ethics Committee 


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IND 
investigational new drug 
INN 
International Nonproprietary Name 
IRB 
Institutional Review Board 
IRF 
independent review facility 
JCV 
John Cunningham virus 
LDH 
lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MF 
mycosis fungoides 
MMAE 
monomethyl auristatin E 
MRI 
magnetic resonance imaging 
MRU 
medical resource utilization 
MTD 
maximum tolerated dose 
MUGA 
multi-gated acquisition 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NHL 
non-Hodgkin lymphoma 
NK 
natural killer 
ORR 
objective response rate 
OS 
overall survival 
PCP 
Pneumocystis jiroveci pneumonia 
PCR 
polymerase chain reaction 
PD 
pharmacodynamics 
PD 
progressive disease 
PET 
positron emission tomography 
PFS 
progression-free survival 
PK  
pharmacokinetics 
PML 
progressive multifocal leukoencephalopathy 
PR 
partial remission 
PRO 
patient-reported outcome 
PTCL 
peripheral T-cell lymphoma 
QLQ-C30 
EORTC core quality of life questionnaire 
SAE 
serious adverse event 
sALCL 
systemic anaplastic large cell lymphoma 
SAP 
statistical analysis plan 
SCT 
stem cell transplant 
TNSn 
Total Neuropathy Score-nurse 
Tmax 
time at which the maximum concentration occurs 
ULN 
upper limit of normal 
USAN 
United States adopted name 
USP 
United States Pharmacopeia 
WHO 
World Health Organization 
 


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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. The anticancer activity of brentuximab 
vedotin is due to the binding of the ADC to CD30-expressing cells, followed by 
internalization of the ADC-CD30 complex, and the release of MMAE via proteolytic 
cleavage. Binding of MMAE to tubulin disrupts the microtubule network within the cell, 
subsequently inducing cell cycle arrest and apoptotic death of the cell. 
This is a randomized, double-blind, placebo-controlled, multicenter, phase 3 clinical trial 
designed to evaluate the efficacy and safety of including brentuximab vedotin in the 
treatment of patients with newly diagnosed, CD30-positive mature T-cell lymphomas. The 
standard of care in this patient population consists of 6-8 cycles of CHOP chemotherapy 
(cyclophosphamide, doxorubicin, vincristine, and prednisone). Patients will be randomized in 
a 1:1 manner to receive 21-day cycles of outpatient treatment, either: 6-8 cycles of CHOP or 
6-8 cycles of brentuximab vedotin (ADCETRIS®) plus CHP (cyclophosphamide, 
doxorubicin, and prednisone), known as A+CHP. 
1.1 CD30-Positive Mature T-Cell Lymphomas 
T-cell lymphomas are a subset of aggressive non-Hodgkin lymphomas (NHL) that comprise 
approximately 10-15% of all newly diagnosed cases of NHL in the United States. According 
to the 2008 World Health Organization (WHO) Classification schema, there are 18 subtypes 
of mature T- and natural killer (NK) cell neoplasms (Swerdlow 2008). Various subtypes of 
T- and NK-cell lymphomas are known to express the cell surface marker CD30; most 
notably, sALCL, in which CD30 expression is a hallmark of the diagnosis (Savage 2008). 
CD30-positive mature T-cell lymphomas, including sALCL, peripheral T-cell lymphoma – 
not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL) and 
others, are aggressive lymphoid neoplasms that often present with advanced stage, 
symptomatic disease. These difficult-to-treat lymphomas are often grouped together for 
enrollment in clinical trials based on their universally dismal outcomes. Five-year overall 
survival (OS) in the over 1,300-patient International Peripheral T-Cell and Natural 
Killer/T-Cell Lymphoma Study was poor and ranged from 12 to 49% depending on 
histologic subtype (Vose 2008). Five-year failure-free survival, defined as time from initial 
diagnosis to progression, relapse after response, or death resulting from any cause, ranged 
from 6 to 36%. Other studies have reported CR rates to CHOP therapy between 40-50% 
(Mercadal 2008; Simon 2010). These data confirm 2 distinct unmet needs. First, there is a 
failure to induce a high rate of initial complete remissions (CRs), and second, those patients 
who do respond to combination chemotherapy experience disease progression at an 
unacceptably high rate. Increasing the proportion of patients achieving and maintaining CRs 
may result in a clinically meaningful improvement in progression-free survival (PFS) and 
OS. 


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1.2 Frontline Therapy for Mature T-cell Lymphomas 
Frontline treatment of mature T-cell and NK-cell neoplasms is dependent on the subtype of 
disease and often includes clinical trials as the preferred therapeutic option (NCCN 2013). 
For most subtypes, anthracycline-based multiagent chemotherapy regimens such as CHOP 
are commonly utilized. The notable exception is extranodal NK/T-cell lymphoma, nasal and 
non-nasal types, where concurrent chemoradiotherapy regimens are employed. 
Although no randomized studies have been conducted to establish the use of CHOP in 
patients with CD30-positive mature T-cell neoplasms, it is the most commonly used regimen 
in the frontline treatment of these patients. The International Peripheral T-Cell and Natural 
Killer/T-Cell Lymphoma Study results indicate that over 85% of patients were treated with 
an anthracycline-based multiagent chemotherapy regimen (Vose 2008). In published studies 
that have compared new treatment approaches to an established standard of care, CHOP 
administered every 3 weeks (CHOP-21) has been used as the control arm (Simon 2010). In 
addition, published guidelines recommend enrollment into a clinical trial or CHOP as 
appropriate frontline treatment options for patients with a diagnosis of “peripheral T-cell 
lymphoma, noncutaneous” (NCCN 2013). Guidelines support administration of 6 cycles of 
CHOP therapy for patients with Stage I-II disease and International Prognostic Index (IPI) 
score of 0–2, and 6–8 cycles of CHOP therapy for Stage I-II patients with an IPI score of 3–5 
and all Stage III-IV patients (Schmitz 2010; NCCN 2013). Comparison of non-randomized 
clinical trials does not support a difference in activity between 6 or 8 cycles of CHOP, with 
6–8 cycles commonly employed in clinical practice (Coiffier 2002; Schmitz 2010). As 
mentioned above, the response to CHOP chemotherapy is suboptimal with CR rates ranging 
from approximately 40-50%, and overall response rates of approximately 75% (Mercadal 
2008; Simon 2010; Dearden 2011). The estimates of long-term outcome in the mature T-cell 
lymphoma population, regardless of the backbone of anthracycline-based multiagent 
chemotherapy, are suboptimal with a median EFS or PFS of 12–18 months and a median OS 
of less than 4 years (depending on histologic subtype and IPI score). 
The high rate of subsequent disease progression among patients responding to frontline 
therapy led some researchers to employ autologous stem cell transplant (SCT) as a means of 
improving long-term outcomes; however, no randomized studies have been conducted. 
National and international guidelines support observation, a clinical trial, or the use of 
autologous SCT as acceptable options for patients who achieve a CR following frontline 
therapy (Dearden 2011; NCCN 2013). 
1.3 Clinical Experience with Brentuximab Vedotin 
The clinical safety data observed in the phase 1 dose-escalation study (Study SG035-0001) of 
brentuximab vedotin administered once every 3 weeks support the 1.8 mg/kg dose level as 
the maximum tolerated dose (MTD) and this dose and schedule was selected for pivotal 
phase 2 studies. In this phase 1 study, the most frequent adverse events (AEs) were nervous 
system (peripheral neuropathy), constitutional (fatigue and pyrexia), gastrointestinal 
(diarrhea, nausea), and hematologic (neutropenia) (Younes 2010). 


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The clinical safety and activity of brentuximab vedotin 1.8 mg/kg administered every 
3 weeks were further evaluated in a pivotal phase 2 study of patients with relapsed or 
refractory sALCL (Study SG035-0004). In this study, all patients had previously received at 
least 1 prior regimen of multiagent systemic chemotherapy with curative intent. The majority 
of patients had a diagnosis of ALK-negative disease (72%); relative to the most recent 
therapy, 50% of patients were refractory. Additionally, approximately 60% of patients had 
primary refractory disease, defined as failure to achieve a complete remission (CR) with 
frontline therapy or progression within 3 months of completing frontline therapy, and 22% of 
patients had never achieved a response with any previous therapy. In this study of highly 
refractory patients, the objective response (CR + PR) rate was 86%, with 57% of patients 
achieving a CR (Pro 2012). The median duration of response was 12.6 months, and in the 
subset of patients who achieved a CR, the median duration of response was 13.2 months. 
Brentuximab vedotin was generally well tolerated, with manageable side effects. 
The clinical safety and activity of brentuximab vedotin administered sequentially and 
concurrently with multiagent chemotherapy were evaluated in a phase 1 study in patients 
with newly diagnosed CD30-positive mature T- and NK-cell neoplasms, including sALCL 
(Study SGN35-011). This phase 1 study was implemented to determine the safety and 
activity of sequential and combination frontline treatment approaches of brentuximab vedotin 
with CHOP or CHP chemotherapy. The maximum tolerated dose of brentuximab vedotin 
was 1.8 mg/kg given concomitantly with CHP. At an interim analysis in this study (data 
presented at the T-Cell Lymphoma Forum 2012), 20 patients in this study had been treated 
with brentuximab vedotin 1.2 or 1.8 mg/kg given concomitantly with CHP for 6 cycles, 
followed by continued brentuximab vedotin every 3 weeks for up to 10 additional cycles for 
responding patients. The most common adverse events were nausea, fatigue, and peripheral 
sensory neuropathy. Of the patients who had a response assessment after 6 cycles of 
brentuximab vedotin plus CHP, 5 of 5 patients achieved a CR. 
A complete summary of the clinical and nonclinical data relevant to brentuximab vedotin and 
its study in human subjects is provided in the Investigator’s Brochure. 
1.4 Rationale for Brentuximab Vedotin in Combination with CHP 
Because of the poor outcomes in mature T-cell lymphomas, 2 strategies have been developed 
in an attempt to improve upon the results of CHOP-21: dose escalation of chemotherapy and 
new combinations/new agents. Neither approach to modifying CHOP has resulted in short- 
or long-term benefit to patients. Simon et al. demonstrated in a small randomized study that a 
more aggressive regimen (etoposide, ifosfamide, cisplatin alternating with doxorubicin, 
bleomycin, vinblastine, dacarbazine; also known as VIP-reinforced-ABVD or VIP-rABVD) 
was not superior to CHOP-21 in terms of event-free survival. Furthermore, VIP-rABVD 
resulted in more toxicities than CHOP-21. These data confirm that CHOP remains the 
reference regimen in these lymphomas. Another strategy to improve outcome has focused on 
autologous SCT consolidation in patients who achieve CRs at the end of induction therapy. 
However, many patients are not candidates for SCT, regardless of response to induction 


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therapy, due to age or intercurrent medical conditions. No randomized studies have been 
conducted, and results of single-arm studies are mixed. 
The results of the pivotal phase 2 study in patients with relapsed or refractory disease 
(described in Section 1.3) suggest a marked treatment effect of brentuximab vedotin as 
monotherapy in sALCL that is anticipated to be both clinically meaningful and associated 
with a positive risk-benefit ratio when introduced into the frontline treatment of patients with 
CD30-positive mature T-cell lymphomas. 
Given the results of treatment with brentuximab vedotin in the relapsed and refractory 
setting, and its demonstrated safety when combined with CHP, it is hypothesized that a 
treatment approach in adults that incorporates brentuximab vedotin as part of multiagent 
frontline induction therapy may yield a PFS and OS benefit. It is also reasonable to evaluate 
the replacement of vincristine with brentuximab vedotin because of the activity previously 
observed. By replacing a non-targeted microtubule-disrupting agent with a CD30-directed 
ADC that delivers a potent microtubule-disrupting agent, the potential overlapping toxicities 
of peripheral neuropathy that would be inherent to delivering both agents in the same 
regimen are avoided. 
2 
OBJECTIVES 
2.1 Primary Objective 
● 
To compare the progression-free survival (PFS) as determined by an independent 
review facility (IRF) between the 2 treatment arms 
2.2 Secondary Objectives 
● 
To compare the PFS per IRF between the 2 treatment arms for patients with sALCL 
● 
To compare the remission rates per IRF following the completion of study treatment 
between the 2 treatment arms 
● 
To compare overall survival (OS) between the 2 treatment arms 
● 
To evaluate the safety and tolerability of the 2 treatment arms 
2.3 Additional Objectives 
● 
To evaluate medical resource utilization (MRU) and calculate utility values 
● 
To characterize the incidence of antitherapeutic antibodies (ATA) to brentuximab 
vedotin 
2.4 Endpoints 
2.4.1 Primary Endpoint 
● 
Progression-free survival (PFS) by IRF 


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2.4.2 Secondary Endpoints 
● 
PFS per IRF for patients with sALCL 
● 
Complete remission (CR) rate per IRF following the completion of study treatment 
● 
Overall survival (OS) 
● 
Objective response rate (ORR) per IRF following the completion of study treatment 
● 
Type, incidence, severity, seriousness, and relatedness of adverse events 
● 
Laboratory abnormalities 
2.4.3 Additional Endpoints 
● 
Incidence of ATA to brentuximab vedotin 
● 
MRU based on the number of medical care encounters 
● 
Quality of life measured by the European Organisation for Research and Treatment of 
Cancer (EORTC) core quality of life questionnaire (QLQ-C30) and European Quality 
of Life 5-Dimensional (EQ-5D) 
3 
INVESTIGATIONAL PLAN 
3.1 Summary of Study Design 
This is a randomized, double-blind, placebo-controlled, multicenter, phase 3 clinical trial 
designed to evaluate the efficacy and safety of including brentuximab vedotin in the 
treatment of newly diagnosed, CD30-positive mature T-cell lymphomas. The standard of 
care in this patient population consists of 6-8 cycles of CHOP chemotherapy. Patients will be 
randomized in a 1:1 manner to receive 21-day cycles of treatment in 1 of the following 
2 treatment groups: 
1. Standard-of-care arm: 6–8 cycles of CHOP; or 
2. Experimental arm: 6–8 cycles of brentuximab vedotin plus CHP (A+CHP) 
A target of 8 cycles of study treatment will be administered, per investigator decision, based 
on patient-specific characteristics, including stage of disease and IPI risk score. 
Brentuximab vedotin or vincristine will be dispensed as a placebo-controlled double-dummy 
and administered to patients in a blinded manner (see Table 1 for a list of study treatments by 
arm). Placebo replacements for brentuximab vedotin/vincristine will be prepared by the 
pharmacist at each study site and a pharmacy blind will be enforced. 
Safety will be monitored over the course of the study by an Independent Data Monitoring 
Committee (IDMC) as described in Section 9.3.9. 


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Approximately 450 patients (approximately 225 patients per treatment arm) will be 
randomized in this study. A study schema is provided in Figure 1. See Appendix A for a 
schedule of evaluations. 
Figure 1: Study design 
 
a 
CT and PET scans required 
b 
Additional CT scans every 6 months thereafter until progression per investigator, death, or analysis of the primary 
endpoint, whichever comes first 
c 
For patients with documented progression, continued follow-up for survival every 6 months until death or study 
closure, whichever comes first 
3.2 Discussion and Rationale for Study Design 
The primary endpoint of this study, PFS, is one of the endpoints recommended by FDA 
(FDA Guidance for Industry “Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics”) and the EMA (“Guideline on the Evaluation of Anticancer Medicinal Products in 
Man”, CPMP/EWP/205/95/Rev.3/Corr.2) for approval of anticancer drugs. Defined as the 
time from randomization until objective tumor progression or death, PFS is a direct reflection 
of tumor growth and can be assessed before determination of a survival benefit. Furthermore, 
because PFS includes deaths from any cause it may be a correlate to overall survival, a 
secondary endpoint of this study. An additional advantage of PFS is that its determination is 
not confounded by subsequent therapy. In this study, post treatment radiotherapy, post 
treatment chemotherapy for the purpose of mobilizing peripheral blood stem cells, or 
consolidative autologous or allogeneic SCT are not considered subsequent new anticancer 
treatments because they are not administered to treat progressive disease. Standardized 
criteria will be employed to evaluate progression (Cheson 2007). To ensure consistent 
unbiased application of these criteria, all imaging studies performed to confirm disease status 
and to assess progression during the study will be submitted to an independent third-party 
imaging core laboratory for blinded review and all patients will have evaluations for 
progression performed on the same schedule. 
Screening/Baseline CT/PET
Randomization 1:1
Experimental Arm:
brentuximab vedotin 
plus CHP
(A+CHP)
Standard-of-Care Arm:
CHOP
Restagea
Restagea
12
9
18
24b
Follow-up 
(including end-of-treatment 
assessments) 
Until progression, death, or analysis of 
the primary endpoint,
whichever comes first
Additional CT restage (months after initiation of 
treatment) for both arms
6-8 x 21-day cycles
Day -28 to 1
15
21
Survival statusc
At completion of 
study treatment
Cycle 4 
Restagea


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The current standard of care, CHOP chemotherapy administered for 6-8 cycles followed by 
either observation and best supportive care, a clinical trial, or an SCT, results in long-term 
disease-free survival in only a minority of patients. Despite this, CHOP is the best available 
therapy in this population, and the use of CHOP administered for 6-8 cycles is therefore 
considered appropriate and ethical. The randomized, blinded design of this trial is based on 
the considerations outlined in the FDA Guidance for Industry “Clinical Trial Endpoints for 
the Approval of Cancer Drugs and Biologics”, which states that PFS is ideally evaluated in a 
randomized and blinded study. 
3.2.1 Method of Assigning Patients to Treatment Groups 
Following informed consent and screening assessments, patients will be randomly assigned 
to study treatment in a 1:1 ratio. Randomization will be performed centrally using a system 
that will assign a unique patient randomization number but will not specify the actual 
treatment assignment. Randomization procedures are detailed in the Study Manual. 
 
 
 
 
 
3.2.2 Rationale for Selection of Doses 
In a phase 1 dose-escalation study of brentuximab vedotin (Study SG035-0001), the MTD 
was defined as 1.8 mg/kg IV administered every 3 weeks. This dose and schedule was further 
evaluated in two pivotal phase 2 studies (Studies SG035-0003 and SG035-0004) in patients 
with CD30-positive hematologic malignancies. 
In a phase 1 study of brentuximab vedotin (Study SGN35-011), the MTD was defined as 
1.8 mg/kg IV administered concomitantly with CHP every 3 weeks. 
3.2.3 Blinding 
A pharmacy blind will be employed in this trial. The adverse event profile of brentuximab 
vedotin 1.8 mg/kg administered IV once every 3 weeks is not anticipated to be discernable 
from vincristine in this population of aggressive CD30-positive mature T-cell lymphomas. 
Maintaining the blind of the study is crucial for achieving the study objectives. Investigators, 
patients, IRF, and the sponsor will be blinded to treatment assignments, unless otherwise 
specified in the Study Manual. 
Individual treatment assignment will remain blinded even after the primary analysis is 
conducted. Unblinding an individual patient treatment assignment will only occur when one 
of the following circumstances is applicable: 
1. At the time of disease progression, a patient’s treatment assignment may be unblinded 
upon request. A formal unblinding procedure will be followed to provide the study 


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treatment assignment directly to the patient for the purpose of further treatment planning 
(see Study Manual). 
2. At the time of study closure, after the primary analysis is completed, the study treatment 
assignment will be provided directly to the patient. 
3. Unblinding a patient’s treatment assignment prior to study closure or disease progression 
must be limited to emergency circumstances where knowledge of the treatment 
assignment would affect decisions regarding the management of the patient. In the event 
of such an emergency circumstance, a formal unblinding procedure, carried out by a third 
party organization, will be followed to allow the investigator to immediately access a 
patient’s treatment assignment (see Study Manual). Information on study treatment 
assignment should not be distributed to any other personnel involved in the clinical trial. 
In the event of any emergency unblinding, Seattle Genetics is to be notified within 
24 hours of the occurrence. 
4 
STUDY POPULATION 
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 patient’s eligibility should be discussed with the sponsor’s study 
management group prior to enrollment. 
Patients must meet ALL of the following inclusion criteria to be eligible for this study: 
4.1 Inclusion Criteria 
1. Patients with newly diagnosed, CD30-positive mature T-cell lymphomas per the Revised 
European-American Lymphoma WHO 2008 classification by local assessment. See 
Section 7.1.1 for details on definition of CD30 positivity. Eligible histologies are limited 
to the following: 
● 
ALK-positive sALCL with an IPI score greater than or equal to 2 
● 
ALK-negative sALCL 
● 
PTCL-NOS 
● 
AITL 
● 
Adult T-cell leukemia/lymphoma (ATLL; acute and lymphoma types only, must be 
positive for human T-cell leukemia virus 1) 
● 
Enteropathy-associated T-cell lymphoma (EATL) 
● 
Hepatosplenic T-cell lymphoma 
 
2. Fluorodeoxyglucose (FDG)-avid disease by PET and measurable disease of at least 
1.5 cm by CT, as assessed by the site radiologist. 
3. Age greater than or equal to 18 years. 
4. An Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2. 


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5. The following required baseline laboratory data: 
● bilirubin ≤1.5X upper limit of normal (ULN) or ≤3X ULN for patients with Gilbert’s 
disease or documented hepatic involvement with lymphoma 
● alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3X ULN or 
≤5X ULN for patients with document hepatic involvement with lymphoma 
● serum creatinine ≤2X ULN 
● absolute neutrophil count (ANC) ≥1000/µL (unless documented bone marrow 
involvement with lymphoma) 
● platelet count ≥50,000/µL (unless documented bone marrow involvement with 
lymphoma) 
 
6. Females of childbearing potential must have a negative serum or urine beta human 
chorionic gonadotrophin (β-hCG) pregnancy test result within 7 days prior to the first 
dose of study treatment and must agree to use an effective contraception method during 
the study and for at least 6 months following the last dose of study drug. Females of non-
childbearing potential are those who are postmenopausal greater than 1 year or who have 
had a bilateral tubal ligation or hysterectomy. 
7. Males who have partners of childbearing potential must agree to use an effective 
contraceptive method during the study and for 6 months following the last dose of study 
drug. 
8. Patients or their legally authorized representative must provide written informed consent. 
4.2 Exclusion Criteria 
1. History of another primary invasive cancer, hematologic malignancy, or myelodysplastic 
syndrome that has not been in remission for at least 3 years. 
2. Current diagnosis of any of the following: 
● Primary cutaneous CD30-positive T-cell lymphoproliferative disorders and 
lymphomas. Cutaneous ALCL with extracutaneous tumor spread beyond locoregional 
lymph nodes is eligible (previous single-agent treatment to address cutaneous and 
locoregional disease is permissible) 
● Mycosis fungoides (MF), including transformed MF 
3. History of progressive multifocal leukoencephalopathy (PML). 
4. Cerebral/meningeal disease related to the underlying malignancy. 
5. Prior treatment with brentuximab vedotin. 
6. Baseline peripheral neuropathy ≥ Grade 2 (per the NCI CTCAE, Version 4.03) or 
patients with the demyelinating form of Charcot-Marie-Tooth syndrome. 


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7. Left ventricular ejection fraction less than 45% or symptomatic cardiac disease (including 
symptomatic ventricular dysfunction, symptomatic coronary artery disease, and 
symptomatic arrhythmias), or myocardial infarction within the past 6 months, or previous 
treatment with complete cumulative doses of doxorubicin or other anthracyclines. 
8. Any active Grade 3 (per the NCI CTCAE, Version 4.03) or higher viral, bacterial, or 
fungal infection within 2 weeks prior to the first dose of study treatment; any known 
human immunodeficiency virus (HIV) infection, hepatitis B surface antigen-positive 
status, or known or suspected active hepatitis C infection. 
9. Current therapy with other systemic anti-neoplastic or investigational agents. 
10. Females who are pregnant or breastfeeding. 
11. Patients with a known hypersensitivity to any excipient contained in any of the drug 
formulations of study treatments. 
12. Patients with known urinary outflow obstruction. 
4.3 Removal of Patients From Therapy or Assessment 
Seattle Genetics or their designee must be notified if a patient is withdrawn from study 
treatment or from the study. The reason(s) for withdrawal must be documented in the 
patient’s medical records and case report form (CRF). If a patient discontinues study 
treatment, every attempt should be made to follow the patient until progression, death, or 
administrative study closure. Final assessments will be performed before any other 
therapeutic intervention if possible. Additionally, any subsequent treatments should be 
documented on the patient’s medical records and CRF. 
4.3.1 Discontinuation of Study Drug 
A patient’s treatment with study drug may be discontinued for any of the following reasons: 
● 
Completed treatment 
● 
Progressive disease 
● 
Adverse event 
● 
Investigator decision 
● 
Patient decision, Non-AE 
● 
Study termination by sponsor 
● 
Other, Non-AE 
 
Patients who discontinue from study treatment will remain on study for follow-up until 
withdrawal from the study (reasons for study discontinuation listed in Section 4.3.2). 


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4.3.2 Patient Withdrawal From Study 
Any patient may be discontinued from the study for any of the following reasons: 
● 
Patient withdrawal of consent 
● 
Study termination by sponsor 
● 
Lost to follow-up 
● 
Death 
● 
Other 
5 
TREATMENTS 
5.1 Treatments Administered 
The study treatments to be administered are described in Table 1. 
Table 1: 
Study treatment by study arm 
Study Treatment in Each 21-Day Cycle 
Experimental 
Arm 
A+CHP 
Standard-of-
Care Arm 
CHOP 
Blinded Study 
Drug Aa 
Brentuximab vedotin 1.8 mg/kg IV on Day 1 
X 
 
Placebo dosing solution IV on Day 1b  
 
X 
Cyclophosphamide 750 mg/m2 IV on Day 1  
X 
X 
Doxorubicin 50 mg/m2 IV on Day 1c 
X 
X 
Prednisone 100 mg po daily on Days 1-5 (±1 day window) 
X 
X 
Blinded Study 
Drug B 
Vincristine 1.4 mg/m2 (dose capped at 2 mg) IV on Day 1 
 
X 
Placebo saline IV on Day 1b 
X 
 
a 
Administered within 1 hour of completing treatment with other agents administered via IV 
b 
Prepared by the site pharmacist; pharmacy blind to be maintained 
c 
May be administered over up to 48 hours according to institutional standards 
5.2 Investigational Study Drug 
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. 
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 Method of Procurement 
Brentuximab vedotin will be provided by the sponsor. 


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5.2.3 Dose and Administration 
The investigational agent will be administered on Day 1 of every 21-day cycle by IV infusion 
given over approximately 30 minutes (see Table 1) and within 1 hour of completing 
treatment with other agents administered via IV. In the absence of infusion-related reactions, 
the infusion rate for all patients should be calculated in order to achieve a 30-minute infusion 
period. Investigational agent must not be administered as an IV push or bolus. Investigational 
agent should not be mixed with other medications. 
Dosing is based on patient weight according to the institutional standard; however, doses will 
be adjusted for patients who experience a ≥10% change in weight from baseline. An 
exception to weight-based dosing is made for patients weighing greater than 100 kg; doses 
will be based on 100 kg for these individuals. Rounding is permissible within 5% of the 
nominal dose. 
Dose modifications of the investigational agent are described in Section 5.5. 
5.2.4 Required Premedication and Postmedication 
Routine premedication should not be administered for the prevention of infusion-related 
reactions prior to the first dose of study treatment. However, patients who experience a 
infusion-related reaction may receive subsequent infusions of study treatment with 
premedication as described in Section 5.2.5. Patients who experience a Grade 3 or Grade 4 
infusion-related reaction may potentially continue to receive treatment at the discretion of the 
investigator after discussion with the sponsor. 
Patients should be individually evaluated to assess the need for tumor lysis prophylaxis prior 
to the first dose of investigational agent. Patients should receive prophylaxis as appropriate 
per the institutional standards. 
5.2.5 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 patient 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. 
Patients who have experienced an infusion-related reaction should be premedicated for 
subsequent infusions. Premedication may include acetaminophen, an antihistamine, and a 
corticosteroid administered 30–60 minutes prior to each infusion or according to institutional 
standards. 
If anaphylaxis occurs, study treatment administration should be immediately and 
permanently discontinued. 


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5.2.6 Management of Suspected PML 
Signs and symptoms of progressive multifocal leukoencephalopathy (PML) may include 
altered mental status, motor deficits such as hemiparesis or ataxia, visual disturbances, or 
higher cortical dysfunction such as dysphasia or agnosia. See the Investigator’s Brochure for 
further details. 
If PML is suspected, hold further 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, brentuximab vedotin should be permanently discontinued. 
5.2.7 Storage and Handling 
In this trial, brentuximab vedotin is provided in a blinded study treatment kit, and the 
guidelines for the storage of this kit should be followed per the Pharmacy Manual. 
Refrigeration should be set at 2–8°C for storage of vials and solutions containing 
brentuximab vedotin. The controlled location must be accessible only to the pharmacist or a 
duly designated person. Brentuximab vedotin does not contain preservatives; therefore, 
opened and reconstituted vials should be used immediately. If not used immediately, 
reconstituted vials and solutions must be stored no longer than 24 hours from vial 
reconstitution under refrigeration at 2–8°C. It is recommended that 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 Manual. 
5.2.8 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. 
In this study, vials of brentuximab vedotin will be provided in a blinded kit, which will be 
labeled to meet country-specific regulatory requirements. 
5.2.9 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 standard. The vial should be 


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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. 
For the standard-of-care arm, the pharmacy at the study site must prepare an IV bag 
containing only diluent (e.g., normal saline). This placebo replacement for brentuximab 
vedotin is to be administered in the same manner as described above and in the Pharmacy 
Instructions. 
Detailed drug preparation instructions are provided in the Pharmacy Instructions. 
5.3 Vincristine 
5.3.1 Description 
Vincristine is a vinca alkaloid. The mechanism of action is related to the inhibition of 
microtubule formation in the mitotic spindle. 
5.3.2 Method of Procurement 
Vincristine is commercially available and approved by the United States FDA and other 
regulatory agencies for use in patients with multiple types of cancer. Globally, vincristine 
will be supplied to study sites by the sponsor. 
5.3.3 Dose and Administration 
Vincristine is typically administered as an IV push (see Table 1 for dose), and will be given 
on Day 1 of each 21-day cycle. Dosing should be based on the patient’s baseline (predose, 
Cycle 1 Day 1) height and weight or per institutional standards at the site. 
Dose modification guidelines for vincristine are described in Section 5.5. 
5.3.4 Required Premedication and Postmedication 
There are no required pre- or postmedications for vincristine. Routine anti-emetic 
prophylaxis should be administered per institution standard. 
5.3.5 Storage and Handling 
In this trial, vincristine is provided in a blinded study treatment kit, and the guidelines for the 
storage of this kit should be followed per the Pharmacy Manual and as described in 
Section 5.2.7. Institutional guidelines for the handling of vincristine are to be followed. 


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5.3.6 Packaging and Labeling 
Vials of vincristine will be labeled in a blinded kit to meet country-specific regulatory 
requirements. 
5.3.7 Preparation 
Vincristine should be prepared per institutional guidelines. 
For the experimental arm, the site pharmacist will prepare a placebo replacement for 
vincristine (e.g., normal saline) to be administered in the same manner as vincristine. 
5.4 Cyclophosphamide, Doxorubicin, and Prednisone 
5.4.1 Description 
All patients in the study will be administered the cyclophosphamide, doxorubicin, and 
prednisone components of the CHOP regimen. 
Cyclophosphamide is a nitrogen mustard alkylating agent. Doxorubicin is a cytotoxic 
anthracycline antibiotic. Prednisone is a corticosteroid. 
5.4.2 Method of Procurement 
Cyclophosphamide, doxorubicin, and prednisone are commercially available and approved 
by the United States FDA and other regulatory agencies for use in treating patients with 
multiple types of cancer. 
In the United States and Canada, cyclophosphamide, doxorubicin, and prednisone will be 
supplied by the study site and will be billed to patients and/or their third-party payer 
(insurance, a healthcare provider, or applicable government program). 
In Japan, cyclophosphamide and doxorubicin will be supplied by the study site. Prednisone 
will be supplied to study sites by the sponsor. 
In regions outside of the United States, Canada, and Japan, cyclophosphamide, doxorubicin, 
and prednisone will be supplied to study sites by the sponsor. 
5.4.3 Dose and Administration 
Refer to Table 1 for specific doses. Administration of study treatment should be according to 
the institutional standard. Dosing should be based on the patient’s baseline (predose, Cycle 1 
Day 1) height and weight or per institutional standards at the site. 
Dose modification guidelines for cyclophosphamide, doxorubicin, or prednisone are 
described in Section 5.5. 
5.4.4 Required Premedication and Postmedication 
There are no protocol-required pre- or postmedications for cyclophosphamide, doxorubicin, 
and prednisone. Routine anti-emetic prophylaxis should be administered per institution 
standard. 


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5.4.5 Packaging and Labeling 
In the United States and Canada, supplies of cyclophosphamide, doxorubicin, and prednisone 
are commercially available. Outside of the United States and Canada, supplies will be labeled 
to meet country-specific regulatory requirements. 
5.4.6 Preparation 
Cyclophosphamide, doxorubicin, and prednisone should be prepared per institutional 
guidelines. 
5.4.7 Storage and Handling 
Cyclophosphamide, doxorubicin, and prednisone should be stored and handled per 
institutional guidelines. 
5.5 Dose Modifications 
Table 2 describes the recommended dose modifications for study treatment-associated 
neuropathy. 
Doses reduced for treatment-related neuropathy should not be re-escalated without discussion 
with the sponsor. 
Table 2: 
Recommended dose modifications for treatment-associated neuropathy 
Grade of Treatment-
Associated 
Neuropathy 
Recommended Dose Modification 
Sensory Neuropathy 
Motor Neuropathy 
1 
Continue study treatment at same dose 
level. 
Continue study treatment at same dose 
level. 
 
 
 
2 
Continue study treatment at the same dose 
level.  
Reduce dose levels of brentuximab 
vedotin/vincristinea. 
 
 
 
3 
Reduce dose levels of brentuximab 
vedotin/vincristinea.  
Discontinue treatment with brentuximab 
vedotin/vincristine. 
 
 
 
4 
Discontinue treatment with brentuximab 
vedotin/vincristine. 
Discontinue treatment with brentuximab 
vedotin/vincristine. 
a 
To maintain the study blind, dose levels of both blinded study treatments must be reduced as follows: 1.2 mg/kg 
brentuximab vedotin and 1 mg vincristine. No further dose reductions are permitted. 
 
Dose modifications of blinded study treatment (brentuximab vedotin/vincristine), 
cyclophosphamide, doxorubicin, or prednisone due to hematologic and non-hematologic 
toxicity are allowed per institutional standards at the discretion of the investigator. Permitted 
dose modifications include discontinuation of a treatment component. For blinded study 
treatment, the reduced dose levels are 1.2 mg/kg brentuximab vedotin and 1 mg vincristine. 
No further dose reductions of brentuximab vedotin or vincristine are permitted. 


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5.6 Concomitant Therapy 
All concomitant medications, blood products, and radiotherapy administered will be 
collected from Day 1 (predose) through the safety reporting period. Any concomitant 
medication given for a study protocol-related adverse event should be recorded from the time 
of informed consent. 
5.6.1 Required Concomitant Therapy 
There are no required concomitant therapies. 
5.6.2 Allowed Concomitant Therapy 
Routine premedication for infusion reactions should not be administered prior to the first 
dose of brentuximab vedotin. However, patients who experience an infusion-related reaction 
may receive subsequent treatment with premedication as described in Section 5.2.5. 
Routine infectious prophylaxis for Pneumocystis jiroveci pneumonia (PCP) should be 
considered for all patients. 
The use of transfusions, platelet and/or colony-stimulating factors per institutional practice is 
permitted. Intrathecal prophylactic treatment for cerebral/meningeal disease is permitted at 
the discretion of the investigator. 
The use of colony-stimulating factors and/or chemotherapy for stem-cell collection to enable 
a future autologous SCT is permitted per institution standard. Chemomobilization of stem 
cells is only permitted after EOT procedures are completed. 
Consolidative SCT or radiotherapy may be given at the investigator’s discretion after EOT 
procedures are completed. At least 6 cycles of study treatment should be given prior to 
initiating post treatment consolidative SCT or radiotherapy. 
5.6.3 Prohibited Concomitant Therapy 
Patients may not receive other investigational drugs, immunosuppressive medications, 
radiotherapy, or systemic anti-neoplastic therapy from Day 1 through EOT. In addition, other 
prohibited concomitant therapies should be excluded in accordance with the approved 
prescribing information for each agent. Exceptions are noted in Section 5.6.2. 
5.7 Treatment Compliance 
Study drug administration is performed by study site staff and documented in source 
documents and the CRF. 
6 
STUDY ACTIVITIES 
6.1 Schedule of Events 
Adverse events and concomitant medications will be collected from Day 1 (predose) through 
the safety reporting period. Any study protocol-related adverse event should be recorded 
from the time of informed consent as well as any concomitant medications given for 


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treatment of the adverse event. A schedule of events is provided in Appendix A. Study 
activities are listed by visit in this section and descriptions of all study assessments are 
presented in Section 7. 
6.2 Screening Visit (Day -28 to 1) 
● Informed consent 
● Study eligibility per inclusion/exclusion criteria 
● Medical history 
● CD30/histological confirmation – submission of tumor specimen for central pathology 
confirmation of histology, CD30 expression, and ALK status (see Section 7.1.1) 
● Human T-cell leukemia virus-1 (HTLV-1) status (see Section 7.1) 
● IPI score (see Section 7.1) 
● Hemoglobin (Hgb) A1c (see Section 7.6.2) 
● CT of chest, neck, abdomen, pelvis (see Section 7.2) 
● PET scan (see Section 7.2) 
● Bone marrow biopsy (may be obtained within 60 days of the first dose of study 
treatment; see Section 7.2) 
● Echocardiogram or multi-gated acquisition (MUGA) scan (may be obtained up to 6 
months prior to the first dose of study treatment) 
6.2.1 Baseline Visit (Day -7 to Day 1) 
● Height and weight 
● Electrocardiogram (ECG) 
● Pregnancy test for females of childbearing potential (see Section 7.6.2) 
● ECOG performance status (see Section 7.6.3) 
● Serum chemistry panel (see Section 7.6.2) 
● CBC with differential (see Section 7.6.2) 
● Randomization – to occur after eligibility is determined and within 1 business day of 
planned first dose of study treatment 
6.3 Treatment Period (21-day cycles) 
6.3.1 Every Cycle: Day 1 
● Lymphoma assessment (see Section 7.2; conducted within ≤48 hours prior to study 
treatment in Cycle 1) 
● ECOG performance status (not required in Cycle 1) 
● Serum chemistry 
● CBC with differential 
● Patient-reported outcome (PRO) questionnaires – EQ-5D, QLQ-C30, and Functional 
Assessment of Cancer Therapy/Gynecologic Oncology Group – Neurotoxicity 
(FACT/GOG-NTX; see Section 7.5) 


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● 
Medical resource utilization (MRU) data collection (see Section 7.4) 
● 
Total Neuropathy Score-nurse (TNSn) assessment; every odd-numbered cycle only 
(see Section 7.6.4) 
● 
Blood samples for pharmacokinetic (PK), pharmacodynamic (PD) assessment (see 
Section 7.3 for details) 
● 
Blood sample for ATA assessment (Cycles 1-4 only; see Section 7.3 for details) 
● 
Study treatment; administered after all assessments have been conducted 
6.3.2 Cycles 1 and 2 Only: Day 3 
● 
Blood sample for PK assessment 
6.3.3 Cycle 4 Only: Day 15-21 
● 
CT of chest, neck, abdomen, pelvis 
● 
PET scan 
● 
Bone marrow biopsy to confirm response (if positive at baseline) 
6.3.4 Last Planned Cycle of Treatment: Day 15-21 
The following assessments must be obtained for patients who complete the last planned cycle 
of treatment. Patients who discontinue treatment prior to the planned last cycle of treatment 
should have an EOT visit, as described in Section 6.4. 
● 
Lymphoma assessment 
● 
CT of chest, neck, abdomen, pelvis 
● 
PET scan 
● 
Bone marrow biopsy to confirm response (if positive at baseline and not found to be 
negative at a prior restage) 
6.4 End-of-Treatment Visit (30-37 days after last dose of study drug) 
If EOT evaluations are completed before 30 days after the last study treatment, the patient 
will be contacted by phone 30-37 days following the last treatment to assess for adverse 
events. 
EOT assessments will be performed before any other therapeutic intervention, if possible. 
● 
Pregnancy test for females of childbearing potential 
● 
Performance status 
● 
Serum chemistry 
● 
CBC with differential 
● 
Blood samples for PK, PD, and ATA assessment 
● 
PRO questionnaires: EQ-5D, QLQ-C30, and FACT/GOG-NTX 
● 
MRU data collection 
● 
TNSn assessment 


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The following response assessments are required if they were not conducted at last cycle of 
treatment: 
● 
Lymphoma assessment 
● 
CT of chest, neck, abdomen, pelvis 
● 
PET scan 
● 
Bone marrow biopsy to confirm response (if positive at baseline and not found to be 
negative at a prior restage) 
6.5 Follow-up 
The following assessments are required during follow up at the time points described. 
Months are relative to the first dose of study treatment. Assessments are to be conducted until 
death or study closure unless otherwise specified. Assessments occurring after 24 months 
from first dose may be conducted via a phone call. 
● 
Survival status and subsequent anticancer therapies received – every 
6 months (+/-1 week up to month 30, +/-1 month after month 30) starting at month 12 
and after disease progression 
● 
TNSn assessment and FACT/GOG NTX – every 3 months (+/-1 week) month 9 
through month 24 or until disease progression or initiation of new anticancer therapy; 
only performed for patients with treatment-emergent neuropathy (a treatment-
emergent event is one that is newly occurring or worsening following study 
treatment; see Section 9.3.8.2)  
● 
QLQ-C30 questionnaire – every 3 months (+/-1 week) month 9 through month 24 and 
at month 30, or until disease progression 
● 
MRU data collection  – every 3 months (+/-1 week) month 9 through month 24 and at 
month 30 
● 
EQ-5D questionnaire – every 3 months (+/-1 week) month 9 through month 24 and 
every 6 months (+/-1 week) thereafter; not required at months 9, 15, and 21 for 
patients with disease progression 
In addition, (prior to Amendment 5), patients who have not yet experienced disease 
progression per investigator assessment [based on the Revised Response Criteria for 
Malignant Lymphoma (Cheson 2007)], the following assessments must be obtained at 9, 12, 
15, 18, 21, and 24 months (+/-1 week) after the first dose of study treatment, and every 
6 months thereafter (+/-1 week) until progression per investigator, death, or analysis of the 
primary endpoint, whichever comes first.  
● 
CT of chest, neck, abdomen, pelvis 
● 
Lymphoma assessment 
 
After the analysis of the primary endpoint (Amendment 5 and later), patients who have not 
yet experienced disease progression should continue to be scanned according to the site’s 


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standard of care schedule. If progression occurs, it should be recorded in the CRF. Scans 
should not be sent to BioClinica. 
6.6 End of Study/End of Follow-up 
The date the patient met criteria for study discontinuation and the reason for study 
discontinuation will be collected. 
7 
STUDY ASSESSMENTS 
7.1 Screening/Baseline Assessments 
Only patients who meet all inclusion and exclusion criteria specified in Section 4 will be 
enrolled in this study. 
Patient 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. 
Cardiac function will be determined by performing either an echocardiogram or MUGA scan 
(may be obtained up to 6 months prior to the first dose of study treatment). 
HTLV-1 status must be obtained by local laboratory assessment to inform the diagnosis. 
IPI score must be determined based on the International Non-Hodgkin Lymphoma 
Prognostic Factors Project (Shipp 1993). 
7.1.1 CD30 Expression and Histologic Subtype 
Histologically confirmed CD30+ disease and histologic subtype must be determined by local 
pathology assessment in a CD30-qualified laboratory to enable enrollment. Local pathology 
will also assess ALK status for patients with a diagnosis of sALCL. 
By local assessment, tissue from the diagnostic biopsy must confirm CD30 positivity by 
immunohistochemistry. The 3 following criteria must be met to declare CD30 positivity: 
1. CD30 detected in 10% or greater of neoplastic cells (in cases where enumeration of 
neoplastic cells is not possible, total lymphocytes may be used). 
2. CD30 staining at any intensity above background. 
3. Membranous, cytoplasmic, and/or golgi pattern of expression of the CD30 antigen. 
Submission of the tumor block or approximately 15 unstained slides from a diagnostic biopsy 
is required prior to randomization for subsequent central confirmation of CD30 expression, 
disease subtype, and ALK status for patients with a diagnosis of sALCL. 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. 


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Details and shipping instructions are provided in the Research Specimen Laboratory Manual. 
7.2 Response/Efficacy Assessments 
Lymphoma assessments are to be performed at the time points outlined in Section 6 and 
Appendix A. An adequate focused lymphoma assessment consists of: 
● 
Patient medical history, including a thorough review of: 
○ 
The patient’s current signs and symptoms, including B symptoms (fever, night 
sweats, or weight loss >10%) 
○ 
Concomitant medications 
● 
Physical examination, including evaluation of skin, HEENT (head, eyes, ears, nose, 
and throat), lymph nodes, heart, lungs, abdomen, back, extremities, and neurology 
 
Radiographic assessments (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 Revised Response Criteria for 
Malignant Lymphoma (Cheson 2007). Treatment decisions by the investigator will be based 
on these assessments. CT and PET scans are required per protocol as directed in Section 6 
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 patient’s 
CRF and images will be submitted for central review. 
A bone marrow biopsy is required at baseline. Information from an assessment performed 
within 60 days of the first dose of study treatment, as part of clinical care, may be used to 
satisfy the baseline bone marrow biopsy requirement. Postbaseline biopsies are required to 
confirm response if bone marrow is positive at baseline; this confirmation is to be obtained 
within 4 weeks of documentation of response by radiographic assessment. Repeat bone 
marrow biopsies are not required once bone marrow is found to be negative. 
If cutaneous lesions are the sole site of progressive disease, a biopsy must be obtained to 
histologically confirm progression. 
All patients’ 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. Refer to the Study Manual for details 
(instructions on collecting and submitting tumor imaging studies for third-party imaging core 
laboratory review). 


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7.3 Pharmacokinetic, Pharmacodynamic, 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 selected time points in Cycles 1 and 2 and 
at predose in subsequent cycles (see Table 3). 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 concentration at 48 hours from the start of 
infusion, concentration at the end of infusion for brentuximab vedotin (Ceoi), and trough 
concentration (Ctrough). PK, demographic, and clinical laboratory data may be incorporated 
into the brentuximab vedotin population PK model for further model refinement and 
parameter estimation. The incidence of ATA to brentuximab vedotin will also be assessed. 
Blood samples will be collected (predose at each cycle) for measurement of PD biomarkers 
such as sCD30. 
Table 3 presents the PK/PD and immunogenicity sample collection time points. All sampling 
times are relative to the start of brentuximab vedotin infusion, except for the end of infusion 
concentrations. Refer to the Research Specimen Manual for information on collection, 
processing, storage, and shipment of samples. 
Table 3: 
Pharmacokinetic, pharmacodynamic, and immunogenicity sampling time 
points 
Cycle 
Study 
Day 
Time 
Window 
Relative Timea 
PK 
PD 
ATA 
1-2 
Day 1 
Pre-dose 
Within prior 24 hr 
Start of infusion 
X 
X 
X 
 
End of infusion 
(30 min) 
Within 30 min post  
end of infusion 
End of infusion 
X 
 
 
Day 3 
48 hr 
± 24 hr 
Start of infusion 
X 
 
 
3+ 
Day 1 
Pre-dose 
Within prior 24 hr 
Start of infusion 
X 
X 
Xb 
EOT 
 
X 
X 
X 
a 
Relative to infusion of Blinded Study Drug A (brentuximab vedotin or placebo replacement) 
b 
Cycles 3 and 4 only 
7.3.1 Biopsy Tissue for Exploratory Correlative Studies 
Patients will be asked to participate in optional exploratory correlative studies involving 
tumor tissue. The tumor tissue will be used to conduct exploratory correlative studies such as 
CD30 expression. 
 
 These optional studies will be conducted on the following tissues: 
● 
Leftover unstained slides or tumor tissue from the diagnostic biopsy 


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● 
Unstained slides or leftover tissue from a core biopsy obtained as part of standard-of-
care clinical interventions while a patient is participating in the study (e.g., for 
treatment failure at any time) 
 
No additional procedures will be conducted to obtain these research tissues, and thus no 
additional patient risk is introduced with these optional exploratory correlative studies. 
7.3.2 Biospecimen Samples for Future Research 
In the United States, remaining de-identified unused blood and tissue will be retained by 
Seattle Genetics and used for future research for patients who provide additional consent. 
 
 
 Blood and tissue samples donated for future 
research will be retained for a period of 25 years. 
For patients treated outside of the United States, or if additional consent is not granted, any 
blood and tissue samples remaining after all study testing is completed will be destroyed 
following study closure. 
 
 
7.4 Medical Resource Utilization Data Collection 
All medical care encounters related to lymphoma, treatment for lymphoma, or lymphoma-
related assessments will be collected for all patients. See Appendix A and Section 6 for 
timing of MRU data collection and see the Study Manual for detailed guidance. 
7.5 Patient-Reported Outcomes 
Questionnaires will be administered as specified in Appendix A and Section 6 and must be 
completed prior to administration of study treatment on treatment days. Questionnaires may 
be collected by phone once a patient experiences disease progression per investigator [based 
on the Revised Response Criteria for Malignant Lymphoma (Cheson 2007)] and is in 
survival follow-up. 
7.5.1 EQ-5D – Utility Measurement 
The European Quality of Life (EuroQOL) EQ-5D is a 5-item questionnaire with a 
“thermometer” visual analog scale ranging from 0 (worst imaginable health state) to 100 
(best imaginable health state). 
7.5.2 FACT/GOG-NTX 
The FACT/GOG-NTX is a self-administered questionnaire for assessing changes in quality 
of life and assessment of treatment-induced neurologic symptoms (sensory, hearing, motor, 
and dysfunction). Patients score their well-being by selecting the frequency with which they 


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associate with a given statement (0 being “not at all”, up to 4 being “very much”). The 
neurotoxicity subscale consists of 11 questions. 
7.5.3 QLQ-C30 
The EORTC QLQ-C30 is a questionnaire developed to assess the quality of life of cancer 
patients. The QLQ-C30 incorporates 9 multi-item scales: 5 functional scales (physical, role, 
cognitive, emotional, and social), 3 symptom scales (fatigue, pain, and nausea and vomiting), 
and a global health and quality of life scale (Aaronson 1993). 
7.6 Safety Assessments 
The assessment of safety during the course of this study will consist of the surveillance and 
recording of adverse events (AEs) including serious adverse events (SAEs), recording of 
concomitant medication and measurements of protocol-specified physical examination 
findings and laboratory tests. 
Safety will be monitored over the course of the study by an IDMC as described in Section 
9.3.9. 
7.6.1 Adverse Events 
7.6.1.1 Definitions 
Adverse Event 
According to the International Conference on Harmonization (ICH) E2A guideline 
Definitions and Standards for Expedited Reporting, and 21 CFR 312.32, IND Safety 
Reporting, an adverse event is any untoward medical occurrence in a patient or clinical 
investigational subject administered a medicinal product and which does not necessarily have 
a causal relationship with this treatment. 
The following information should be considered when determining whether or not to record a 
test result, medical condition, or other incident on the Adverse Events and Pre-existing 
Conditions case report form (CRF): 
● 
From the time of informed consent through the day prior to study Day 1, only study 
protocol-related adverse events should be recorded. 
● 
All medical conditions present or ongoing predose on study Day 1 should be 
recorded. 
● 
All adverse events (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. 


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● 
Changes in medical conditions and adverse events, 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 adverse event 
unless it is associated with clinical signs or symptoms, requires an intervention, 
results in a serious adverse event, or results in study termination or 
interruption/discontinuation of study treatment. When recording an adverse event 
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”). 
Serious Adverse Events 
An adverse event should be classified as a serious adverse event (SAE) if it meets one of the 
following criteria: 
Fatal: 
Adverse event resulted in death 
 
Life threatening: 
The adverse events placed the patient at immediate risk of death. This 
classification does not apply to an adverse event that hypothetically might cause 
death if it were more severe. 
 
Hospitalization: 
The AE required or prolonged an existing inpatient hospitalization. 
Hospitalizations for elective medical or surgical procedures or treatments planned 
before the signing of informed consent in the study or routine check-ups are not 
serious adverse events 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: 
Resulted in a persistent or significant incapacity or substantial disruption of the 
patient’s ability to conduct normal life functions. 
 
Congenital anomaly or 
birth defect: 
An adverse outcome in a child or fetus of a patient exposed to the molecule or 
study treatment regimen before conception or during pregnancy. 
 
Medically significant: 
The adverse event did not meet any of the above criteria, but could have 
jeopardized the patient and might have required medical or surgical intervention to 
prevent one of the outcomes listed above or involves suspected transmission via a 
medicinal product of an infectious agent. 
Adverse Event Severity 
AE severity should be graded using the National Cancer Institute’s Common Terminology 
Criteria for Adverse Events (NCI CTCAE), Version 4.03. 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 Serious Adverse Events). 


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Relationship of the Adverse Event to Study Treatment 
The relationship of each adverse event to each study treatment [blinded study treatment 
(brentuximab vedotin or vincristine) or any component of CHP] should be evaluated by the 
investigator using the following criteria: 
Related: 
There is evidence to suggest a causal relationship between the drug and the adverse 
event, such as: 
● an event that is uncommon and known to be strongly associated with drug 
exposure (e.g., angioedema, hepatic injury, Stevens-Johnson Syndrome) 
● 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 adverse event 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 adverse event and administration of the study 
treatment, or a causal relationship is considered biologically implausible 
7.6.1.2 Procedures for Eliciting and Recording Adverse Events 
Investigator and study personnel will report all AEs and SAEs whether elicited during patient 
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 Adverse Events and Pre-existing 
Conditions CRF: 
● 
Description including onset and resolution dates 
● 
Whether it met serious criteria 
● 
Severity 
● 
Relationship to study treatment or other causality 
● 
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 adverse event. 
Important exceptions for this study are adverse reactions associated with the infusion of the 
investigational agent. For infusion-related reactions, do not use the NCI CTCAE terms of 
‘cytokine release syndrome,’ ‘acute infusion reaction,’ or ‘allergic or hypersensitivity 


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reaction.’  Instead, record each sign or symptom as an individual adverse event. 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 primary event on both the CRF and an SAE form; events occurring 
secondary to the primary event should be described on the SAE form in the narrative 
description of the case. 
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. 
Progression of the Underlying Cancer 
Do not use the term ‘disease progression’ when reporting an AE because it is too general. 
Instead, report the specific disease (clinical) manifestation of the progression 
(e.g., ‘malignant pleural effusion’, ‘spinal bone metastases’, ‘lymphadenopathy from 
underlying non-Hodgkin lymphoma’, ‘brain metastases’). 
Pregnancy 
Notification to Drug Safety: Based on the estimated date of conception, complete a 
Pregnancy Report Form for all pregnancies that occur from the time of informed consent to 
the end of the protocol-defined contraception period, including any pregnancies that occur in 
the partner of a male study patient. Fax the form to the sponsor’s Drug Safety Department 
within 48 hours of becoming aware of the pregnancy. All pregnancies that occur during this 
time period 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: Based on the estimated date of conception, all pregnancies that occur 
from time of informed consent to within 30 days of last study drug dose, including any 
pregnancies that occur in the partner of a male study patient, will also be recorded on the 
Adverse Events and Pre-Existing Conditions CRF. Abortion, whether accidental, therapeutic, 
or spontaneous, should be reported as an SAE. Congenital anomalies or birth defects, as 
defined by the ‘serious’ criterion above (see definitions Section 7.6.1.1) should be reported as 
SAEs. 
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 (blinded study treatment or any component 


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of CHP), whichever is later. However, all study protocol-related AEs are to be collected 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 patient 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. 
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 (or designee), 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: 
● 
Patient 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 faxed to the sponsor’s Drug 
Safety Department at (425) 527-4308 within 24 hours, unless otherwise instructed on the 
sponsor’s SAE 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 Requirements in the United States 
According to the final rule amending the IND safety reporting requirements under  21 CFR 
312.32 and the FDA draft guidance Safety Reporting Requirements for INDs and BA/BE 
Studies (September 2010), endpoints that assess disease-related mortality or major morbidity 
as well 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. 
In this study, SAEs of disease progression do not require individual IND safety reports. 
These anticipated SAEs will be reviewed periodically by an Independent Data Monitoring 
Committee and/or Seattle Genetics Drug Safety Department. If, upon review, an SAE is 
occurring at a higher rate than that which would be expected for the experimental arm, then 
an IND safety report for the SAE will be submitted to the FDA by the sponsor. 


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These safety reporting requirements apply only to the process by which the sponsor reports 
SAEs to the FDA. Investigators are required to report all SAEs, including anticipated SAEs, 
to the sponsor. In addition, the sponsor will report all SAEs to international authorities as 
required per local regulatory reporting requirements. 
7.6.2 Clinical Laboratory Tests 
Samples will be drawn for central and local labs. Local laboratory testing will include 
institutional standard tests for evaluating safety and making clinical decisions. The following 
laboratory assessments will be performed by the central lab to evaluate safety at scheduled 
time points (see Appendix A) during the course of the study: 
● 
The chemistry panel is to include the following tests: albumin, alkaline phosphatase, 
alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea 
nitrogen, calcium, creatinine, chloride, lactate dehydrogenase (LDH), phosphorus, 
potassium, sodium, total bilirubin, uric acid, and glucose. 
● 
The CBC with differential is to include the following tests: white blood cell count 
with five-part differential (neutrophils, lymphocytes, monocytes, eosinophils, and 
basophils), red blood cell count, platelet count, and hemoglobin/hematocrit. 
● 
Hgb A1c will be obtained at baseline. 
The following laboratory assessment will be performed by local laboratories at scheduled 
time points (see Appendix A) during the course of the study: 
● 
A serum or urine β-hCG pregnancy test for females of childbearing potential 
7.6.3 ECOG Performance Status 
ECOG performance status (see Appendix B) will be evaluated at protocol-specified time 
points. 
7.6.4 TNSn 
The Total Neuropathy Score-nurse is a tool used in the assessment of neuropathy, including 
an examination conducted by a healthcare professional. A composite neuropathy score is 
calculated which includes subjective sensory symptoms, subjective report of symptoms and 
amount of difficulty with daily activities, deep tendon reflexes, manual muscle testing, and 
pin sensibility. 
7.6.5 Monitoring of Patients with Hepatitis 
Carriers of chronic hepatitis C should be closely monitored for clinical and laboratory signs 
of active infection during study treatment. 
7.7 Appropriateness of Measurements 
Internationally accepted criteria for the evaluation of lymphoma will be employed to assess 
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study (Cheson 2007). The schedule for tumor imaging is consistent with general oncological 
practice and appropriately balances measurement of tumor control with the expense and 
patient inconvenience associated with CT and PET scanning. 
The safety measures that will be used in this trial are considered standard procedures for 
evaluating the potential adverse effects of study medications. 
The QLQ-C30 is a validated questionnaire developed by the EORTC to assess the quality of 
life of cancer patients (Aaronson 1993). In this study, the neurotoxicity subscale of the 
FACT/GOG-NTX questionnaire was selected as a measure to enable assessment of the effect 
of neurotoxicity on patients in the study. The EQ-5D is a validated instrument for use as a 
measure of health outcome. These PROs have been incorporated into previous clinical trials 
that seek to quantify the quality of life in patients. The TNSn is a tool that will allow precise 
measurement of the onset, resolution, and characterization of peripheral neuropathy. 
Immunogenicity is commonly assessed for biologics; therefore, standard tests will be 
performed to detect the possible presence of specific antibodies to brentuximab vedotin. 
Pharmacokinetic assessments for drug activity are also common in clinical studies. 
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 patients 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 AE and SAE 
● 
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 
● 
GCP guidelines and related regulatory documentation requirements 
● 
Key study team roles and responsibilities 
● 
Investigational product storage, accountability, labeling, dispensing and record 
keeping 


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● 
Patient 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 
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 patients, 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 suitable for inspection 
by Seattle Genetics or its designated monitors and by quality assurance auditors, FDA 
representatives, or representatives of other regulatory agencies. 
8.2 Data Management Procedures 
Seattle Genetics will provide CRF Completion Guidelines for 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 patient confidentiality are to be employed 
during monitoring. The CRFs and related source documents will be reviewed in detail by the 
monitor at each site visit. Original source documents or certified copies are needed for 
review. This review includes inspection of data acquired as a requirement for participation in 
this study and other medical records as required to confirm information contained in the 
CRFs, such as past history, secondary diagnoses, disease assessment records, adverse events, 
and concomitant medications. 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 the 
FDA or other regulatory agencies. 


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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 by the designated monitor(s) 
during monitoring visits to the study centers. Any discrepancies will be resolved with 
the investigator or designees as appropriate. 
8.5 Quality Assurance Procedures 
The Clinical Quality Assurance 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 
Clinical Quality Assurance group of Seattle Genetics as part of the written record. 
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. 
The investigator should retain records of the changes and corrections, written and/or 
electronic. 
Data handling procedures for this trial have been designed to permit data changes so that they 
are documented by an audit trail. Data changes may only be made by those individuals so 
authorized. 
8.6.2 Investigator Record Retention 
The investigator shall retain study drug disposition records, copies of CRFs (or electronic 
files), and all source documentation (such as original ECG tracings, laboratory reports, 
inpatient or office patient 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. 


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9 
DATA ANALYSIS METHODS 
9.1 Determination of Sample Size 
Approximately 450 patients (~225 patients per treatment arm) will be randomized in this 
study. The target proportion of patients with a diagnosis of sALCL per central pathology 
assessment will be 75% (+/-5%), i.e., 338 (+/-23) patients. The sponsor will monitor the 
proportion of sALCL and non-sALCL patients per central pathology assessment to ensure 
that the enrollment targets are reached and not exceeded. 
 
  
 
 
 
9.2 Study Endpoint Definitions 
9.2.1 Primary Endpoint: PFS per IRF 
Progression-free survival (PFS) is defined as the time from the date of randomization to the 
date of first documentation of PD, death due to any cause, or receipt of subsequent anticancer 
chemotherapy to treat residual or progressive disease, whichever occurs first. Note that 
receipt of post treatment radiotherapy, post treatment chemotherapy for the purpose of 
mobilizing peripheral blood stem cells, or consolidative autologous or allogeneic SCT will 
not be considered as disease progression or as having started new anticancer therapy. Patients 
without documentation of PD/relapse, subsequent anticancer therapy for residual or 
progressive disease, or death at the time of analysis, will be censored at the date of last 
radiographic disease assessment. In the absence of a PFS event, patients receiving post 
treatment radiotherapy, post treatment chemotherapy for the purpose of mobilizing peripheral 
blood stem cells, or consolidative autologous or allogeneic SCT will be censored at the most 
recent tumor assessment before the data cutoff or study withdrawal, whichever occurs first. 
If PD is not documented, no subsequent anticancer chemotherapy to treat residual or 
progressive disease has been initiated, and the patient is alive at the time of the data cutoff or 
study withdrawal, PFS will be censored as follows: 
If there is no radiographic postbaseline tumor assessment, PFS will be censored at the date of 
randomization. 
If there are radiographic postbaseline tumor assessments, PFS will be censored at the most 
recent tumor assessment before the data cutoff or study withdrawal, whichever occurs first. 


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Detailed methodology, including handling rules for missing assessments and censoring 
approaches for the analysis of PFS, is provided in the Statistical Analysis Plan (SAP). 
9.2.2 Secondary Efficacy Endpoints 
9.2.2.1 PFS per IRF in Patients with sALCL 
PFS per IRF in patients with sALCL is defined in the same manner as the primary endpoint 
of PFS per IRF. For this endpoint, PFS per IRF will be analyzed in the subset of patients with 
a central pathology confirmed diagnosis of sALCL 
9.2.2.2 Complete Remission (CR) Rate per IRF 
Complete remission (CR) rate is defined as the proportion of patients with CR at the end of 
treatment per IRF according to the Revised Response Criteria for Malignant Lymphoma 
(Cheson 2007). Patients whose disease response cannot be assessed will be scored as non-
responders for calculating the CR rate. 
9.2.2.3 Overall Survival 
Overall survival (OS) is defined as the time from randomization to death due to any cause. 
Specifically, 
 
OS = Date of death – Date of randomization + 1 
For a patient who is not known to have died by the end of study follow-up, observation of OS 
is censored on the date the patient was last known to be alive (i.e., date of last contact). 
Patients lacking data beyond the day of randomization will have their survival time censored 
on the date of randomization (i.e., OS duration of 1 day). 
9.2.2.4 Objective Response Rate per IRF 
ORR per IRF is defined as the proportion of patients with CR or partial remission (PR) per 
IRF following the completion of study treatment (at EOT) according to the Revised 
Response Criteria for Malignant Lymphoma (Cheson 2007). Patients whose disease response 
cannot be assessed will be scored as non-responders for calculating the ORR. 
9.2.3 Additional Endpoints 
9.2.3.1 Incidence of ATA 
The ATA incidence rate is defined as the proportion of patients that develop ATA at any time 
during the study. 
9.2.3.2 Medical Resource Utilization 
Medical resource utilization data include medical care encounters (e.g., hospital admissions 
or major diagnostic procedures) related to study treatment or treatment for lymphoma. 


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9.2.3.3 Quality of Life 
Changes in quality of life will be measured based on PROs according to the QLQ-C30, 
FACT/GOG-NTX subscale, and EQ-5D. 
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 a principal 
feature of the protocol. The SAP was finalized prior to first patient visit. 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 
This is a randomized, double-blind, placebo controlled comparative study that will enroll 
approximately 450 patients. Patients will be randomized in a 1:1 manner to receive either 
CHOP or brentuximab vedotin plus CHP. Brentuximab vedotin or vincristine will be 
administered as a placebo-controlled double-dummy and provided to sites in a blinded 
manner. 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization will be performed centrally using a system that will assign a unique patient 
randomization number but will not specify the actual treatment assignment. Randomization 
procedures are detailed in the Study Manual. 
9.3.1.2 Adjustments for Covariates 
This is a phase 3 study. Stratified analyses will include adjustment for the stratification 
factors as recorded at randomization (described in Section 9.3.1.1). Covariates may be 
considered for adjustment in exploratory regression analyses. 
9.3.1.3 Handling of Dropouts and Missing Data 
Missing data will not be imputed, with the exception of AE start dates while calculating 
duration of events. Patients with missing values of a variable other than the time-to-event 
endpoints (PFS and OS) will be excluded from the analysis of that endpoint. Censoring rules 
will be applied to the estimation of the distribution of the time-to-event endpoints (see 
Sections 9.2.1 and 9.2.2.3). 


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9.3.1.4 Multicenter Studies 
There are multiple centers in this study, however it is not anticipated that any center will 
accrue enough patients to warrant an analysis by center. 
 
 
 
 
 
 
 
 
 
 
 
 
9.3.1.6 Data Transformations and Derivations 
The date of progression will be the earliest of all radiologic scan dates for the given disease 
assessment. No other data transformation is planned for the primary or secondary efficacy 
endpoints. 
9.3.1.7 Analysis Sets 
Intent-to-Treat (ITT) Analysis Set: The ITT analysis set will include all randomized patients. 
Patients will be included in the treatment group assigned at randomization regardless of the 
actual treatment received. 
Safety Set: The safety analysis set will include all patients who receive any amount of 
brentuximab vedotin or any component of CHOP. Treatment group will be determined using 
the actual treatment received, regardless of the randomization treatment assignment. Patients 
receiving any dose of brentuximab vedotin will be grouped into the experimental group. 
Patients who do not receive brentuximab vedotin but receive any dose of any component of 
CHOP will be grouped into the standard-of-care group. 
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. 
 
 


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9.3.2 Patient Disposition 
An accounting of study patients by disposition will be tabulated by treatment group. The 
number of patients in each analysis population will be summarized by treatment group. 
Patients who discontinue study treatment and patients who withdraw from the study will be 
summarized by treatment and reason for discontinuation or withdrawal and listed. 
9.3.3 Patient Characteristics 
Demographics, other baseline characteristics, and concomitant medications will be 
summarized by treatment group and listed. 
9.3.4 Treatment Compliance 
The dose administered at each cycle for each treatment agent 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 
Kaplan-Meier methods will be used to assess PFS. The stratified log-rank test without 
adjustments for covariates will be used in the primary evaluation of PFS differences between 
the experimental arm and the standard-of-care arm in the ITT analysis set using a one-sided, 
α = 0.025 level test. All events entered in the database at the time of analysis that have been 
source data-verified will be included in the analysis of PFS, even if there are more than the 
prespecified number of events. 
Kaplan-Meier Curves depicting PFS in the 2 arms will be generated. Additionally, median 
PFS and probability of PFS from 3 months to the end of the follow-up period will be reported 
at 3-month intervals. The two-sided 95% confidence intervals (CI) for the median and 
3-month intervals will be calculated using the complementary log-log transformation method 
(Collett 1994). Detailed methodology is provided in the SAP. 
9.3.5.2 Secondary Efficacy Analyses 
ORR and CR rate will be summarized by treatment group using the ITT analysis set. An 
exact two-sided 95% confidence interval using the Clopper-Pearson method (Clopper 1934) 
will be calculated. 


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OS will be analyzed using Kaplan-Meier methodology and Kaplan-Meier plots will be 
provided by treatment group using the ITT analysis set. The median OS and its two-sided 
95% CI using the complementary log-log transformation method (Collett 1994) will be 
calculated by treatment group. 
9.3.6 Pharmacokinetic and Pharmacodynamic 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 Health Outcomes Analyses 
EQ-5D scores and MRU data will be summarized using descriptive statistics by treatment 
group. 
Quality of life total and subscale scores will be summarized with descriptive statistics by 
treatment group and visit using the ITT analysis set. In addition, change from baseline will be 
tabulated by treatment group and visit. Descriptive summaries of individual items may also 
be presented. 
Additional statistical modeling for MRU and PRO measures may be performed separately in 
post hoc analyses. 
9.3.8 Safety Analyses 
9.3.8.1 Extent of Exposure 
Duration of treatment, number of cycles, total dose and dose intensity will be summarized by 
treatment arm using the safety analysis set. Dose modifications will also be summarized. 
Details will be provided in the SAP. 
9.3.8.2 Adverse Events 
Adverse events will be defined as treatment emergent if they are newly occurring or worsen 
following treatment with brentuximab vedotin, cyclophosphamide, doxorubicin, vincristine, 
or prednisone. The incidence of all AEs, treatment-emergent AEs, and treatment-related AEs 
will be tabulated by treatment group using the safety analysis set. AEs will be classified by 
system organ class and preferred term using the Medical Dictionary for Regulatory Activities 
(MedDRA). 
AEs will be listed and summarized by treatment group, MedDRA preferred term, severity, 
and relationship to study drug using the safety analysis set. In the event of multiple 
occurrences of the same AE with the same preferred term in one patient, the AE will be 
counted once as the occurrence. The incidence of AEs will be tabulated by preferred term 
and treatment group. AEs leading to premature discontinuation of study drug or withdrawal 
from the study will be summarized and listed in the same manner. 


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9.3.8.3 Deaths and Serious Adverse Events 
Serious adverse events will be listed and summarized in the same manner as all AEs. 
Adverse events with a fatal outcome will be listed. 
9.3.8.4 Clinical Laboratory Results 
Summary statistics for actual values and for change from baseline will be tabulated as 
appropriate for laboratory results by treatment group and scheduled visit using the safety 
analysis set. Patients with laboratory values outside of the normal reference range at any 
postbaseline assessment will be listed by treatment group. 
9.3.9 Interim Analysis 
An Independent Data Monitoring Committee (IDMC) will periodically monitor the trial for 
safety and will review expedited SAEs as they arise. 
 
 
 
The IDMC conduct of ongoing safety reviews
 
will be documented in the IDMC Charter. 
10 INFORMED CONSENT, ETHICAL REVIEW, AND REGULATORY 
CONSIDERATIONS 
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 patients 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 patient, or legally authorized representative, if applicable, by obtaining the 
signature and date on the informed consent document prior to the performance of protocol 
evaluations or procedures. 
If informed consent is obtained from a legally authorized representative for a patient who is 
unable to provide informed consent at study entry, but the patient is later able to provide 
informed consent, the investigator must obtain written informed consent from the patient. 
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: 


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● 
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. 
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 federal, state, and local 
laws, rules, and regulations. 
All data recorded in the CRF for patients participating in this study will be transcribed from 
medical records or other source documents. 
10.3.1 Investigator Information 
The contact information and qualifications of the principal investigator and subinvestigators 
and name and address of the research facilities are included in the investigator file. 
10.3.2 Protocol Amendments and Study Termination 
Any investigator-initiated changes to the protocol (with the exception of changes to eliminate 
an immediate hazard to a study patient) must be approved by the sponsor prior to seeking 
approval from the IRB/IEC, and prior to implementing. The investigator is responsible for 
enrolling patients 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 
Government agency regulations and directives require that all study documentation 
pertaining to the conduct of a clinical trial must be retained by the investigator until notified 
by the sponsor in writing that retention is no longer necessary. 
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 patient 
medical records in the patient files as original source documents for the study. If requested, 


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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 patient medical information must be handled in accordance with the 
requirements of the Health Information Portability and Accountability Act (HIPAA) Privacy 
Rule and consistent with the terms of the patient 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, case report forms 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 patient 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 
Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, Filiberti A, Flechtner H, Fleishman SB, 
de Haes JC and et al. (1993). The European Organization for Research and Treatment of Cancer QLQ-C30: a 
quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 85: 365-76. 
Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, Coiffier B, Fisher RI, Hagenbeek A, 
Zucca E, Rosen ST, Stroobants S, Lister TA, Hoppe RT, Dreyling M, Tobinai K, Vose JM, Connors JM, 
Federico M and Diehl V (2007). Revised response criteria for malignant lymphoma. J Clin Oncol 25: 579-86. 
Clopper CJ and Pearson ES (1934). The use of confidence or fiducial limits illustrated in the case of the 
binomial. Biometrika 26: 404-413. 
Coiffier B, Lepage E, Briere J, Herbrecht R, Tilly H, Bouabdallah R, Morel P, Van Den Neste E, Salles G, 
Gaulard P, Reyes F, Lederlin P and Gisselbrecht C (2002). CHOP chemotherapy plus rituximab compared with 
CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 346: 235-42. 
Collett D (1994). Interval-censored survival data. Modelling survival data in medical research. Boca Raton, 
Fla., Chapman & Hall/CRC: 237-251. 
Dearden CE, Johnson R, Pettengell R, Devereux S, Cwynarski K, Whittaker S and McMillan A (2011). 
Guidelines for the management of mature T-cell and NK-cell neoplasms (excluding cutaneous T-cell 
lymphoma). Br J Haematol 153: 451-85. 
Mercadal S, Briones J, Xicoy B, Pedro C, Escoda L, Estany C, Camos M, Colomo L, Espinosa I, Martinez S, 
Ribera JM, Martino R, Gutierrez-Garcia G, Montserrat E and Lopez-Guillermo A (2008). Intensive 
chemotherapy (high-dose CHOP/ESHAP regimen) followed by autologous stem-cell transplantation in 
previously untreated patients with peripheral T-cell lymphoma. Ann Oncol 19: 958-63. 
National Comprehensive Cancer Network (2013). NCCN Guidelines Version 1.2013: Non-Hodgkin's 
Lymphomas. Available at: http://www.nccn.org. Accessed February 21, 2013. 
Pro B, Advani R, Brice P, Bartlett NL, Rosenblatt JD, Illidge T, Matous J, Ramchandren R, Fanale M, Connors 
JM, Yang Y, Sievers EL, Kennedy DA and Shustov A (2012). Brentuximab vedotin (SGN-35) in patients with 
relapsed or refractory systemic anaplastic large cell lymphoma: Results of a phase II study. J Clin Oncol 30: 
2190-6. 
Savage KJ (2008). Prognosis and primary therapy in peripheral T-cell lymphomas. Hematology Am Soc 
Hematol Educ Program: 280-8. 
Schmitz N, Trumper L, Ziepert M, Nickelsen M, Ho AD, Metzner B, Peter N, Loeffler M, Rosenwald A and 
Pfreundschuh M (2010). Treatment and prognosis of mature T-cell and NK-cell lymphoma: an analysis of 
patients with T-cell lymphoma treated in studies of the German High-Grade Non-Hodgkin Lymphoma Study 
Group. Blood 116: 3418-25. 
Shipp MA (1993). A predictive model for aggressive non-Hodgkin's lymphoma. The International Non-
Hodgkin's Lymphoma Prognostic Factors Project. N Engl J Med 329: 987-94. 
Simon A, Peoch M, Casassus P, Deconinck E, Colombat P, Desablens B, Tournilhac O, Eghbali H, Foussard C, 
Jaubert J, Vilque JP, Rossi JF, Lucas V, Delwail V, Thyss A, Maloisel F, Milpied N, le Gouill S, Lamy T and 
Gressin R (2010). Upfront VIP-reinforced-ABVD (VIP-rABVD) is not superior to CHOP/21 in newly 
diagnosed peripheral T cell lymphoma. Results of the randomized phase III trial GOELAMS-LTP95. Br J 
Haematol 151: 159-66. 
Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J and Vardiman JW (2008). Chapter 
11: Mature T- and NK-cell Neoplasms. WHO classification of tumours of haematopoietic and lymphoid tissues. 
Lyon, France, International Agency for Research on Cancer: 269-319. 
Vose J, Armitage J and Weisenburger D (2008). International peripheral T-cell and natural killer/T-cell 
lymphoma study: pathology findings and clinical outcomes. J Clin Oncol 26: 4124-30. 


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Younes A, Bartlett NL, Leonard JP, Kennedy DA, Lynch CM, Sievers EL and Forero-Torres A (2010). 
Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas. N Engl J Med 363: 1812-21. 
 


 
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APPENDIX A: STUDY SCHEDULE  
 
Baseline/Screening 
Enrollment 
Cycle 1 
Cycles 2+ Cycle 4 only 
Last planned 
cycle of tx 
EOT  
visit 
Long-term F/U 
Months after first dose 
9 12 15 18 21 24 
>24 
Visit Window 
D-28 to 1 
D-7 to 1 
D-7 to 1 
D1 
D1±1 
Day
 15-21 
Day
 15-21  
30-37 days 
post last dose
f  
±1 wk 
Every 6 mos  
±1 wk 
Screening/ 
Baseline 
Assessments 
Informed consent 
X 
 
Eligibility documentation submitted to sponsor prior to 
 study start; randomization
j 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
CD30/histologya 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
HTLV-1 status 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hgb A1c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
IPI score 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Echocardiogram or MUGA scan 
Xo 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height & weight 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Electrocardiogram 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy
 test 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
Treatment 
Study
 treatment administration 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
ATA/PK/PD Samples for ATA/PK/PD  
 
 
See Section 7.3 
 
 
 
 
 
 
 
Response 
Assessment 
Lymphoma assessmentb 
 
 
Xl 
X 
 
X 
Xf 
Xg Xg Xg Xg Xg Xg 
Xg 
CT (chest, neck, abdomen, pelvis) 
X 
 
 
 
X 
X 
Xf 
Xg Xg Xg Xg Xg Xg 
Xg 
PETc 
X 
 
 
 
X 
X 
Xf 
 
 
 
 
 
 
 
Bone marrow
 biopsy 
Xd 
 
 
 
Xe 
Xe 
Xe
,f 
 
 
 
 
 
 
 
Survival status 
 
 
 
 
 
 
 
 Xh  Xh  Xh 
Xh 
Safety
 
Assessments 
ECOG performance status 
 
X 
 
X 
 
 
X 
 
 
 
 
 
 
 
Serum chemistry 
 
X 
X 
X 
 
 
X 
 
 
 
 
 
 
 
CBC with differential 
 
X 
X 
X 
 
 
X 
 
 
 
 
 
 
 
Con meds & AEs 
Collect any
 related to study
 protocol 
procedures  
Collect from Day 1 (predose) through 30 days post last dose or through EOT 
visit, whichever is later 
 
 
 
 
 
 
 
TNSn assessment 
 
 
 
X 
Xm 
 
 
X 
Xn Xn Xn Xn Xn Xn 
 
PRO/MRU 
QLQ-C30 
 
 
 
X 
X 
 
 
X 
Xi Xi Xi Xi Xi Xi 
Xi 
Medical Resource Utilization 
 
 
 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X (30 mo post 
first dose only) 
FACT/GOG-NTX subscale 
 
 
 
X 
X 
 
 
X 
Xn Xn Xn Xn Xn Xn 
 
EQ-5D 
 
 
 
X 
X 
 
 
X 
Xp X Xp X Xp X 
Xk 
 
a 
Locally assessed to enable enrollment (see Section 7 1 1 for definition of CD30-positivity); tumor specimen 
must be submitted for central pathology review before randomization to confirm histology (and ALK status, if 
applicable) and CD30 expression 
b 
Consists of the following: physical examination, patient medical history, including a thorough review of the 
patient’s current signs and symptoms, B symptoms, and concomitant medications See Section 72 
c 
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 
d 
Obtained within 60 days of first dose of study treatment 
e 
Bone marrow biopsy is required to confirm response if bone marrow is positive at baseline and should be 
obtained within 4 weeks after documentation of response; does not need to be repeated once bone marrow is 
negative 
f 
Response assessments at EOT required if not performed at last cycle of treatment 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 patient’s last study 
treatment to ensure that no changes in AE profile have occurred 
g 
After 24 months following the first dose of study drug, required every 6 months Obtain until patient 
experiences PD per investigator assessment, death, or analysis of the primary endpoint, whichever comes first 
h 
Once a patient experiences PD per investigator assessment, survival status is required every 6 months until 
death or study closure, whichever comes first After 30 months, the window for the assessment is ±1 month  
Collect information regarding subsequent anticancer therapies 
i 
Collect until patient experiences PD per investigator assessment or 30 months post first dose of study treatment, 
whichever comes first 
j 
Randomization to occur after eligibility is determined and within 1 business day of planned first dose of study 
treatment 
k 
Required every 6 months until death or study closure, whichever comes first 
l 
Within ≤48 hours prior to study treatment 
m Every odd-numbered cycle only 
n 
Only for patients with treatment-emergent peripheral neuropathy; collect until patient experiences PD per 
investigator, initiates a subsequent anticancer therapy, or until 24 months post first dose, whichever comes first 
o 
May be obtained up to 6 months prior to first dose of study treatment 
p 
Not required if patient has experienced PD per investigator assessment 


 
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APPENDIX B: ECOG PERFORMANCE STATUS 
Score Description 
0 
Normal activity. Fully active, able to carry on all pre-disease performance without 
restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous activity, but 
ambulatory and able to carry out work of a light or sedentary nature (e.g., light 
housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but unable to carry 
out any work activities. Up and about more than 50% of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined to bed or chair 
more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally 
confined to bed or chair. 
5 
Dead. 
 


 
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APPENDIX C: INTERNATIONAL PROGNOSTIC INDEX FOR NHL 
Score 
 
Score 
Risk Factor 
0 point 
1 point 
Age 
≤60 years 
>60 years 
Serum LDH 
≤1 x ULN 
>1 x ULN 
ECOG Performance Status 
0 or 1 
2, 3, or 4 
Stage 
I or II 
III or IV 
Extranodal Involvement 
≤1 site 
>1 site 
LDH = lactate dehydrogenase 
ECOG = Eastern Cooperative Oncology Group 
ULN = upper limit of normal 
Risk Category 
● Low:     
  
0–1 
● Low-intermediate:   2 
● High-intermediate:   3 
● High:     
  
4–5 
 
Based on The International Non-Hodgkin’s Lymphoma Prognostic Factors Project  
(Shipp 1993) 


 
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APPENDIX D: INVESTIGATOR SIGNATURE PAGE 
 
Investigator Statement and Signature 
I have read the attached protocol entitled “A randomized, double-blind, placebo-controlled, phase 3 study of 
brentuximab vedotin and CHP (A+CHP) versus CHOP in the frontline treatment of patients with CD30-positive 
mature T-cell lymphomas”. 
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 E: DOCUMENT HISTORY 
Version 
Date 
Original 
28-Jun-2012 
Amendment 1 
27-Sep-2012 
Amendment 2 
31-Jan-2013 
Amendment 3 
05-Mar-2015 
Amendment 4 
15-May-2018 
Amendment 5 
12-Dec-2018 






 
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Section(s) 
Change 
Rationale 
Schedule of 
Events 
EQ-5D assessments at months 9, 15, and 21 of long-term follow up are not required 
if patient has experience progressive disease per investigator assessment 
Clarification 
 


 
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Summary of Changes in Amendment 2 
Section(s) 
Change 
Rationale 
Title Page 
Added study name, ECHELON-2 
Study has been given the name ECHELON-2 
Synopsis, 2.2 
Changed secondary objective to refer to remission rates rather than CR: 
To compare the complete remission (CR) rate rates per IRF following the 
completion of study treatment between the 2 treatment arms 
To pre-specify the analysis of both the complete 
remission rate and objective response rate per IRF 
Synopsis, 4.1 
Added the following additional baseline laboratory inclusion criteria: 
● absolute neutrophil count (ANC) ≥1000/µL (unless documented bone marrow 
involvement with lymphoma) 
● platelet count ≥50,000/µL (unless documented bone marrow involvement with 
lymphoma) 
Additional safety precaution to address a 
doxorubicin contraindication for myelosuppression 
Synopsis, 4.1 
Female contraception period increased from 30 days to at least 6 months following 
the last dose of study drug 
Additional safety precaution  
Synopsis, 4.2 
Excluded patients with the demyelinating form of Charcot-Marie-Tooth syndrome 
Additional safety precaution to address a 
vincristine contraindication 
Synopsis, 4.2 
Excluded patients who have had previous treatment with complete cumulative doses 
of doxorubicin or other anthracyclines 
Additional safety precaution to address a 
doxorubicin contraindication 
Synopsis, 4.2 
Excluded patients with known urinary outflow obstruction 
Additional safety precaution to address a 
cyclophosphamide contraindication 
Synopsis, 2.4.2 
Added new secondary endpoint: 
Objective response rate (ORR) per IRF following the completion of study treatment 
Additional secondary endpoint related to the 
modified secondary objective 
Synopsis, 9.3.1.9 
Added estimated duration of study through final primary analysis and through final 
analysis of OS 
To provide greater clarity regarding the estimated 
duration of the study 
1.2, 11 
Updated NCCN non-Hodgkin lymphoma guidelines to version 1.2013 
To reference current NCCN guideline document 
5.2.9 
Brentuximab vedotin should be reconstituted with the appropriate amount of Sterile 
Water for Injection, United States Pharmacopeia (USP), or equivalent standard. 
To allow for equivalent standards of sterile water 
for injection in regions outside the United States 
5.4.2 
Specified that in Japan, cyclophosphamide and doxorubicin will be supplied by the 
study site and prednisone will be supplied by the sponsor 
Clarification 
5.6.3 
Specified that concomitant therapies should be excluded in accordance with 
approved prescribing information for each agent 
Additional safety precaution 


 
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Section(s) 
Change 
Rationale 
7.1.1 
Submission of the tumor block or approximately 15 unstained slides from a 
diagnostic biopsy is required prior to randomization for subsequent central 
confirmation of CD30 expression, disease subtype, and ALK status for patients with 
a diagnosis of sALCL. The diagnostic specimen must be from a malignant lymph 
node or extranodal tissue obtained by core or excisional/incisional biopsy. 
Cutaneous samples alone are unacceptable. Fine needle aspirate and cytology 
samples are also unacceptable. 
Clarification 
7.3 
Specified that blood samples for PK testing will be collected at selected time points 
in Cycles 1 and 2 and at predose in subsequent cycles 
Clarification 
7.3 
ATA to brentuximab vedotin will be measured predose at Cycles 1 through 4 and at 
EOT. 
Clarification 
7.6.1.3 
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 patient dies or withdraws consent, or study closure. 
Additional safety precaution 
9.2.1 
If death or PD occurs after 2 or more consecutively missed radiographic tumor 
assessments, censoring will be as above, where the most recent tumor assessment is 
the last radiologic tumor assessment prior to the missed assessments. 
Detailed methodology is, including handling rules for missing assessments and 
censoring approaches for the analysis of PFS, is provided in the Statistical Analysis 
Plan (SAP). Details of differing censoring approaches are also presented in the 
SAP. 
Handling rules for missed events and censoring 
approaches will be provided in the SAP 
9.2.2.4 
Added definition of ORR per IRF endpoint 
To characterize the new secondary endpoint 
9.3 
Specified that the SAP was finalized prior to first patient visit 
Clarification 
9.3.1.5 
Added the key secondary endpoint, ORR per IRF, to the analysis plan in fourth 
position after PFS per IRF in patients with sALCL, CR rate per IRF, and OS 
Addition of ORR per IRF to analysis plan 
9.3.5.2 
Complete response ORR and CR rate will be summarized by treatment group using 
the ITT analysis set. An exact two-sided 95% confidence interval using the 
Clopper-Pearson method (Clopper 1934) will be calculated. 
Clarification that ORR will also be summarized in 
the secondary efficacy analyses 
Schedule of 
Events 
Specified that the TNSn assessment will also be performed during odd-numbered 
cycles from cycle 2 onwards 
Clarification 
Schedule of 
Events 
Removed footnote ‘d’ from Cycle 2 (Day 1 ±1) that specified “Obtained within 60 
days of first dose of study treatment” 
Correction 
 




 
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Section(s) 
Change 
Rationale 
9.2.1 
If there is no radiographic postbaseline tumor assessment, PFS will be censored at 
Study Day 1 the date of randomization. 
Clarification 
Schedule of 
Events 
Removed footnote that indicated that QLQ-C30 should only be collected at EOT if 
patient has not experienced disease progression 
Correction 




 
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Summary of Changes in Amendment 5 
Section(s) 
Change 
Rationale 
Synopsis 
 
The IDMC will provide 
recommendations to the sponsor's Steering Committee as to appropriate study 
direction. 
Correction. Recommendations were to be provided 
to the sponsor, not the sponsor’s Steering 
Committee. 
6.5 
Reorganized section for clarity. Specified that patients who have not progressed by 
the time of the primary analysis should get scanned per standard of care. Corrected 
inconsistencies with Appendix A. 
Clarify assessments for the long-term follow up 
period, including assessments for patients who 
have not progressed by the time of the primary 
analysis 
6.5 and 
Appendix A 
Changed the window for survival assessments to ± 1 month after 30 months from 
first dose 
To provide additional flexibility 
 

SAP_001.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: 
SGN35-014 
Version: 
Version 5; 15 May 2018 
Protocol Title: 
A randomized, double-blind, placebo-controlled, phase 3 study 
of brentuximab vedotin and CHP (A+CHP) versus CHOP in the 
frontline treatment of patients with CD30-positive mature T-cell 
lymphomas 
Sponsor: 
Seattle Genetics, Inc. 
21823 30th Drive SE 
Bothell, WA 98021, USA 




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Statistical Analysis Plan 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ................................................................................................................................ 5 
1 
INTRODUCTION ........................................................................................................................................... 6 
2 
STUDY OBJECTIVES ................................................................................................................................... 6 
2.1 
Primary Objectives ................................................................................................................................ 6 
2.2 
Secondary Objectives ............................................................................................................................ 6 
2.3 
Additional Objectives ............................................................................................................................ 6 
3 
STUDY ENDPOINTS .................................................................................................................................... 6 
3.1 
Primary Endpoint .................................................................................................................................. 6 
3.2 
Secondary Endpoints ............................................................................................................................. 6 
3.2.1 
Key Secondary Endpoints ........................................................................................................ 6 
3.2.2 
Safety Endpoints ....................................................................................................................... 7 
3.3 
Additional Endpoints ............................................................................................................................. 7 
4 
STUDY DESIGN ............................................................................................................................................ 7 
5 
ANALYSIS SETS ........................................................................................................................................... 8 
5.1 
Intent-to-Treat (ITT) Analysis Set ......................................................................................................... 8 
5.2 
Safety Analysis Set ................................................................................................................................ 8 
6 
STATISTICAL CONSIDERATIONS ............................................................................................................ 8 
6.1 
General Principles ................................................................................................................................. 8 
6.2 
Determination of Sample Size ............................................................................................................... 9 
6.3 
Randomization and Blinding ................................................................................................................. 9 
6.4 
Data Transformations and Derivations .................................................................................................. 9 
6.5 
Handling of Dropouts and Missing Data ............................................................................................. 10 
6.6 
Pooling Strategy for Strata .................................................................................................................. 10 
6.7 
Multicenter Studies ............................................................................................................................. 11 
6.8 
Multiple Comparison/Multiplicity ....................................................................................................... 11 
6.9 
Examination of Subgroups .................................................................................................................. 11 
6.10 Covariates ............................................................................................................................................ 12 
6.11 Timing of Analyses ............................................................................................................................. 12 
7 
PLANNED ANALYSES .............................................................................................................................. 13 
7.1 
Disposition .......................................................................................................................................... 13 
7.2 
Demographic and Baseline Characteristics ......................................................................................... 13 
7.3 
Protocol Deviations ............................................................................................................................. 13 
7.4 
Treatment Administration ................................................................................................................... 13 
7.5 
Efficacy Analyses ................................................................................................................................ 16 
7.5.1 
Primary Endpoint ................................................................................................................... 16 
7.5.2 
Secondary Efficacy Endpoints ................................................................................................ 19 
7.6 
Safety Analyses ................................................................................................................................... 20 
7.6.1 
Adverse Events ....................................................................................................................... 20 
7.6.2 
Clinical Laboratory Parameters .............................................................................................. 21 
7.6.3 
ECOG Performance Status ..................................................................................................... 22 
7.6.4 
Concomitant Medications ....................................................................................................... 22 
7.6.5 
Deaths ..................................................................................................................................... 22 
7.7 
Additional Endpoints ........................................................................................................................... 22 
7.7.1 
Antitherapeutic Antibody (ATA) Incidence Rate ................................................................... 22 
7.7.2 
Medical Resource Utilization (MRU) .................................................................................... 22 
7.7.3 
Quality of Life (QoL) ............................................................................................................. 22 
7.7.4 
Pharmacokinetics .................................................................................................................... 23 
7.7.5 
Biomarkers ............................................................................................................................. 23 
7.8 
Exploratory Analyses .......................................................................................................................... 23 
8 
INTERIM ANALYSIS.................................................................................................................................. 24 
9 
CHANGES FROM PLANNED ANALYSES .............................................................................................. 24 


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9.1 
Changes from the Original Protocol .................................................................................................... 24 
9.2 
Changes from the Original SAP .......................................................................................................... 24 
9.2.1 
Version 2 Changes .................................................................................................................. 24 
9.2.2 
Version 3 Changes .................................................................................................................. 24 
9.2.3 
Version 4 Changes .................................................................................................................. 25 
9.2.4 
Version 5 Changes .................................................................................................................. 25 
10 REFERENCES .............................................................................................................................................. 26 
APPENDIX A: IMPUTATION OF PARTIALLY UNKNOWN ADVERSE EVENT DATES ......................... 27 
 


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LIST OF ABBREVIATIONS 
A+CHP 
brentuximab vedotin (ADCETRIS®), cyclophosphamide, doxorubicin, and prednisone 
AE 
adverse event 
ATA 
antitherapeutic antibodies  
ALK 
anaplastic lymphoma kinase 
CHOP 
cyclophosphamide, doxorubicin (hydrodoxorubicin), vincristine (Oncovin®), and 
prednisone 
CHP 
cyclophosphamide, doxorubicin (hydrodoxorubicin), and prednisone 
CI 
confidence interval 
CMH 
Cochran-Mantel-Haenszel 
CR 
complete remission 
CRF 
case report form 
CT 
computed tomography 
ECOG 
Eastern Cooperative Oncology Group 
EQ-5D 
European Quality of Life 5-Dimensional 
EMA 
European Medicines Agency 
FACT/GOG-NTX 
Functional Assessment of Cancer Therapy/Gynecologic Oncology Group – Neurotoxicity 
HR 
hazard  ratio 
IDMC 
Independent Data Monitoring Committee 
IRF 
independent review facility 
IPI 
International Prognostic Index 
ITT 
intent-to-treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRU 
medical resource utilization 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease 
PET 
positron emission tomography 
PFS 
progression-free survival  
PR 
partial remission 
PRO 
patient reported outcomes  
QLQ-C30 
EORTC core quality of life questionnaire 
QoL 
quality of life 
SAE 
serious adverse event 
sALCL 
systemic anaplastic large cell lymphoma 
SCT 
stem cell transplant 
SPD 
sum of the products of diameters 
SUV 
standard uptake value 


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1 
INTRODUCTION 
This document outlines the statistical methods to be implemented within the scope of Protocol 
SGN35-014, entitled “A randomized, double-blind, placebo-controlled, phase 3 study of 
brentuximab vedotin and CHP (A+CHP) versus CHOP in the frontline treatment of patients with 
CD30-positive mature T-cell lymphomas”. Results of the proposed analyses will become the 
basis of the clinical study report (CSR) for 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 
final clinical study report. Any changes will either be reflected in amendments to this plan 
before the database lock or specifically documented in the clinical study report. 
2 
STUDY OBJECTIVES 
2.1 Primary Objectives 
● 
To compare the progression-free survival (PFS) as determined by an independent 
review facility (IRF) between the 2 treatment arms 
2.2 Secondary Objectives 
● 
To compare the PFS per IRF between the 2 treatment arms for patients with systemic 
anaplastic large cell lymphoma (sALCL) 
● 
To compare the remission rates per IRF following the completion of study treatment 
between the 2 treatment arms 
● 
To compare overall survival (OS) between the 2 treatment arms 
● 
To evaluate the safety and tolerability of the 2 treatment arms 
2.3 Additional Objectives 
● 
To evaluate medical resource utilization (MRU) and calculate utility values 
● 
To characterize the incidence of antitherapeutic antibodies (ATA) to brentuximab 
vedotin 
3 
STUDY ENDPOINTS 
3.1 Primary Endpoint 
● 
PFS per IRF 
3.2 Secondary Endpoints 
3.2.1 Key Secondary Endpoints 
● 
PFS per IRF for patients with sALCL 
● 
Complete remission (CR) rate per IRF following the completion of study treatment 


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● 
OS  
● 
Objective response rate (ORR) per IRF following the completion of study treatment 
3.2.2 Safety Endpoints 
● 
Type, incidence, severity, seriousness, and relatedness of adverse events 
● 
Type, incidence, and severity of laboratory abnormalities 
3.3 Additional Endpoints 
● 
Incidence of ATA to brentuximab vedotin 
● 
MRU based on the number of medical care encounters 
● 
Quality of Life (QoL) measured by the European Organisation for Research and 
Treatment of Cancer (EORTC) core quality of life questionnaire (QLQ-C30) and 
European Quality of Life 5-Dimensional (EQ-5D) score 
4 
STUDY DESIGN 
This is a randomized, double-blind, placebo-controlled, multicenter, phase 3 clinical trial 
designed to evaluate the efficacy and safety of including brentuximab vedotin in the 
treatment of newly-diagnosed, CD30-positive mature T-cell lymphomas. The standard of 
care in this patient population consists of 6 to 8 cycles of CHOP chemotherapy 
(cyclophosphamide, doxorubicin [hydrodoxorubicin], vincristine [Oncovin®], prednisone). 
Patients will be randomized in a 1:1 manner to receive 21-day cycles of treatment in 1 of the 
following 2 treatment groups: 
1. Standard-of-care arm: 6–8 cycles of CHOP; or 
2. Experimental arm: 6–8 cycles of brentuximab vedotin plus CHP (A+CHP) 
A target of 8 cycles of study treatment will be administered, per investigator decision, based 
on patient-specific characteristics, including stage of disease and IPI risk score. For patients 
tolerating study treatment, at least 6 cycles of study treatment should be completed prior to 
initiating post treatment consolidative stem cell transplant (SCT). Consolidative SCT is 
defined as SCT following completion of study treatment in the absence of any new 
anticancer treatment other than stem cell mobilization or conditioning. 
Brentuximab vedotin or vincristine will be administered as a placebo-controlled double-
dummy and administered to patients in a blinded manner. Placebo replacements for 
brentuximab vedotin/vincristine will be prepared by the pharmacist at each study site and a 
pharmacy blind will be enforced. 
Approximately 450 patients (~225 patients per treatment arm) will be randomized in this 
study. 
Radiographic disease evaluations, including CT scans of neck, chest, abdomen and pelvis, 
will be assessed at baseline, after completion of Cycle 4 of study treatment, after completion 


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of study treatment, at 9, 12, 15, 18, 21, and 24 months after initiation of study treatment, and 
every 6 months thereafter until disease progression, patient death, or analysis of the primary 
endpoint, whichever comes first. Patients will be followed for survival until death or study 
closure, whichever comes first. 
Safety assessments will include the incidence and severity of adverse events and changes in 
clinical laboratory values. Serum concentrations of ATA to brentuximab vedotin will also be 
measured. 
 
 
 
5 
ANALYSIS SETS 
This section defines each of the analysis sets that will be utilized. The use of each analysis set 
will be discussed in Section 7. 
5.1 Intent-to-Treat (ITT) Analysis Set 
The ITT analysis set will include all randomized patients. Patients will be included in the 
treatment group assigned at randomization regardless of the actual treatment received. 
5.2 Safety Analysis Set 
The safety analysis set will include all patients who receive any amount of brentuximab 
vedotin or any component of CHOP. Treatment group will be determined using the actual 
treatment received, regardless of the randomization treatment assignment. Patients receiving 
any dose of brentuximab vedotin will be grouped into the experimental group. Patients who 
do not receive brentuximab vedotin but any dose of any component of CHOP will be 
grouped into the standard-of-care group. 
6 
STATISTICAL CONSIDERATIONS 
6.1 General Principles 
Descriptive statistics (mean, median, standard deviation, minimum and maximum) will be 
used to summarize continuous variables. Frequencies and percentages will be used to 
summarize categorical variables. 
Unless otherwise specified, all statistical tests will be performed using a two-sided alpha of 
0.05. Confidence intervals will be calculated at two-sided 95% level. Multiplicity adjustment 
for alpha level is discussed in Section 6.8. 
Any analysis not described in this plan will be considered exploratory, and will be 
documented in the CSR as a post hoc analysis or a change to the planned analysis. 
To comply with regulatory electronic submission guidelines, listings of all clinical data will 
be submitted as electronic data sets. To facilitate data review for the study report, only 
pertinent data listings will be created and attached to the appendix of the CSR. 




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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 for brentuximab vedotin or any component of multiagent 
chemotherapy (CHOP or CHP). 
Other time variables based on 2 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 
Baseline values used in all analyses will be the most recent measurement prior to the first 
dose of study drug (brentuximab vedotin or any component of multiagent chemotherapy 
(CHOP or CHP). 
The end-of-treatment (EOT) date will be the date the EOT visit is performed, or 30 days after 
the last dose of study drug (other than prednisone) if an EOT visit is not performed. 
The date of progression will be the earliest of all radiologic scan dates for the given disease 
assessment, unless otherwise specified by the IRF Charter. 
The date of progression per Investigator will be the earliest of all radiological scan dates or 
date of biopsy confirming malignancy for the given disease assessment.  
6.5 Handling of Dropouts and Missing Data 
Missing data will not be imputed, with the exception of AE dates (see Appendix A). Patients 
with missing values of a variable other than the time-to-event endpoints (PFS and OS) will 
be excluded from the analysis of that endpoint. Censoring rules will be applied to the 
estimation of the distribution of the time-to-event endpoints (Section 7.5). 
 
 
 
 
 
 
 


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6.7 Multicenter Studies 
There are multiple centers in this study, however it is not anticipated that any center will 
accrue enough patients to warrant an analysis by center. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.9 Examination of Subgroups 
As exploratory analyses, subgroup analyses may be conducted for selected endpoints (see 
Section 7). Subgroups may include but are not limited to the following: 
● 
Age (18–64 years, ≥65 years old) 
● 
Age (<60 years, ≥60 years old) 
● 
Gender (Male, Female) 
● 
Race 
● 
Geographic region 
● 
Categorized weight at baseline (<70, 70–<100, and 100+ kg) 
● 
Prior cutaneous ALCL (yes, no) 
● 
Baseline Eastern Cooperative Oncology Group (ECOG) performance status (0, 1, or 
2) 
● 
Disease indication (histologic subtype) 
● 
Anaplastic lymphoma kinase (ALK) status (positive, negative) in sALCL patients 
● 
Disease stage (Stage I, Stage II, Stage III, Stage IV) 
● 
International prognostic index (IPI) Score (0, 1, 2, 3, 4, 5); 


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○ For all patients 
○ For ALK+ sALCL patients 
○ For ALK- sALCL patients 
● 
 
 
 
 
 
 
 
 
 
 
 
● Malignant cutaneous lesions at baseline (yes, no) 
● Bone marrow involvement at baseline (yes, no) 
● Patients with central pathology-confirmed histologic subtype 
● Patients with central pathology-confirmed CD30 expression 
● Patients with and without consolidative autologous or allogeneic SCT 
● Cycles of study treatment received (≤6 cycles, >6 cycles) 
 
6.10 Covariates 
This is a phase 3 study. Stratified analyses specified in Section 7 will include adjustment for 
the stratification factors as recorded at randomization. Covariates may be considered for 
adjustment in exploratory regression analyses. 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 


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7 
PLANNED ANALYSES 
7.1 Disposition 
Patient enrollment and disposition will be summarized by treatment group and total using the 
ITT analysis set. The table will present the number and percentage of patients who were 
randomized, received study drug, received treatment per randomization assignment, and 
participated in follow-up visits. The number and percentage of patients who discontinued 
treatment will be summarized by the reason for treatment discontinuation. The number and 
percentage of patients who discontinued the study will be summarized by the primary reason 
for study discontinuation. 
Number of patients who signed informed consent and number of patients in each analysis set 
will be summarized by treatment group and total. 
The number of patients enrolled in each country and at each site will be summarized by 
treatment group and total. 
7.2 Demographic and Baseline Characteristics 
Demographics and baseline characteristics, including age, gender, ethnicity, race, baseline 
height, weight, body mass index, and ECOG score will be summarized by treatment group 
and total using the ITT analysis set. Disease-specific characteristics, including time from 
diagnosis, ALK status, and IPI score will be summarized by treatment group and total using 
the ITT analysis set. Demographics, baseline characteristics and disease-specific 
characteristics will also be summarized by treatment group within the subgroup of patients 
receiving ≤6 cycles of study treatment and the subgroup of patients receiving >6 cycles of 
study treatment. Previous cancer-related treatments for primary cutaneous ALCL patients 
who transformed to sALCL will be summarized by treatment group and total. A comparison 
of the stratification factors as recorded at randomization and as recorded in the CRF at 
baseline will be presented. 
7.3 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 by treatment group and total. A list of patients with important 
protocol deviations will be presented. 
7.4 Treatment Administration 
Treatment administration will be summarized by treatment agent, treatment group and total using 
the safety analysis set. Summary statistics for duration of therapy (weeks) and the number of 


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cycles per patient will be presented, as well as the number and percentage of patients who were 
treated at each cycle and completed each cycle. Cumulative dose (mg), intended dose intensity 
(IDI), absolute dose intensity (ADI) and relative dose intensity (RDI) will be described. The 
number and percentage of patients whose dose was ever modified will be summarized by 
modification type, cycle and overall (i.e. overall drug administrations for a patient). 
Duration of treatment for IV-administered treatments is defined as time from the first study 
dose to 21 days after the last study dose [(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]. 
Duration of treatment for prednisone is defined as the time from first study dose to 21 days 
after the Day 1 dose date of the last cycle [(last cycle Day 1 date +21) – first dose date]. If 
death occurs less than 21 days after the Day 1 dose date of the last cycle, duration of 
treatment for prednisone is defined as [date of death – first dose date +1]. 
IDI is defined as is the intended dose of drug (e.g. mg/kg) per unit of time. For example, for 
brentuximab vedotin this is (1.8 mg/kg)/3 weeks=0.6. For vincristine only, IDI is defined as 
2 mg per 3 weeks=0.667 mg per week. For prednisone, IDI is defined as 
500 mg/3weeks=166.67 mg/week. 
ADI is defined as the actual dose (e.g. mg/kg) per unit of time that the patient received over 
the entire treatment period. For vincristine and prednisone, ADI is defined as the total actual 
dose in mg per unit of time that the patient received over the entire treatment period. 
RDI is defined as the percent of the intended dose intensity over the entire treatment period: 
RDI=ADI/IDI * 100 
Example 1: 
For brentuximab vedotin, consider a patient treated for three cycles. The second dose was 
delayed for one week, and for the third cycle the infusion was not completed and the patient 
received less than the full dose, as represented in the following table: 
Visit 
Intended Dose 
Regimen (mg/kg) 
Intended Dose 
(mg) 
Actual Dose 
(mg) 
Cycle Length 
C1D1 
1.8 
38 
38 
3 weeks + 1 week delay 
C2D1 
1.8 
38 
38 
3 weeks 
C3D1 
1.8 
38 
19 
3 weeks 
 
ADI (per week): 
 
=(1.8 + 1.8 + (1.8*[19/38])) / (3 wks + 1 wk delay + 3 wks + 3 wks) mg/kg per week 
 
=0.45 mg/kg per week 


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RDI: 
 
=0.45/0.6 * 100 
 
=75% 
Example 2: 
For vincristine, consider a patient in the standard-of-care arm, treated for 6 cycles. The 
second dose was delayed for 1 week, and for the third cycle and beyond the dose was 
reduced, as represented in the following table: 
Visit 
Intended Dose  
(mg) 
Cycle Length 
C1D1 
2 
3 weeks + 1 week delay 
C2D1 
2 
3 weeks 
C3D1 
1 
3 weeks 
C4D1 
1 
3 weeks 
C5D1 
1 
3 weeks 
C6D1 
1 
3 weeks 
 
ADI (per week): 
=(2 + 2 + 1 + 1 + 1 + 1) / (3 wks + 1 wk delay + 3 wks + 3 wks + 3 wks + 3 wks + 
3 wks) mg per week 
=0.421 mg per week 
RDI: 
=0.421/0.667 * 100  
= 63% 
Example 3: 
For prednisone, consider a patient treated with CHOP or CHP for six cycles. The second 
cycle was delayed for one week, and for the fourth cycle and beyond the patient took only 4 
of the 5 doses of prednisone, as represented in the following table: 
Visit 
Intended Dose  
(mg) 
Cycle Length 
C1D1 
500 
3 weeks + 1 week delay 
C2D1 
500 
3 weeks 
C3D1 
500 
3 weeks 
C4D1 
400 
3 weeks 
C5D1 
400 
3 weeks 
C6D1 
400 
3 weeks 
 


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ADI (per week): 
=(500 + 500 + 500 + 400 + 400 + 400) / (3 wks + 1 wk delay + 3 wks + 3 wks + 3 wks + 
3 wks + 3 wks) mg per week 
=142 mg per week 
RDI: 
=142/166.67 * 100  
= 85%   
7.5 Efficacy Analyses 
All efficacy analyses will be presented using the ITT analysis set. All stratified analyses will 
utilize the stratification factors as entered at the time of randomization. Analyses may also be 
performed using the subgroups listed in Section 6.9. 
7.5.1 Primary Endpoint 
7.5.1.1 Progression Free Survival (PFS) per IRF 
PFS is defined as the time from the date of randomization to the date of first documentation 
of PD, death due to any cause, or receipt of subsequent anticancer chemotherapy to treat 
residual or progressive disease, whichever occurs first. Note that receipt of post-treatment 
consolidative radiotherapy, post-treatment chemotherapy for the purpose of mobilizing 
peripheral blood stem cells, or consolidative autologous or allogeneic SCT will not be 
considered as disease progression or as having started new anticancer therapy. Specifically, 
PFS = The earliest of the dates of first documented PD, receipt of subsequent 
anticancer chemotherapy to treat residual or progressive disease or death – 
Date of randomization + 1. 
If PD is not documented, no subsequent anticancer chemotherapy to treat residual or 
progressive disease has been initiated, and the patient is alive at the time of the data cutoff or 
study withdrawal,  PFS will be censored as follows: 
● 
If there is no radiographic post-baseline tumor assessment, PFS will be censored at 
the date of randomization. 
● 
If there are radiographic post-baseline tumor assessments, PFS will be censored at the 
most recent tumor assessment before the data cutoff or study withdrawal, whichever 
occurs first. 
Specifically, 
 
Censored PFS = max(1, last scan date – date of randomization + 1), 
where the last scan is the last CT or PET scan obtained during study. 


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Full censoring rules for the primary endpoint are detailed in the table below. 
Situation 
Date of Progression or Censoring 
Outcome 
No baseline and/or post baseline tumor 
assessment 
Day following date of randomization 
Censored 
No documented progression 
Date of last radiographic tumor assessment (or  
the date of randomization in the absence of a 
post-baseline radiographic tumor assessment) 
Censored  
PD documented between scheduled 
visits 
Date of radiologic tumor assessment 
demonstrating PD 
Event 
Treatment discontinuation for 
undocumented progression after the last 
radiographic tumor assessment 
Date of last radiographic tumor assessment or  
the date of randomization in the absence of a 
post-baseline radiographic tumor assessment 
Censored  
New anticancer therapy to treat residual 
or progressive disease initiated prior to 
documented progression, including 
palliative radiotherapy (excludes post-
treatment chemotherapy given for stem 
cell mobilizations, excludes 
consolidative autologous or allogeneic 
SCT and excludes post-treatment 
consolidative radiotherapy)  
Start date of new anticancer therapy 
Event 
Post-treatment consolidative 
radiotherapy, post-treatment 
chemotherapy given for stem cell 
mobilizations, consolidative autologous 
or allogeneic SCT  
Date of last radiographic tumor assessment or 
the date of randomization  in the absence of a 
post-baseline radiographic tumor assessment 
Censored 
Death before first PD assessment 
Date of death 
Event 
Death between radiographic tumor 
assessment visits 
Date of death 
Event 
Death or progression after more than 
one consecutively missed radiographic 
tumor assessment 
Date of last radiologic tumor assessment  prior 
to missed visits or the date of randomization in 
the absence of a post-baseline radiographic 
tumor assessment prior to missed visits 
Censored 
 
The primary statistical hypothesis can be expressed in terms of the hazard ratio 
λExperimental arm/λStandard-of-Care arm where λExperimental arm represents the hazard of progression on 
the experimental arm (A+CHP ) and λStandard-of-Care arm  represents the hazard of progression on 
the standard-of-care arm (CHOP). A hazard ratio <1 indicates that the duration of PFS is 
prolonged for patients on the experimental arm compared with patients on the standard-of-
care arm. 
The null and alternative hypotheses can be written respectively as: 
H0 = λExperimental arm/λStandard-of-Care arm ≥1 
HA = λExperimental arm/λStandard-of-Care arm <1 
Kaplan-Meier methods will be used to assess PFS. The stratified log-rank test without 
adjustments for covariates will be used in the primary evaluation of PFS differences between 
the experimental arm and the standard-of-care arm in the ITT analysis set using an overall 


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one-sided, α=0.025 level test. All events entered in the database at the time of analysis that 
have been source-data-verified will be included in the analysis of PFS,
 
 
Kaplan-Meier Curves depicting PFS in the 2 arms will be generated. Additionally, median 
PFS and probability of PFS from 3 months to the end of the follow-up period will be reported 
at 3 month intervals. The two-sided 95% confidence intervals (CI) for the median and 
3-month intervals will be calculated using the complementary log-log transformation method 
(Collett 1994). 
The primary analysis of PFS may be performed for each of the subgroups specified in 
Section 6.9. An analysis may also be performed on the subgroup of patients without 
consolidative radiotherapy, consolidative autologous or allogeneic SCT. An analysis of PFS 
per Investigator will also be performed and an evaluation of the agreement between PFS per 
IRF and PFS per Investigator will be provided. 
Descriptive statistics of PFS will be presented for each individual histologic subtype where 
possible. 
Cox regression of PFS may be used to estimate the hazard ratio of the experimental arm to 
the standard-of-care arm. Baseline covariates may be included in the model in addition to 
centrally determined CD30 expression level as a continuous variable. The treatment group 
variable will always be included in the model. Interaction effects may be considered 
whenever possible. 
Sensitivity Analyses 
Sensitivity analyses of PFS per IRF will be performed. Sensitivity analyses will include, but 
will not be limited to, the following: 
1. A stratified log-rank analysis using the stratification factors as recorded in the CRF at 
baseline 
2. An analysis where patients receiving SCT or consolidative radiotherapy are censored 
3. An analysis where patients receiving new anticancer therapy are censored rather than 
considered to have had an event 
4. An analysis assessing the impact of missing data/assessments where patients who missed 
one or more of the most recent scheduled assessments are treated as events at the time of 
the next scheduled assessment on the experimental arm 
5. An analysis where initiation of consolidative  radiotherapy and undocumented 
progression (e.g. progression identified by the Investigator on the basis of symptomatic 
deterioration) are considered events 
6. An analysis where, for patients with a CR at EOT, initiation of consolidative radiotherapy 
or receipt of SCT are considered events 


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7. An analysis where patients  who discontinue treatment for undocumented progression 
after the last radiographic tumor assessment are considered to have had an event at the 
time of treatment discontinuation; and where patients who die or progress after more than 
one consecutively missed radiographic tumor assessment are considered to have had an 
event on the date of death or progression 
8. An analysis following EMA censoring guidelines where receipt of new anticancer 
therapy is not considered an event nor a reason for censoring and where patients who die 
or progress after more than one consecutively missed radiographic tumor assessment are 
considered to have had an event on the date of death or progression   
No p-values will be calculated and no formal adjustments for multiplicity will be made when 
performing the above sensitivity analyses. 
7.5.2 Secondary Efficacy Endpoints 
7.5.2.1 PFS per IRF in Patients with sALCL 
PFS per IRF in patients with sALCL is defined in the same manner as PFS per IRF (see 
Section 7.5.1.1). For this endpoint, PFS per IRF will be analyzed in the subset of patients 
with a central pathology confirmed diagnosis of sALCL. 
7.5.2.2 Complete Remission Rate (CR rate) 
CR rate is defined as the proportion of patients with CR per IRF following the completion of 
study treatment (at EOT or the first assessment after the last dose of study treatment and prior 
to long-term follow-up) according to the Revised Response Criteria for Malignant 
Lymphoma (Cheson 2007). Patients whose disease response cannot be assessed will be 
scored as non-responders for calculating the CR rate. 
The CR rate between the experimental arm and the standard-of-care arm will be tested using 
the Cochran-Mantel-Haenszel (CMH), stratified by the randomization stratification factors 
(see Section 6.3). The absolute CR rate and exact two-sided 95% confidence interval using 
the Clopper-Pearson method (Clopper 1934) will also be summarized by treatment group. 
7.5.2.3 Objective Response Rate (ORR rate) 
ORR is defined as the proportion of patients with CR or partial remission (PR) per IRF 
following the completion of study treatment (at EOT or the first assessment after the last 
dose of study treatment and prior to long-term follow-up) according to the Revised Response 
Criteria for Malignant Lymphoma (Cheson 2007). Patients whose disease response cannot be 
assessed will be scored as non-responders for calculating the ORR. 
The ORR between the experimental arm and the standard-of-care arm will be tested using the 
Cochran-Mantel-Haenszel (CMH), stratified by the randomization stratification factors (see 
Section 6.3). The absolute ORR and exact two-sided 95% confidence interval using the 
Clopper-Pearson method (Clopper 1934) will also be summarized by treatment group. 


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7.5.2.4 Overall Survival (OS) 
OS is defined as the time from randomization to death due to any cause. Specifically, 
 
OS=Date of death – Date of randomization + 1 
For a patient who is not known to have died by the end of study follow-up, observation of OS 
is censored on the date the patient was last known to be alive (i.e., date of last contact). 
Patients lacking data beyond the day of randomization will have their survival time censored 
on the date of randomization (i.e., OS duration of 1 day). 
The stratified log-rank test without adjustments for covariates will be used in the evaluation 
of OS differences between the experimental arm and the standard-of-care arm. OS will be 
analyzed using Kaplan-Meier methodology and Kaplan-Meier plots will be provided by 
treatment group. Additionally, median PFS and probability of PFS from 3 months to the end 
of the follow-up period will be reported at 3-month intervals by treatment group. The 
two-sided 95% confidence intervals (CI) for the median and 3-month intervals will be 
calculated using the complementary log-log transformation method (Collett 1994). 
7.6 Safety Analyses 
The safety analysis set will be used to summarize all safety endpoints. 
Adverse events will be coded using Medical Dictionary for Regulatory Activities (MedDRA, 
Version 15.1 or higher). 
Laboratory values will be graded according to the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE version 4.03 or higher). 
Concomitant medications will be coded using WHO Drug (version: June 2012 or more 
recent). 
7.6.1 Adverse Events 
Adverse events (AEs) will be summarized by descending MedDRA preferred term unless 
otherwise specified. For incidence reporting, if a patient reports more than one AE that was 
coded to the same system organ class or preferred term, the patient will be counted only once 
for that specific system organ class or preferred term. 
A treatment-emergent AE is defined as a newly occurring or worsening AE after the first 
dose of any study drug component. Unless documented as a pre-existing condition, AEs with 
unknown start date will be counted as treatment emergent. Summary of AEs will be provided 
by treatment group and total for the following: 
● 
Pre-existing Adverse Events, 
● 
All treatment-emergent AEs, 
● 
AEs related to blinded study treatment, 
● 
AEs related to CHP, 


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● 
Serious Adverse Events (SAEs), 
● 
SAEs related to blinded study treatment, 
● 
SAEs related to CHP, 
● 
AEs leading to dose reduction of blinded study treatment, 
● 
AEs leading to dose reduction of cyclophosphamide or doxorubicin, 
● 
AEs leading to dose delay of blinded study treatment, 
● 
AEs leading to dose delay of cyclophosphamide or doxorubicin, 
● 
AEs leading to dose interruption of blinded study treatment (full dose received), 
● 
AEs leading to dose interruption of cyclophosphamide or doxorubicin (full dose 
received), 
● 
AEs leading to the dose of blinded study treatment being stopped early (full dose not 
received), 
● 
AEs leading to the dose of cyclophosphamide or doxorubicin being stopped early 
(full dose not received), 
● 
AEs leading to discontinuation of blinded study treatment, 
● 
AEs leading to discontinuation of cyclophosphamide, doxorubicin, or prednisone 
● 
Treatment-emergent AEs by system organ class, preferred term and maximum 
severity. At each system organ class or preferred term, multiple occurrences of events 
within a patient are counted only once at the highest severity, 
● 
Grade 3 - 5 treatment-emergent AEs, 
● 
Treatment-emergent AEs by system organ class and preferred term, 
● 
AEs of peripheral neuropathy identified by the broad search MedDRA SMQ 
“Peripheral neuropathy” 
Additional analyses of peripheral neuropathy may also be presented. 
7.6.2 Clinical Laboratory Parameters 
Clinical laboratory data (hematology, serum chemistry and coagulation panel) will be 
summarized by treatment group. All laboratory results through the end of treatment visit will 
be presented in standardized units by treatment group. Both observed data and changes from 
baseline for chemistry and hematology will be summarized with descriptive statistics. In 
addition, laboratory data will be summarized by the worst post-baseline NCI CTCAE grade 
for each parameter. 
Laboratory results and NCI CTCAE grades for hematology, and serum chemistry will be 
presented in data listings. Normal ranges will be documented and out-of-range values will be 
flagged. 


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7.6.3 ECOG Performance Status 
ECOG status will be summarized for each visit by treatment group. Shifts from baseline to 
the best and worst post-baseline score will be tabulated by treatment group. 
7.6.4 Concomitant Medications 
Concomitant medications will be summarized by the WHO Drug substance name by 
treatment group and total and listed by patient. 
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, primary cause of death and 
relationship to disease will be summarized by treatment group and total. 
7.7 Additional Endpoints 
The ITT analysis set will be used to summarize all additional endpoints. 
7.7.1 Antitherapeutic Antibody (ATA) Incidence Rate 
The ATA incidence rate is defined as the proportion of patients that develop ATA at any time 
during the study. ATA incidence will be summarized by treatment group. 
7.7.2 Medical Resource Utilization (MRU) 
Medical resource utilization data include medical care encounters (e.g., hospital admissions 
or major diagnostic procedures) related to study treatment or treatment for lymphoma. 
Medical resource utilization (MRU) data will be summarized using descriptive statistics by 
treatment group. Additional statistical modeling may be performed separately in post hoc 
analyses. 
7.7.3 Quality of Life (QoL) 
Quality of life is measured using the QLQ-C30, FACT/GOG-NTX, and EQ-5D scores 
patient-reported outcome (PRO) instruments. 
The FACT/GOG-NTX assesses changes in quality of life, and includes an additional 
concerns subscale for assessing treatment-induced neurologic symptoms (sensory, hearing, 
motor, dysfunction). The neurotoxicity subscale of this tool consists of 11 questions. The 
FACT/GOG-NTX manual for scoring and handling missing data will be used for scoring and 
handling of missing data. 
The QLQ-C30 consists of 5 subscales on functioning (physical, role cognitive, emotional, 
social), 3 symptom scales (fatigue, pain, nausea/vomiting), and a global quality of life scale 
as well as questions on symptoms and the financial impact of cancer and treatment. The 
EORTC QLC-C30 manual will be used for scoring and handling of missing data. 
PRO instrument total and subscale scores will be summarized with descriptive statistics by 
treatment group and visit. In addition, change from baseline will be tabulated by treatment 


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group and visit. Descriptive summaries of individual items may also be presented. Additional 
statistical modeling may be performed separately in post hoc analyses. 
7.7.4 Pharmacokinetics 
Antibody drug-conjugate (brentuximab vedotin), total antibody, 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 performed and 
presented in a separate report. 
7.7.5 Biomarkers 
Exploratory correlative studies will be defined in a separate analysis plan and reported in a 
separate report. 
7.8 Exploratory Analyses 
The following exploratory analyses may also be presented using the ITT analysis set. 
● 
Duration of response per IRF 
● 
Duration of response per Investigator 
● 
PFS per Investigator 
● 
CR rate at EOT per Investigator 
● 
ORR at EOT per Investigator 
● 
Clinical response at EOT per IRF 
● 
Clinical response at EOT per Investigator 
● 
Evaluation of agreement between IRF and Investigator for clinical response, CR and 
ORR at EOT 
● 
Change from baseline to EOT of the sum of the products of diameters of nodes or 
nodal masses (SPD) 
● 
Maximum SPD reduction at EOT 
● 
Failure-free survival 
● 
B-symptom resolution 
● 
Cutaneous lesion resolution 
● 
Proportion of patients PET negative per IRF at Cycle 4 
● 
Proportion of patients PET negative per IRF at EOT 
● 
Proportion of patients PET negative per Investigator at Cycle 4 
● 
Proportion of patients PET negative per Investigator at EOT 
● 
Onset, resolution and characterization of neuropathy based on the Total Neuropathy 
Score-nurse assessment 


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● 
Summary Deauville Scale PET assessments per IRF at Cycle 4 
● 
Summary of PET Standard Uptake Values (SUV) per IRF at Baseline, Cycle 4 and 
EOT and change in maximum SUV from Baseline 
8 
INTERIM ANALYSIS 
An Independent Data Monitoring Committee (IDMC) will periodically monitor the trial for 
safety. After each periodic safety review, the IDMC will make a recommendation to the 
sponsor to continue the study as planned or stop the study for safety concerns. The IDMC 
will review expedited SAEs as they arise
 
 
 
 
 
 
 
 
In addition, an ongoing, real-time review of serious adverse events will be conducted by 
Seattle Genetics Pharmacovigilance. 
9 
CHANGES FROM PLANNED ANALYSES 
9.1 Changes from the Original Protocol 
There are no changes from the current version of the protocol. 
9.2 Changes from the Original SAP 
Changes from the original Statistical Analysis Plan are as follows: 
9.2.1 Version 2 Changes 
● 
 
● 
 
9.2.2 Version 3 Changes 
● 
Elevated ORR per IRF from Exploratory analysis to Secondary Objective/Secondary 
Endpoint  
● 
ORR per IRF removed from Exploratory Analyses 
● 
Clarified type of radiotherapy in PFS censoring rules and Exploratory Analyses 


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● Added Exploratory Analyses to summarize additional assessment of PET scans by the 
IRF (Deauville Scale and SUV) 
● Specified an additional sensitivity analysis for the primary endpoint 
9.2.3 Version 4 Changes 
● Definition of Consolidative SCT added to study design for clarification 
● 
 
● Updated definition of AE imputation rules to match the current Seattle Genetics 
standards 
● Specified use of CRF age when available due to changes in ability to collect full birth 
date in all countries 
● Definition for the date of progression per investigator has been added for clarification  
● Pooling strategy for stratified analyses clarified to address scenario where no further 
pooling can be done 
● 
 
● PFS censoring dates  have been updated from study day 1 or first dose date  to the 
date of randomization for consistency 
● Post-treatment radiotherapy that triggers PFS censoring in the absence of progression 
in the PFS censoring table clarified as consolidative for consistency 
● Statement regarding descriptive statistics of PFS for each subtype was added per 
request from CDRH 
● PFS sensitivity analysis following EMA censoring guidelines added to support 
submission to EMA 
● Clarification that no p-values will be calculated for PFS sensitivity analyses  
● Definition of the completion of study treatment has been clarified for analysis of CR 
and ORR rates 
● Approximately added to timing of futility analysis for clarification 
9.2.4 Version 5 Changes 
•
 
• Clarified that new anticancer therapy for progressive disease will also be considered a 
PFS event. 
 
 


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10 REFERENCES 
Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, Coiffier B, Fisher RI, Hagenbeek A, 
Zucca E, Rosen ST, Stroobants S, Lister TA, Hoppe RT, Dreyling M, Tobinai K, Vose JM, Connors JM, 
Federico M and Diehl V (2007). Revised response criteria for malignant lymphoma. J Clin Oncol 25: 579-86. 
Clopper CJ and Pearson ES (1934). The use of confidence or fiducial limits illustrated in the case of the 
binomial. Biometrika 26: 404-413. 
Collett D (1994). Interval-censored survival data. Modelling survival data in medical research. Boca Raton, 
Fla., Chapman & Hall/CRC: 237-251. 
Westfall PH and Krishen A (2001). Optimally weighted, fixed sequence and gatekeeper multiple testing 
procedures. Journal of Statistical Planning and Inference 99: 25-40. 
 


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APPENDIX A: IMPUTATION OF PARTIALLY UNKNOWN ADVERSE EVENT 
DATES 
The algorithm below should be used to impute pre-existing condition and adverse event (AE) 
start dates for which only partial information is known. For ease of reading, both pre-existing 
conditions and AEs will be referred to as AE for the remainder of this document. The 
algorithm should be applied to every AE record on a record by record basis. AE start dates 
should be imputed before imputation of AE condition end date in all cases. The AE condition 
end date should only be used in the imputation of the AE start date if it a full known date. 
● 
AE day and month are missing: 
○ 
If the year is the same as the year of first dose of investigational agent and the 
onset period and/or onset time indicate that the start of the AE was pre-dose: 
● 
AE start date will be imputed as the minimum of (AE condition end date*, day prior 
to first dose of investigational agent) 
○ 
If the year is the same as the year of first dose of investigational agent and the 
onset period and/or onset time indicate that the start of the AE was post-dose: 
● 
AE start date will be imputed as the minimum of (AE condition end date*, first dose 
date of investigational agent) 
○ 
If the year is before the year of first dose of investigational agent: 
● 
AE start date will be imputed as the minimum of (AE condition end date*, December 
31st see example 2 below) 
○ 
If the year is after the year of first dose of investigational agent: 
● 
AE start date will be imputed as the minimum of (AE condition end date*, January 
31st see example 2 below) 
● 
AE month only is missing: 
○ 
Treat day as missing and replace both month and day according to the above 
procedure 
● 
AE day only is missing: 
○ 
If the month/year is the same as the month/year of first dose of investigational 
agent and the onset period and/or onset time indicate that the start of the AE was 
pre-dose: 
● 
AE start date will be imputed as the minimum of (AE condition end date*, day prior 
to first dose of investigational agent) 
○ 
If the month/year is the same as the month/year of first dose of investigational 
agent and the onset period and/or onset time indicate that the start of the AE was 
post-dose: 


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● 
AE start date will be imputed as the minimum of (AE condition end date*, first dose 
date of investigational agent) 
○ 
If the month/year is before the month/year of first dose of investigational agent: 
● 
AE start date will be imputed as the minimum of (AE condition end date*, last day of 
the month) 
○ 
If the month/year is after the month/year of first dose of investigational agent: 
● 
AE start date will be imputed as the minimum of (AE condition end date*, last day of 
the month) 
*only use condition end date if known and full end date is available. 
The following algorithm should be used to impute AE condition end dates. The AE records 
for a condition/event should be sorted by the imputed start dates then record position (order 
of entry into the eCRF). After sorting, if any condition end date month/year is greater than 
any subsequent record end date month/year, then change the imputed start day only to end of 
month. Repeat as necessary. 
For all records excluding the last chronological record for a condition/event: 
● 
AE condition end date will be imputed as the start date of the subsequent record 
For the last chronological record for a condition/event: 
● 
If outcome is “recovered/resolved”, “recovered/resolved with sequelae”, or “fatal” 
apply the following:  
○ 
If only year is provided for the end date and 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) 
○ 
If only year is provided for the end date and 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) 
○ 
If month and year are provided for the end date: 
■ 
AE condition end date will be imputed as the minimum of (death date, data 
extraction date, last day of the end date month/year) 
● 
If outcome is “recovering/resolving”, “not recovered/resolved”, “unknown”, or blank: 
○ 
AE condition end date will not be imputed. 


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Example 1 
AESPID 1: Condition/Event HEADACHE 
First dose date 01JAN2012 
Prior to imputation 
Start date 
Condition end date 
Severity 
Outcome 
Onset 
UNUNK2011 
15APR2012 
1 
not recovered/resolved 
pre-ICF 
15APR2012 
UNMAY2012 
2 
recovering/resolving 
post 1st dose 
UNMAY2012 
UNJUN2012 
1 
not recovered/resolved 
post 1st dose 
UNJUN2012 
UNJUN2012 
3 
recovering/resolving 
post 1st dose 
UNJUN2012 
10JUL2012 
2 
recovering/resolving 
post 1st dose 
10JUL2012 
-- 
1 
not recovered/resolved 
post 1st dose 
Post imputation 
Start date 
Condition end date 
Severity 
Outcome 
31DEC2011 
15APR2012 
1 
not recovered/resolved 
15APR2012 
31MAY2012 
2 
recovering/resolving 
31MAY2012 
30JUN2012 
1 
not recovered/resolved 
30JUN2012 
30JUN2012 
3 
recovering/resolving 
30JUN2012 
10JUL2012 
2 
recovering/resolving 
10JUL2012 
-- 
1 
not recovered/resolved 
Example 2 (highlights choice of last day of the month as opposed to the 1st or the 15th) 
AESPID 4: Condition/Event NAUSEA 
First dose date 01APR2012 
Prior to imputation 
Start date 
Condition end date 
Severity 
Outcome 
Onset 
UNUNK2011 
25APR2012 
1 
not recovered/resolved 
pre-ICF 
25APR2012 
UNAPR2012 
2 
recovering/resolving 
post 1st dose 
UNAPR2012 
04MAY2012 
1 
recovered/resolved 
post 1st dose 
Post imputation 
Start date 
Condition end date 
Severity 
Outcome 
31DEC2011 
25APR2012 
1 
not recovered/resolved 
25APR2012 
31APR2012 
2 
recovering/resolving 
31APR2012 
04MAY2012 
1 
recovered/resolved