Conditions: Diffuse Large B-cell Lymphoma Refractory Follicular B-cell Non-Hodgkin's Lymphoma
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 25
Healthy volunteers: no

Brief summary:
This is a randomized, open-label, multicenter, Phase 2 clinical trial designed to evaluate the efficacy and safety of brentuximab vedotin in combination with rituximab and bendamustine for the treatment of patients with relapsed or refractory CD30-positive diffuse large B-cell lymphoma (DLBCL) after failure of second-line salvage therapy or as second-line treatment in patients ineligible for autologous stem cell transplant (ASCT).

Detailed description:
Patients will be randomized in a 1:1 manner to receive rituximab plus bendamustine with or without brentuximab vedotin. Patients who respond to combination treatment containing brentuximab vedotin and do not experience excessive toxicity may receive additional single-agent brentuximab vedotin following combination treatment, for up to an additional 10 cycles (up to 16 total cycles of treatment).

Arms:
arm 1: Subjects randomized to the brentuximab vedotin arm will receive IV infusions of brentuximab vedotin followed by bendamustine on day 1, and rituximab followed by bendamustine on day 2 of each 21 day cycle. arm 2: Subjects randomized to the control arm will receive IV infusions of rituximab on day 1 or day 2 and bendamustine on both days 1 and 2 of each 21 day cycle.

Interventions: intervention 1: Brentuximab Vedotin intervention 2: Rituximab intervention 3: Bendamustine
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

Protocol document:
Prot_000.pdf: 




 
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Investigator 
 
I have read and agree to the protocol SGN35-023, titled ‘A Randomized, Open Label, 
Phase 2 Study of Rituximab and Bendamustine with or without Brentuximab Vedotin for 
Relapsed or Refractory CD30-Positive Diffuse Large B-Cell Lymphoma’.  I am aware of my 
responsibilities as an Investigator under the guidelines of GCP, local regulations (as 
applicable), and the study protocol.  I agree to conduct the study according to these 
responsibilities and to appropriately direct and assist the staff under my control, who will be 
involved in the study. 
 
 
Clinical Site:  
 
 
 
Site Number: 
 
 
 
Site Principal Investigator: 
 
 
 
 
Print Name 
 
Title 
 
 
 
 
Signature 
 
Date 
 
 


 
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2. 
SYNOPSIS 
 
NAME OF SPONSOR: Seattle Genetics, Inc. 
PROTOCOL No.: SGN35-023 
NAME OF STUDY TREATMENT: Rituximab and Bendamustine with or without Brentuximab Vedotin 
TITLE OF STUDY: A Randomized, Open Label, Phase 2 Study of Rituximab and Bendamustine with or 
without Brentuximab Vedotin for Relapsed or Refractory CD30-Positive Diffuse Large B-Cell Lymphoma 
STUDY CENTERS:  Subjects will be enrolled at approximately 50 sites in Europe and North America. 
STUDY PERIOD: 
First subject in:  September 2015  
 
All subjects completed treatment:  January 2018   
 
End of follow-up:  January 2020 
PHASE OF 
DEVELOPMENT: 
Phase 2 
OBJECTIVES: 
Primary Objective: 
• 
To compare the objective response rate (ORR) among subjects with relapsed or refractory 
CD30-positive diffuse large B-cell lymphoma (DLBCL) or follicular non-Hodgkin lymphoma 
(NHL) grade 3b receiving rituximab and bendamustine plus brentuximab vedotin (treatment arm) 
with that among subjects receiving rituximab and bendamustine alone (control arm)  
Secondary Objectives: 
• 
To compare progression-free survival (PFS) among subjects with relapsed or refractory 
CD30-positive DLBCL or follicular NHL grade 3b receiving rituximab and bendamustine plus 
brentuximab vedotin (treatment arm) with that among subjects receiving rituximab and 
bendamustine alone (control arm)  
• 
To compare the complete remission (CR) rate between the 2 arms of the study 
• 
To compare duration of response (DOR) between the 2 arms of the study 
• 
To compare overall survival (OS) between the 2 arms of the study 
• 
To evaluate the safety and tolerability of the 2 arms of the study 
Exploratory Objectives: 
• 
To characterize the incidence of antitherapeutic antibodies (ATA) to brentuximab vedotin among 
subjects with relapsed or refractory CD30-positive DLBCL or follicular NHL grade 3b receiving 
rituximab and bendamustine plus brentuximab vedotin  
• 
To explore the relationship between CD30 expression and clinical responses 
• 
To explore the relationship between potential patient stratification biomarkers and clinical 
responses  
• 
To evaluate brentuximab vedotin (and monomethyl auristatin E [MMAE]) exposures when 
administered in combination with rituxumab and bendamustine 
• 
To characterize pharmacodynamic markers such as soluble CD30 in the 2 treatment arms 
STUDY DESIGN AND METHODOLOGY: This is a randomized, open-label, multicenter, Phase 2 
clinical trial designed to evaluate the efficacy and safety of brentuximab vedotin in combination with 
rituximab and bendamustine for the treatment of patients with relapsed or refractory CD30-positive DLBCL 
or follicular NHL grade 3b after failure of second-line salvage therapy or as second-line treatment in 
patients ineligible for autologous stem cell transplant (ASCT).  Patients will be randomized in a 1:1 manner 
to receive rituximab plus bendamustine with or without brentuximab vedotin (stratified by second-line 
age-adjusted International Prognostic Index [sAAIPI] score [0 vs 1 vs 2-3] and duration of remission after 
initiation of frontline therapy [refractory or relapse <12 months vs relapse ≥12 months]).  Patients who 
respond to combination treatment containing brentuximab vedotin and do not experience excessive toxicity 
may receive additional single-agent brentuximab vedotin following combination treatment, for up to an 


 
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additional 10 cycles (up to 16 total cycles of treatment). 
DLBCL or follicular NHL grade 3b will be histologically determined by local pathology assessment, and 
CD30 expression will be determined by local or central laboratory visual assessment of any detectable level 
of CD30 on tumor cells by immunohistochemistry (IHC; using anti-CD30 BerH2 antibody) to determine 
eligibility for enrollment.  Tissue will be sent to a central laboratory for disease confirmation and 
retrospective evaluation of biomarkers including, but not limited to, CD30 expression by IHC and 
computer-assisted image analysis.  
STUDY POPULATION AND MAIN CRITERIA FOR INCLUSION/EXCLUSION:  
Subjects cannot be enrolled before all inclusion criteria (including test results) are confirmed. 
Inclusion Criteria:  
1. Patients with histologically confirmed CD30-positive DLBCL or follicular NHL grade 3b, defined 
as any detectable CD30 expression on tumor cells based on local or central pathologic assessment. 
2. Patients must have relapsed or refractory disease following:  
a. 
second-line or greater salvage systemic therapy, or 
b. frontline cytotoxic systemic therapy, for patients who are ineligible for stem cell 
transplant (SCT). 
3. Age 18 and older. 
4. Fluorodeoxyglucose (FDG)-avid disease by positron emission tomography (PET) and measurable 
disease of at least 1.5 cm by CT, as assessed by the site radiologist. 
5. An Eastern Cooperative Oncology Group (ECOG) performance status score of 0–2. 
6. The following baseline laboratory data: 
a. 
Absolute neutrophil count (ANC) ≥1000/µL (unless documented bone marrow 
involvement) 
b. Platelet count ≥75,000/µL (unless documented bone marrow involvement) 
c. 
Serum bilirubin ≤1.5 × upper limit of normal (ULN) or ≤3 × ULN for patients with 
Gilbert’s disease  
d. Estimated creatinine clearance (CrCL) ≥40 mL/min (calculated using the Cockcroft-Gault 
formula) 
e. 
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × ULN. 
7. Females of childbearing potential must have a negative serum beta human chorionic gonadotropin 
(β-hCG) pregnancy test result within 7 days prior to the first 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 bilateral oophorectomy or hysterectomy. 
8. Females of childbearing potential and males who have partners of childbearing potential must 
agree to use 2 effective contraceptive methods during the study and for 6 months following the last 
dose of brentuximab vedotin or 12 months following the last dose of rituximab, whichever is later. 
9. Patients must be willing and able to provide written informed consent. 
Exclusion Criteria:  
1. History of another invasive malignancy that has not been in remission for at least 1 year.  The 
following are exempt from the 1-year limit: nonmelanoma skin cancer, curatively treated localized 
prostate cancer, ductal carcinoma in situ (DCIS), and cervical carcinoma in situ on biopsy or a 
squamous intraepithelial lesion on Pap smear.   
2. History of progressive multifocal leukoencephalopathy (PML). 
3. Cerebral/meningeal disease related to the underlying malignancy.  Patients with a history of 
cerebral/meningeal disease related to the underlying malignancy are allowed if prior central 
nervous system (CNS) disease has been definitively treated. 
4. Any active Grade 3 or higher (per the National Cancer Institute [NCI, US] Common Terminology 
Criteria for Adverse Events [CTCAE], Version 4.03) viral, bacterial, or fungal infection within 
2 weeks prior to the first dose of brentuximab vedotin.  Routine antimicrobial prophylaxis is 


 
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permitted. 
5. Chemotherapy, radiotherapy, biologics, and/or other antitumor treatment with immunotherapy that 
is not completed 4 weeks prior to first dose of study drug.  Concomitant use of other systemic 
antineoplastic agents (including bleomycin) while on study is excluded. 
6. Females who are pregnant or breastfeeding. 
7. Known hypersensitivity to any study drug or excipient contained in the drug formulation of any of 
the study drugs. 
8. Known to be positive for hepatitis B by surface antigen expression (HBsAg) and hepatitis B core 
antibody (HBcAb).  Known to have active hepatitis C infection (positive by polymerase chain 
reaction) or on antiviral therapy for hepatitis C within the last 6 months. 
9. Known to be positive for human immunodeficiency virus (HIV).   
10. Patients with previous allogeneic SCT. 
11. Previous treatment with brentuximab vedotin or bendamustine. 
12. Intolerable toxicity to prior rituximab therapy (per Investigator discretion). 
13. Current therapy with other investigational agents. 
14. Grade 3 or higher pulmonary disease unrelated to underlying malignancy. 
15. Documented history of a cerebral vascular event (stroke or transient ischemic attack), unstable 
angina, myocardial infarction, or cardiac symptoms consistent with New York Heart Association 
(NYHA) Class III-IV within 6 months prior to the first dose of brentuximab vedotin. 
16. Congestive heart failure, Class III or IV, by the NYHA criteria. 
17. Grade 2 or higher (per NCI CTCAE, Version 4.03) peripheral sensory or motor neuropathy at 
baseline. 
18. Major surgery less than 30 days prior to first dose of study drug.  Major surgery is any invasive 
operative procedure in which a more extensive resection is performed, eg, a body cavity is entered, 
organs are removed, or normal anatomy is altered. 
19. Live vaccines (in particular yellow fever vaccination) within 1 month prior to the first dose of 
study drug. 
20. Current severe immunodeficiency, or history of recurring or chronic infections, or with underlying 
conditions which may further predispose patients to serious infection. 
NUMBER OF SUBJECTS: Approximately 110 patients with relapsed or refractory DLBCL or follicular 
NHL grade 3b will be enrolled in the study (approximately 55 patients in each treatment arm).  
STUDY TREATMENT(S):  
Test Product, Dose and Mode of Administration: 
Brentuximab vedotin:  1.8 mg/kg IV infusion (over 30 minutes) on Day 1 of each 21-day cycle 
Rituximab:  375 mg/m2 IV infusion (per institutional standard of care) on Day 2 (+1) of each 21-day cycle 
Bendamustine:  90 mg/m2 IV infusion (over 60 minutes) on Day 1 AND Day 2 (+1) of each 21-day cycle 
Reference Therapy, Dose and Mode of Administration: 
Rituximab:  375 mg/m2 IV infusion (per institutional standard of care) on Day 1 OR Day 2 (+1) of each 
21-day cycle 
Bendamustine:  90 mg/m2 IV infusion (over 60 minutes) on Day 1 AND Day 2 (+1) of each 21-day cycle 
 
Bendamustine Timing 
On days when bendamustine is administered with other study drugs (brentuximab vedotin or rituximab),  
bendamustine will be the last study drug administered, beginning 30-60 minutes after completion of the 
brentuximab vedotin or rituximab infusion. 
DURATION OF TREATMENT: Study treatment consists of six 3-week cycles of combination treatment.  
The maximum total duration of combination therapy is 6 cycles, or approximately 4 months.  Patients who 
respond to combination treatment containing brentuximab vedotin and do not experience excessive toxicity 
may receive additional treatment with single-agent brentuximab vedotin for up to an additional 10 cycles 




 
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DATE AND VERSION: 13 July 2016, Version 05 
 


 
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3. 
TABLE OF CONTENTS 
1. 
SIGNATURES ........................................................................................................... 2 
2. 
SYNOPSIS ................................................................................................................. 4 
3. 
TABLE OF CONTENTS .......................................................................................... 9 
4. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ........................ 14 
5. 
ETHICS .................................................................................................................... 17 
5.1 
Ethics Committee ...................................................................................................... 17 
5.2 
Ethical Conduct of the Study..................................................................................... 17 
5.3 
Subject Information and Consent .............................................................................. 17 
6. 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ........... 19 
7. 
INTRODUCTION ................................................................................................... 21 
7.1 
Disease Review ......................................................................................................... 21 
7.2 
Compound Review .................................................................................................... 22 
7.3 
Clinical Study Rationale ............................................................................................ 22 
8. 
STUDY OBJECTIVES ........................................................................................... 24 
8.1 
Primary Study Objective ........................................................................................... 24 
8.2 
Secondary Study Objectives ...................................................................................... 24 
8.3 
Exploratory Objectives .............................................................................................. 24 
8.4 
Endpoints ................................................................................................................... 25 
8.4.1 
Primary Endpoint....................................................................................................... 25 
8.4.2 
Secondary Endpoints ................................................................................................. 25 
8.4.3 
Pharmacokinetic / Pharmacodynamic Measurements ............................................... 25 
9. 
INVESTIGATIONAL PLAN ................................................................................. 26 
9.1 
Overall Study Design and Plan.................................................................................. 26 
9.2 
Discussion of Study Design ...................................................................................... 27 
9.3 
Study Duration .......................................................................................................... 27 
9.4 
Study Population ....................................................................................................... 28 
9.4.1 
Inclusion Criteria ....................................................................................................... 28 
9.4.2 
Exclusion Criteria ...................................................................................................... 29 
9.4.3 
Withdrawal and Replacement of Subjects ................................................................ 30 
9.4.3.1 
Discontinuation of Study Drug .................................................................................. 30 
9.4.3.2 
Patient Withdrawal From Study ................................................................................ 31 
9.4.3.3 
Replacement of Subjects ........................................................................................... 31 
9.5 
Treatment ................................................................................................................... 31 
9.5.1 
Treatments Administered .......................................................................................... 31 
9.5.1.1 
Required Premedication and Postmedication ............................................................ 32 
9.5.1.2 
Brentuximab Vedotin ................................................................................................ 33 


 
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9.5.1.2.1 
Description ................................................................................................................ 33 
9.5.1.2.2 
Method of Procurement ............................................................................................. 33 
9.5.1.2.3 
Dose and Administration ........................................................................................... 33 
9.5.1.2.4 
Preparation ............................................................................................................... 34 
9.5.1.2.5 
Study Treatment Labeling and Packaging ................................................................ 34 
9.5.1.2.6 
Study Treatment Storage and Accountability ............................................................ 34 
9.5.1.3 
Rituximab .................................................................................................................. 35 
9.5.1.3.1 
Description ................................................................................................................ 35 
9.5.1.3.2 
Method of Procurement ............................................................................................. 35 
9.5.1.3.3 
Dose and Administration ........................................................................................... 35 
9.5.1.3.4 
Preparation ............................................................................................................... 35 
9.5.1.3.5 
Storage and Accountability ....................................................................................... 35 
9.5.1.4 
Bendamustine ............................................................................................................ 36 
9.5.1.4.1 
Description ................................................................................................................ 36 
9.5.1.4.2 
Method of Procurement ............................................................................................. 36 
9.5.1.4.3 
Dose and Administration ........................................................................................... 36 
9.5.1.4.4 
Preparation ............................................................................................................... 36 
9.5.1.4.5 
Storage and Accountability ....................................................................................... 36 
9.5.1.5 
Management of Adverse Reactions ........................................................................... 36 
9.5.1.5.1 
Management of Infusion Reactions ........................................................................... 36 
9.5.1.5.2 
Management of Suspected PML ................................................................................ 37 
9.5.1.5.3 
Dose Modifications ................................................................................................... 38 
9.5.2 
Blinding of Study Medication ................................................................................... 39 
9.5.3 
Prior and Concomitant Therapy ................................................................................ 39 
9.5.4 
Treatment Compliance .............................................................................................. 40 
9.5.5 
Assignment to Treatment .......................................................................................... 40 
9.6 
Efficacy and Safety Variables ................................................................................... 40 
9.6.1 
Efficacy and Safety Measurements Assessed ........................................................... 40 
9.6.1.1 
Efficacy Measurements ............................................................................................. 40 
9.6.1.2 
Pharmacokinetic/Pharmacodynamic Measurements ................................................. 41 
9.6.1.3 
Safety Measurements ................................................................................................ 41 
10. 
STUDY EVALUATIONS BY VISIT ..................................................................... 42 
10.1 
Screening (Day -28 to 1) ........................................................................................... 46 
10.2 
Treatment Period ....................................................................................................... 46 
10.3 
End of Treatment ....................................................................................................... 49 
10.4 
Follow-Up .................................................................................................................. 49 
10.5 
End of Study/End of Follow-up ................................................................................ 50 
11. 
METHODS OF ASSESSMENT ............................................................................. 51 


 
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11.1 
Medical History ......................................................................................................... 51 
11.2 
Histology / CD30 Assessment ................................................................................... 51 
11.3 
Second-line Age-adjusted International Prognostic Index ........................................ 52 
11.4 
Electrocardiograms .................................................................................................... 52 
11.5 
Physical Examination, ECOG Performance Status, and Weight .............................. 52 
11.6 
Lymphoma Assessment ............................................................................................. 53 
11.7 
Clinical Laboratory Tests .......................................................................................... 53 
11.8 
Pharmacokinetic, Pharmacodynamic, and Immunogenicity Samples ....................... 53 
11.9 
Imaging/Response Assessment .................................................................................. 54 
11.10 
Long-term and Survival Status Follow-up ................................................................ 54 
12. 
SAFETY MEASUREMENTS AND VARIABLES .............................................. 55 
12.1 
Adverse Events .......................................................................................................... 55 
12.1.1 
Definitions ................................................................................................................. 55 
12.1.2 
Procedures for Eliciting and Recording Adverse Events .......................................... 57 
12.1.3 
Reporting Periods for Adverse Events and Serious Adverse Events ........................ 58 
12.1.4 
Serious Adverse Events Require Immediate Reporting ............................................ 59 
12.1.5 
Sponsor Safety Reporting Requirements .................................................................. 59 
13. 
DATA MANAGEMENT AND STATISTICAL ANALYSIS .............................. 61 
13.1 
Data Management ...................................................................................................... 61 
13.2 
Sample Size Estimation ............................................................................................. 61 
13.3 
Statistical Analysis Plan ............................................................................................ 61 
13.4 
Randomization ........................................................................................................... 62 
13.5 
Analysis Populations ................................................................................................. 62 
13.5.1 
Intent-to-Treat Population ......................................................................................... 62 
13.5.2 
Safety Population ...................................................................................................... 62 
13.5.3 
Efficacy Evaluable Population .................................................................................. 62 
13.5.4 
Per-Protocol Population ............................................................................................ 62 
13.6 
Statistical Methods .................................................................................................... 62 
13.6.1 
Missing Data .............................................................................................................. 62 
13.6.2 
Demographic and Baseline Data ............................................................................... 63 
13.6.3 
Subject Disposition ................................................................................................... 63 
13.6.4 
Efficacy ..................................................................................................................... 63 
13.6.4.1 
Response to Treatment .............................................................................................. 63 
13.6.4.2 
Secondary Efficacy Endpoints .................................................................................. 63 
13.6.5 
Pharmacokinetics and Pharmacodynamics ................................................................ 64 
13.6.6 
Safety ......................................................................................................................... 64 
13.6.7 
Additional Data ......................................................................................................... 65 
13.6.8 
Interim Analysis ........................................................................................................ 65 


 
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13.6.9 
Independent Data Monitoring Committee ................................................................. 65 
14. 
MONITORING PROCEDURES (QUALITY ASSURANCE) ........................... 67 
14.1 
Routine Monitoring ................................................................................................... 67 
14.2 
Inspections and Auditing Procedures ........................................................................ 67 
15. 
STUDY MANAGEMENT AND MATERIALS .................................................... 68 
15.1 
Electronic Case Report Forms ................................................................................... 68 
15.2 
Data Collection .......................................................................................................... 68 
15.3 
Source Documents Maintenance ............................................................................... 69 
15.4 
Record Maintenance .................................................................................................. 69 
15.5 
Confidentiality ........................................................................................................... 70 
16. 
ADMINISTRATION PROCEDURES .................................................................. 71 
16.1 
Regulatory Approval ................................................................................................. 71 
16.2 
Protocol Amendments ............................................................................................... 71 
16.3 
Protocol Adherence and Deviations .......................................................................... 71 
16.4 
Study Documentation, Privacy, and Records Retention ........................................... 72 
16.5 
Publication Policy...................................................................................................... 72 
16.6 
Clinical Study Report ................................................................................................ 72 
16.7 
Contractual and Financial Details ............................................................................. 73 
16.8 
Insurance, Indemnity, and Compensation ................................................................. 73 
16.9 
Discontinuation of the Study ..................................................................................... 73 
16.10 
Study Center File Management ................................................................................. 73 
17. 
REFERENCE LIST ................................................................................................ 75 
18. 
APPENDICES.......................................................................................................... 79 
18.1 
Appendix 1: Declaration of Helsinki ........................................................................ 79 
18.2 
Appendix 2: Elements of Informed Consent ............................................................. 86 
18.3 
Appendix 3: Eastern Cooperative Oncology Group Performance Status ................. 88 
18.4 
Appendix 4: Common Terminology Criteria for Adverse Events (CTCAE; v 4.03) 89 
18.5 
Appendix 5: Second-line Age-adjusted International Prognostic Index ................... 90 
18.6 
Appendix 6: Response Assessment – The Lugano Classification ............................ 91 
18.7 
Appendix 7: Futility Boundaries for the Interim Analysis ........................................ 94 
18.8 
Appendix 8: Summary of Amendment 1.0 ................................................................ 96 
18.9 
Appendix 9: Summary of Amendment 2.0 ................................................................ 97 
18.10 
Appendix 10: Summary of Amendment 3.0 ............................................................ 114 
18.11 
Appendix 11: Summary of Amendment 4.0 ............................................................ 124 
 
 


 
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LIST OF TABLES 
 
Table 1: 
Recommended dose modifications for brentuximab vedotin-associated 
toxicity .................................................................................................................. 38 
Table 2: 
Study Schedule ..................................................................................................... 43 
Table 3: 
Schedule of Follow-up Assessments .................................................................... 45 
Table 4 
Observed improvements in ORR and corresponding p-values ............................ 61 
 
 
LIST OF FIGURES 
 
Figure 1: 
Study Schematic ................................................................................................... 27 
 


 
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4. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Term 
Definition 
ABS 
Acrylonitrile-butadiene-styrene  
ADC 
Antibody-drug conjugate 
ADCC 
Antibody-dependent cell-mediated cytotoxicity  
AE 
Adverse event  
ALT 
Alanine aminotransferase (serum glutamic-pyruvic transaminase) 
ANC 
Absolute neutrophil count 
ASCT 
Autologous stem cell transplant 
AST 
Aspartate aminotransferase (serum glutamic-oxaloacetic transaminase) 
ATA 
Antitherapeutic antibodies 
CDC 
Complement-dependent cytotoxicity 
CFR 
Code of Federal Regulations 
CLL  
Chronic lymphocytic leukemia 
CMH 
Cochran-Mantel-Haenszel  
CMR 
Complete metabolic response 
CNS 
Central nervous system  
COO 
Cell of origin  
CR 
Complete remission 
CrCL 
Creatinine clearance  
CRO 
Clinical research organization 
CSTD 
Closed system transfer devices  
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCIS 
Ductal carcinoma in situ  
DLBCL 
Diffuse large B-cell lymphoma 
DOR 
Duration of response  
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EOT 
End of treatment 
EU 
European Union 
FDA 
Food and Drug Administration 
FDG  
[18F]fluorodeoxyglucose 
G-CSF 
Granulocyte colony-stimulating factor 
GCP 
Good Clinical Practice 
GM-CSF 
Granulocyte-macrophage colony-stimulating factor 


 
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HbA1c 
Hemoglobin A1c 
HBcAb 
Hepatitis B core antibody  
HBsAg 
Hepatitis B surface antigen  
β-hCG 
Beta human chorionic gonadotropin  
HIV 
Human immunodeficiency virus  
HL 
Hodgkin lymphoma 
ICH 
International Conference on Harmonisation 
IDMC 
Independent Data Monitoring Committee  
IEC 
Independent Ethics Committee 
Ig 
Immunoglobulin 
IHC 
Immunohistochemistry  
IND 
Investigational New Drug 
INN 
International Nonproprietary Name 
IPI 
International Prognostic Index  
IRB 
Institutional Review Board 
ITT 
Intent-to-treat  
IV 
Intravenous(ly) 
IXRS 
Interactive voice and web recognition system  
JCV 
John Cunningham virus 
LDH 
Lactate dehydrogenase  
MedDRA 
Medical Dictionary for Regulatory Activities 
MMAE 
Monomethyl auristatin E 
MRI 
Magnetic resonance imaging 
NCI 
National Cancer Institute 
NHL 
Non-Hodgkin lymphoma 
NMR 
No metabolic response  
NYHA 
New York Heart Association  
ORR  
Objective response rate 
OS 
Overall survival 
PCR 
Polymerase chain reaction 
PD 
Progressive disease 
PET 
Positron emission tomography 
PFS 
Progression-free survival 
PK 
Pharmacokinetic(s) 
PMD 
Progressive metabolic disease  
PML 
Progressive multifocal leukoencephalopathy 
PMR 
Partial metabolic response 


 
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PR 
Partial remission 
R-CHOP 
Rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone  
sAAIPI 
Second-line age-adjusted International Prognostic Index  
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SCT 
Stem cell transplant 
SD 
Stable disease 
SmPC 
Summary of Product Characteristics 
SPD 
Sum of the product of the diameters 
Study drug 
Rituximab and bendamustine with or without brentuximab vedotin  
TAb 
Total antibody 
TEAE 
Treatment-emergent AEs  
ULN 
Upper limit of normal 
US 
United States 
USAN 
United States adopted name 
USP 
United States Pharmacopeia 
USPI 
US prescribing information  
WHO 
World Health Organization 


 
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5. 
ETHICS 
5.1 
Ethics Committee 
This study will be conducted in compliance with Institutional Review Board (IRB)/ 
Independent Ethics Committee (IEC) and International Conference On Harmonisation (ICH) 
Good Clinical Practice (GCP) Guidelines - including Title 21 Part 56 of the USA Code of 
Federal Regulations (CFR) relating to IRBs and GCP as described in the United States (US) 
Food and Drug Administration (FDA) CFR (21 CFR § 50, 56, 312) - in accordance with 
applicable ICH regulations regarding clinical safety data management (E2A, E2B[R3]), 
European Community directives 2001/20, 2001/83, 2003/94 and 2005/28 as enacted into 
local law, and with ICH regulations regarding scientific integrity (E4, E8, E9, and E10).  In 
addition this study will adhere to all local regulatory requirements and requirements for data 
protection. 
Before initiating a trial/study, the Investigator/institution must have written and dated 
approval/favorable opinion from the IRB/IEC for the study protocol/amendment(s), written 
informed consent form, any consent form updates, subject recruitment procedures (eg, 
advertisements), and any written information to be provided to subjects and a statement from 
the IRB that they comply with GCP requirements.  The IRB/IEC approval must identify the 
protocol version as well as the documents reviewed. 
5.2 
Ethical Conduct of the Study 
This study will be conducted in accordance with the Note for Guidance on GCP (ICH 
Harmonized Tripartite Guideline E6 (R1); FDA CFR [21 CFR § 50, 56, 312]), Declaration of 
Helsinki (Fortaleza, Brazil, October 2013; Appendix 18.1), and all applicable regulatory 
requirements. 
5.3 
Subject Information and Consent 
The Investigator will explain the benefits and risks of participation in the study to each 
subject and obtain written informed consent.  Written informed consent must be obtained 
prior to the subject entering the study and before initiation of any study related procedure 
(including administration of study drug).  
The Sponsor will provide a sample informed consent form, based on the elements of 
informed consent in Appendix 18.2.  The final, version dated form must be agreed to by the 
Sponsor and the IRB/IEC and will contain all elements in the sample form, in language 
readily understood by the subject.  Each subject’s original consent form, personally signed 
and dated by the subject and by the person who conducted the informed consent discussion, 
will be retained by the Investigator.  The Investigator will supply all enrolled subjects with a 
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The consent form may need to be revised during the study should important new information 
become available that may be relevant to the safety of the subject.  In this instance approval 
should always be given by the IRB/IEC.  Subjects on treatment should be informed of the 
changes and reconsented if the consent was updated for safety reasons.  This is documented 
in the same way as previously described. 


 
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6. 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE 
The study will be performed at approximately 55 sites in Europe and North America. 
Monitoring and Evaluation Committee(s): 
The Independent Data Monitoring Committee (IDMC) will consist of individuals external to 
Seattle Genetics, Inc. and PRA Health Sciences, chosen for their expertise in oncology and 
familiarity with clinical trials.  Members of the IDMC will include, at a minimum, physicians 
and appropriate statistical representation.  The primary role of this IDMC will be to monitor 
safety data and to review the results of the planned futility analysis, as described further in the 
IDMC charter. 
Randomization: 
Perceptive Informatics 
US:  1-877-819-6025 
Europe:  +44 115 855 8220 
Central Pathologist: 
Ventana Medical Systems, Inc. 
1910 E. Innovation Park Drive 
Tucson, Arizona 85755 USA 
1-520-887-2155 
1-800-227-2155 
Clinical Laboratories: 
Central clinical laboratory services will be provided by Covance.  Additional analyses of 
clinical laboratory samples may be conducted by certified local laboratories.  Documentation 
of certification and laboratory normal ranges will be filed with study documentation. 
Analyses of brentuximab vedotin antibody-drug conjugate (ADC) and monomethyl 
auristatin E [MMAE] concentrations; analyses of soluble CD30 and other 
chemokines/cytokines of interest; and analyses of CD30 antigen expression, mRNA levels of 
CD30 and related genes, and cell of origin (COO) classification will be performed at central 
facilities that will be identified in the study manual. 




 
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7. 
INTRODUCTION 
7.1 
Disease Review 
Non-Hodgkin lymphoma (NHL) is the most common hematological malignancy, and it is 
estimated that 71,850 new cases of NHL will be diagnosed in the US during 2015 and that 
19,790 people will die as a result of the disease. [1]  Diffuse large B-cell lymphoma 
(DLBCL) is the most common form of NHL and comprises 30% of newly diagnosed cases. 
[2]  Early stage DLBCL is frequently curable with combined modality therapy or 
combination chemotherapy alone [3], but most patients present with advanced disease, 
including rapidly enlarging masses and both local and systemic symptoms.  Histologically, 
DLBCL is defined by the expression of B-cell markers including CD20, and approximately 
25% of tumors co-express CD30. [4-6]   
For patients with advanced-stage disease, over 50% of newly diagnosed patients are cured 
with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), the 
current frontline standard of care for DLBCL. [7-12]  However, a significant number of 
patients either fail to respond or relapse following first-line treatment. [13,14]  The 
International Prognostic Index (IPI) for aggressive NHL recognizes 5 significant risk factors 
prognostic of overall survival (OS):  age >60 years, elevated serum lactate dehydrogenase 
(LDH), Eastern Cooperative Oncology Group (ECOG) performance status ≥2, disease stage 
III or IV, and >1 site of extranodal involvement. [15]  Patients with 2 or more risk factors 
have less than 50% chance of relapse-free survival and OS at 5 years.  Molecular profiling of 
DLBCL indicates the overexpression of bcl-2, mutation of the myc gene, or both, confers a 
particularly poor prognosis. [16-19]  Follicular NHL grade 3b, an aggressive follicular 
lymphoma, is often treated under the same guidelines. [31] 
For patients with relapsed DLBCL, the second-line age-adjusted IPI (sAAIPI) is composed of 
3 risk factors: ECOG performance status ≥2, LDH level greater than normal, and stage III or 
IV disease; patients with 0, 1, 2, or 3 risk factors are considered to have low, low-
intermediate, high-intermediate, or high risk disease, respectively. [20,21]  Second-line 
treatment usually consists of salvage therapy followed by autologous stem cell transplantation 
(ASCT).  However, ASCT results in long-term disease control for only 20% to 40% of 
patients. [20-28] 
For patients who relapse after ASCT and those ineligible for transplant, prognosis is 
extremely poor, and options are limited.  Recently, several studies have demonstrated that 
combination therapy with rituximab and bendamustine has clinical benefit in patients with 
relapsed or refractory DLBCL (objective response rate [ORR] 45.8% - 62.7%).  Patients have 
included those with prior response to rituximab-containing therapy and those who were 
ineligible for ASCT. [13, 29-32]  However, the median progression-free survival (PFS) in 
these studies was only 3.6 – 6.7 months, indicating an ongoing need for improved therapies 
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7.2 
Compound Review 
Brentuximab vedotin (ADCETRIS™; also called SGN-35) is a CD30-directed ADC 
consisting of 3 components: 1) the chimeric immunoglobulin G (IgG)1 antibody cAC10, 
specific for human CD30, 2) the microtubule-disrupting agent 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. 
In patients with relapsed Hodgkin lymphoma (HL) after ASCT, a pivotal Phase 2 study using 
single agent brentuximab vedotin demonstrated a complete remission (CR) rate of 34%, and 
an ORR (CR plus partial remission [PR]) of 75%.  The median duration of CR was 
20.5 months, and the duration of any remission (CR or PR) was 6.7 months. [33]  For further 
information, please refer to the Investigator’s Brochure.  Brentuximab vedotin has also been 
previously evaluated in 49 patients with relapsed or refractory CD30-positive DLBCL, 
demonstrating an ORR of 44% with a mean duration of 16.6 months. [34] 
Rituximab (Rituxan®) is a genetically engineered chimeric murine/human monoclonal IgG1 
kappa antibody directed against the CD20 antigen.  Upon binding to CD20, rituximab 
mediates B-cell lysis.  Possible mechanisms of cell lysis include complement-dependent 
cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC).  Rituximab 
is marketed in the US and the European Union (EU) for use in combination chemotherapy for 
previously untreated NHL, including indolent B-cell lymphomas and DLBCL; it is also 
approved for chronic lymphocytic leukemia (CLL) and other diseases. [35] 
Bendamustine is a bifunctional mechlorethamine derivative containing a purine-like 
benzimidazole ring, approved in the US for CLL and NHL; bendamustine is administered as 
an intravenous (IV) infusion on Days 1 and 2 for up to six 28-day cycles in CLL and for up to 
eight 21-day cycles in NHL.  Though the exact mechanisms of action of bendamustine are 
unknown, mechlorethamine derivatives form electrophilic alkyl groups, which form covalent 
bonds with electron-rich nucleophilic moieties, resulting in interstrand DNA crosslinks and 
leading to cell death via several pathways. [36]  
As brentuximab vedotin, rituximab, and bendamustine are each active agents in DLBCL and 
act via independent mechanisms, the combination is likely to represent an effective treatment 
for subjects with relapsed/refractory CD30-positive DLBCL. 
7.3 
Clinical Study Rationale 
In the relapsed or refractory setting, DLBCL and follicular NHL grade 3b patients who co-
express CD20 and CD30 present a unique treatment opportunity for rescue therapy targeting 
both CD20 and CD30 with rituximab and brentuximab vedotin, respectively, in combination 
with bendamustine.  This combination has the potential to provide an important new 
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The combination of rituximab and bendamustine has been previously evaluated for the 
treatment of relapsed or refractory DLBCL patients ineligible for ASCT. [31]  Rituximab has 
been administered at a dose of 375 mg/m2 on Day 1 of repeated 21-day cycles and 
bendamustine has been administered at a starting dose of 90 or 120 mg/m2 on Days 1 and 2 
[30] or Days 2 and 3 [29] of each cycle, with a treatment duration of up to 6 cycles.  These 
regimens were well tolerated, although the degree of Grade 3 or 4 neutropenia was 76% with 
bendamustine at a dose of 120 mg/m2. [29] 
The combination of rituximab and brentuximab vedotin has been previously evaluated in a 
cohort of patients with relapsed or refractory CD30-positive DLBCL, demonstrating an ORR 
of 46%. [33]  Rituximab plus brentuximab vedotin was given at dose levels of 375 mg/m2 
and 1.8 mg/kg, respectively, on Day 1 of each cycle, and this regimen was well tolerated with 
a safety profile similar to single agent brentuximab vedotin. 
The safety and efficacy of brentuximab vedotin combined with bendamustine in patients with 
HL is currently being evaluated in an ongoing clinical trial.  Preliminary data indicate that 
this is both a safe and highly active regimen, with the most common adverse event (AE) 
being infusion-related reactions. [37]  Brentuximab vedotin is given at a starting dose of 
1.8 mg/kg on Day 1, and bendamustine is given at 90 mg/m2 on Days 1 and 2.  
In this study, the combination of brentuximab vedotin, rituximab, and bendamustine 
(treatment arm) will be compared with rituximab and bendamustine (control arm).  Subjects 
on the treatment arm will receive brentuximab vedotin on Day 1 of each 21-day cycle at a 
starting dose of 1.8 mg/kg, rituximab on Day 2 (+1 day) at 375 mg/m2 (per institutional 
standard of care), and bendamustine on Days 1 and 2 (+1 day) at 90 mg/m2.  Subjects on the 
control arm will receive rituximab on Day 1 OR 2 of each 21-day cycle at 375 mg/m2, and 
bendamustine on Days 1 AND 2 (+1 day) at 90 mg/m2.  The starting dose of 90 mg/m2 
bendamustine is within the effective range and is predicted to reduce toxicities, dose delays, 
and dose reductions compared with a starting dose of 120 mg/m2.  In addition, in an ongoing 
trial evaluating the combination of brentuximab vedotin and bendamustine in elderly patients 
with HL, a decrease in the dose of bendamustine from 90 mg/m2 to 70 mg/m2 was required to 
improve tolerability.  The safety of the 3-drug combination will be monitored in an ongoing 
process as part of the clinical study, including a scheduled evaluation by an IDMC.  A formal 
futility assessment to assess efficacy will be performed after 50% of subjects have had the 
Cycle 2 disease assessment.   


 
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8. 
STUDY OBJECTIVES  
8.1 
Primary Study Objective 
• To compare the objective response rate (ORR) among subjects with relapsed or 
refractory CD30-positive DLBCL or follicular NHL grade 3b receiving rituximab and 
bendamustine plus brentuximab vedotin (treatment arm) with that among subjects 
receiving rituximab and bendamustine alone (control arm)  
8.2 
Secondary Study Objectives 
• To compare progression-free survival (PFS) among subjects with relapsed or 
refractory CD30-positive DLBCL or follicular NHL grade 3b receiving rituximab and 
bendamustine plus brentuximab vedotin (treatment arm) with that among subjects 
receiving rituximab and bendamustine alone (control arm)  
• To compare the complete remission (CR) rate between the 2 arms of the study 
• To compare duration of response (DOR) between the 2 arms of the study 
• To compare overall survival (OS) between the 2 arms of the study 
• To evaluate the safety and tolerability of the 2 arms of the study 
8.3 
Exploratory Objectives 
• To characterize the incidence of antitherapeutic antibodies (ATA) to brentuximab 
vedotin among subjects with relapsed or refractory CD30-positive DLBCL or 
follicular NHL grade 3b receiving rituximab and bendamustine plus brentuximab 
vedotin  
• To explore the relationship between CD30 expression and clinical responses 
• To explore the relationship between potential patient stratification biomarkers and 
clinical responses  
• To evaluate brentuximab vedotin (and MMAE) exposures when administered in 
combination with rituxumab and bendamustine 
• To characterize pharmacodynamic markers such as soluble CD30 in the 2 treatment 
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8.4 
Endpoints 
8.4.1 
Primary Endpoint 
The primary efficacy endpoint of this study is objective response rate (ORR) as assessed by 
the 2014 Lugano Classification. [38, Appendix 18.6]   
8.4.2 
Secondary Endpoints 
Secondary efficacy endpoints are the following:  
• Progression-free survival (PFS) 
• Complete response (CR) rate  
• Best clinical response 
• Duration of response (DOR) 
• Overall survival (OS) 
• Type, incidence, severity, seriousness, and relatedness of AEs 
• Type, incidence, and severity of laboratory abnormalities 
• Incidence and severity of infusion-related and hypersensitivity reactions. 
8.4.3 
Pharmacokinetic / Pharmacodynamic Measurements 
Blood will be collected from subjects assigned to receive brentuximab vedotin (treatment 
arm) for measurement of ATA to brentuximab vedotin and both brentuximab vedotin and 
MMAE exposures. 
Blood will be collected from all subjects for pharmacodynamic (soluble CD30 and other 
chemokines/cytokines of interest) assessments.  Tumor samples from prior biopsies/aspirates 
will be collected from all subjects for assessment of CD30 antigen expression, mRNA levels 
of CD30 and related genes, and cell of origin (COO) classification.  


 
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9. 
INVESTIGATIONAL PLAN 
9.1 
Overall Study Design and Plan 
This is a randomized, open-label, multicenter, Phase 2 clinical trial designed to evaluate the 
efficacy and safety of brentuximab vedotin in combination with rituximab and bendamustine 
for the treatment of patients with relapsed or refractory CD30-positive DLBCL or follicular 
NHL grade 3b after failure of second-line salvage therapy, or after failure of front-line 
treatment in patients ineligible for ASCT.  The study design is presented in Figure 1.  Patients 
will be randomized in a 1:1 manner to receive rituximab plus bendamustine with or without 
brentuximab vedotin (stratified by sAAIPI score [0 vs 1 vs 2-3] and duration of remission 
after initiation of frontline therapy [refractory or relapse <12 months vs relapse ≥12 months]).  
Patients who respond to combination treatment containing brentuximab vedotin and do not 
experience excessive toxicity may receive additional single-agent brentuximab vedotin (on 
Day 1 of each 21-day cycle) following combination treatment, for up to an additional 
10 cycles (up to 16 total cycles of treatment). 
DLBCL or follicular NHL grade 3b will be histologically determined by local pathology 
assessment, and CD30 expression will be determined by local or central laboratory visual 
assessment of any detectable level of CD30 on tumor cells by immunohistochemistry (IHC; 
using anti-CD30 BerH2 antibody) to determine eligibility for enrollment.  Tissue will be sent 
to a central laboratory for disease confirmation and retrospective evaluation of biomarkers 
including, but not limited to, CD30 expression by IHC and computer-assisted image analysis.  
Once stained for CD30 expression by the central pathology laboratory, slides may be retained 
to support future research efforts by the sponsor.  




 
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9.4 
Study Population 
9.4.1 
Inclusion Criteria 
Subjects cannot be enrolled before all inclusion criteria (including test results) are confirmed. 
1. Patients with histologically confirmed CD30-positive DLBCL or follicular NHL 
grade 3b, defined as any detectable CD30 expression on tumor cells based on local or 
central pathologic assessment. 
2. Patients must have relapsed or refractory disease following:  
a. second-line or greater salvage systemic therapy, or 
b. frontline cytotoxic systemic therapy, for patients who are ineligible for stem 
cell transplant (SCT). 
3. Age 18 and older. 
4. Fluorodeoxyglucose (FDG)-avid disease by positron emission tomography (PET) and 
measurable disease of at least 1.5 cm by computed tomography (CT), as assessed by 
the site radiologist. 
5. An ECOG performance status score of 0–2. 
6. The following baseline laboratory data: 
a. Absolute neutrophil count (ANC) ≥1000/µL (unless documented bone marrow 
involvement) 
b. Platelet count ≥75,000/µL (unless documented bone marrow involvement) 
c. Serum bilirubin ≤1.5 × upper limit of normal (ULN) or ≤3 × ULN for patients 
with Gilbert’s disease  
d. Estimated creatinine clearance (CrCL) ≥40 mL/min (calculated using the 
Cockcroft-Gault formula) 
e. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 
≤2.5 × ULN. 
7. Females of childbearing potential must have a negative serum beta human chorionic 
gonadotropin (β-hCG) pregnancy test result within 7 days prior to the first 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 bilateral 
oophorectomy or hysterectomy. 


 
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8. Females of childbearing potential and males who have partners of childbearing 
potential must agree to use 2 effective contraceptive methods (see Section 9.5.3) 
during the study and for 6 months following the last dose of brentuximab vedotin or 
12 months following the last dose of rituximab, whichever is later. 
9. Patients must be willing and able to provide written informed consent. 
9.4.2 
Exclusion Criteria 
If any of the following apply, the subject MUST NOT enter the study: 
1. History of another invasive malignancy that has not been in remission for at least 
1 year.  The following are exempt from the 1-year limit: nonmelanoma skin cancer, 
curatively treated localized prostate cancer, ductal carcinoma in situ (DCIS), and 
cervical carcinoma in situ on biopsy or a squamous intraepithelial lesion on Pap 
smear.   
2. History of progressive multifocal leukoencephalopathy (PML). 
3. Cerebral/meningeal disease related to the underlying malignancy.  Patients with a 
history of cerebral/meningeal disease related to the underlying malignancy are 
allowed if prior central nervous system (CNS) disease has been definitively treated. 
4. Any active Grade 3 or higher (per the National Cancer Institute [NCI, US] Common 
Terminology Criteria for Adverse Events [CTCAE] Version 4.03) viral, bacterial, or 
fungal infection within 2 weeks prior to the first dose of brentuximab vedotin.  
Routine antimicrobial prophylaxis is permitted. 
5. Chemotherapy, radiotherapy, biologics, and/or other antitumor treatment with 
immunotherapy that is not completed 4 weeks prior to first dose of study drug.  
Concomitant use of other systemic antineoplastic agents (including bleomycin) while 
on study is excluded. 
6. Females who are pregnant or breastfeeding. 
7. Known hypersensitivity to any study drug or excipient contained in the drug 
formulation of any of the study drugs. 
8. Known to be positive for hepatitis B by surface antigen expression (HBsAg) and 
hepatitis B core antibody (HBcAb).  Known to have active hepatitis C infection 
(positive by polymerase chain reaction [PCR]) or on antiviral therapy for hepatitis C 
within the last 6 months. 
9. Known to be positive for human immunodeficiency virus (HIV).   
10. Patients with previous allogeneic SCT. 


 
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11. Previous treatment with brentuximab vedotin or bendamustine. 
12. Intolerable toxicity to prior rituximab therapy (per Investigator discretion). 
13. Current therapy with other investigational agents. 
14. Grade 3 or higher pulmonary disease unrelated to underlying malignancy. 
15. Documented history of a cerebral vascular event (stroke or transient ischemic attack), 
unstable angina, myocardial infarction, or cardiac symptoms consistent with New 
York Heart Association (NYHA) Class III-IV within 6 months prior to the first dose 
of brentuximab vedotin. 
16. Congestive heart failure, Class III or IV, by the NYHA criteria. 
17. Grade 2 or higher (per NCI CTCAE, Version 4.03) peripheral sensory or motor 
neuropathy at baseline. 
18. Major surgery less than 30 days prior to first dose of study drug.  Major surgery is any 
invasive operative procedure in which a more extensive resection is performed, eg, a 
body cavity is entered, organs are removed, or normal anatomy is altered. 
19. Live vaccines (in particular yellow fever vaccination) within 1 month prior to the first 
dose of study drug. 
20. Current severe immunodeficiency, or history of recurring or chronic infections, or 
underlying conditions which may further predispose patients to serious infection. 
9.4.3 
Withdrawal and Replacement of Subjects 
In accordance with the Declaration of Helsinki (Appendix 18.1) and applicable regulations, a 
subject has the right to discontinue treatment or withdraw from the study at any time and for 
any reason without prejudice to his or her future medical care by the physician or at the 
institution. 
9.4.3.1 Discontinuation of Study Drug 
A subject’s treatment with study drug may be discontinued for any of the following reasons: 
• Completed treatment 
• Progressive disease (PD) 
• AE 
• Investigator decision 


 
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• Patient decision, non-AE 
• Study termination by Sponsor 
• Other, non-AE 
Study drug must be discontinued in the case of pregnancy. 
The reason for treatment discontinuation will be recorded in the clinical records and the 
electronic Case Report Form (eCRF).  All subjects who discontinue treatment will undergo 
an end of treatment (EOT) visit (see Section 10.3).  These subjects will continue to be 
followed for survival and disease status (see Section 10.4) unless they withdraw from the 
study (see Section 9.4.3.2).  For replacement of withdrawn/discontinued subjects, see 
Section 9.4.3.3. 
9.4.3.2 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 
Subjects who withdraw from study will not be further contacted.  For replacement of 
withdrawn/discontinued subjects, see Section 9.4.3.3. 
9.4.3.3 Replacement of Subjects 
Subjects who discontinue from treatment or study will not be replaced; the sample size was 
calculated assuming a 10% drop-out rate. 
9.5 
Treatment 
9.5.1 
Treatments Administered 
The Investigator must ensure that the investigational product will be used only in accordance 
with the protocol.   


 
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Subjects randomized to the brentuximab vedotin arm will receive treatment as follows: 
• Brentuximab vedotin:  1.8 mg/kg IV infusion (over 30 minutes) on Day 1 of each 
21-day cycle 
• Rituximab:  375 mg/m2 IV infusion (per institutional standard of care) on Day 2 (+1) 
of each 21-day cycle 
• Bendamustine:  90 mg/m2 IV infusion (over 60 minutes) on Day 1 AND Day 2 (+1) 
of each 21-day cycle 
On each treatment day, bendamustine will be the last study drug administered, beginning 
30-60 minutes after completion of the brentuximab vedotin or rituximab infusion. 
Subjects randomized to the control arm will receive treatment as follows: 
• Rituximab:  375 mg/m2 IV infusion (per institutional standard of care) on Day 1 OR 
Day 2 (+1) of each 21-day cycle 
• Bendamustine:  90 mg/m2 IV infusion (over 60 minutes) on Day 1 AND Day 2 (+1) 
of each 21-day cycle 
On each treatment day, bendamustine will be the last study drug administered, beginning 
30-60 minutes after the completion of the rituximab infusions on days when multiple 
infusions are performed. 
Subjects will receive up to 6 cycles of rituximab and bendamustine with or without 
brentuximab vedotin.  Subjects randomized to brentuximab vedotin who respond to 
combination treatment and do not experience excessive toxicity may receive additional 
single-agent brentuximab vedotin (once every 21 days) for up to an additional 10 cycles (up 
to 16 total cycles of treatment). 
9.5.1.1 Required Premedication and Postmedication 
Prophylactic premedication with corticosteroids, antihistamines, and acetaminophen will be 
administered to all subjects within 60 minutes prior to infusion of the first study drug 
(brentuximab vedotin, rituximab, or bendamustine) each day of treatment.  Recommended 
doses for premedication are:  
1. Methylprednisolone 100 mg IV or equivalent (eg, dexamethasone 20 mg IV) 
2. Diphenhydramine 25–50 mg IV or equivalent (50 mg is required for Cycles 1 and 2; 
at the Investigator’s discretion, dose may be reduced to 25 mg subsequent to Cycle 2). 
3. Acetaminophen per institutional standard 
 


 
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Prophylactic medications can be repeated at 6-hour intervals per Investigator discretion, as 
long as study medication infusions are ongoing.  
For individual subjects who discontinue rituximab and bendamustine and continue on 
brentuximab vedotin, premedication for single-agent brentuximab vedotin may be reduced or 
discontinued at the discretion of the Investigator. 
The use of transfusions per institutional practice is permitted. The use of white blood cell 
growth factors (eg, G-CSF) is recommended for all patients.  Intrathecal prophylactic 
treatment for cerebral/meningeal disease is permitted at the discretion of the Investigator.  
Prophylactic antibiotics should be administered according to institutional standards.  The use 
of the NCCN 2015 guideline for the prevention and treatment of cancer-related infections is 
recommended.  Prophylactic antiemetics should be administered according to institutional 
standards. 
Subjects should be individually evaluated to assess the need for tumor lysis prophylaxis (eg, 
uric acid correction and hydration/fluid monitoring) prior to the first dose of brentuximab 
vedotin or rituximab.  Subjects should receive prophylaxis as appropriate per the US 
prescribing information (USPI) or EU Summary of Product Characteristics (SmPC) or 
institutional standard of care. 
9.5.1.2 Brentuximab Vedotin  
Detailed information describing the preparation, administration, and storage of brentuximab 
vedotin is located in the Pharmacy Manual. 
9.5.1.2.1 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 Manual for further information. 
9.5.1.2.2 Method of Procurement 
Brentuximab vedotin will be provided by the Sponsor. 
9.5.1.2.3 Dose and Administration 
Brentuximab vedotin, 1.8 mg/kg, will be administered on Day 1 of each 21-day cycle (up to 
6 cycles of combination treatment) by IV infusion given over approximately 30 minutes.  In 
the absence of infusion-related reactions, the infusion rate for all subjects should be 
calculated in order to achieve a 30-minute infusion period.  Brentuximab vedotin must not be 
administered as an IV push or bolus.  Brentuximab vedotin should not be mixed with other 
medications. 


 
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Brentuximab vedotin will be administered before bendamustine on Day 1 of each treatment 
cycle.   
Dosing is based on subject weight.  Doses will be adjusted for subjects who experience a 
≥10% change in weight from baseline.  An exception to weight-based dosing is made for 
subjects weighing greater than 100 kg; doses will be based on 100 kg for these individuals.  
Rounding is permissible within 5% of the nominal dose. 
9.5.1.2.4 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).  The vial should be gently swirled until the 
contents are completely dissolved.  The vial must not be shaken.  The reconstituted drug 
product should be inspected visually for any particulate matter and discoloration. 
The required volume of reconstituted drug product should be diluted into an infusion bag.  
The bag should be gently inverted to mix the solution.  The bag must not be shaken.  Prior to 
administration, the reconstituted and diluted drug product should be inspected visually for 
any particulate matter and discoloration. 
Detailed drug preparation instructions are provided in the Pharmacy Manual. 
9.5.1.2.5 Study Treatment Labeling and Packaging 
Drug product vials may be labeled as brentuximab vedotin, the US adopted name (USAN) 
and the International Nonproprietary Name (INN), or as SGN-35, the compound code; the 
2 names can be used interchangeably. 
9.5.1.2.6 Study Treatment Storage and Accountability 
It is forbidden to use investigational drug material for purposes other than as defined in this 
protocol. 
Study Treatment Storage 
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, the Investigator, 
or a duly designated person.  Brentuximab vedotin does not contain preservatives; therefore, 
opened and reconstituted vials of brentuximab vedotin should be used immediately.  If not 
used immediately, the in-use storage should not be longer than 24 hours.  It is recommended 
that brentuximab vedotin vials and solutions be protected from direct sunlight until the time 
of use.  Reconstituted vials and solutions must not be shaken. 


 
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Study Treatment Accountability 
Drug accountability instructions are provided in the Pharmacy Manual. 
9.5.1.3 Rituximab 
Rituximab is marketed in the US as Rituxan® by Genentech, Inc. (South San Francisco, CA 
USA) and in Europe as MabThera by Roche Registration Limited (Welwyn Garden City, 
Hertfordshire UK).  Please refer to the approved USPI or EU SmPC for detailed information. 
9.5.1.3.1 Description 
Rituximab is a genetically engineered chimeric murine/human monoclonal IgG1 kappa 
antibody directed against the CD20 antigen.   
Rituximab is marketed as Rituxan® in the US and as MabThera® in Europe and is a sterile, 
clear, colorless, preservative-free liquid concentrate for IV administration.  Rituxan and 
Mabthera are supplied at concentrations of 10 mg/mL in either 100 mg/10 mL or 
500 mg/50 mL single-use vials and are formulated in polysorbate 80 (0.7 mg/mL), sodium 
chloride (9 mg/mL), sodium citrate dihydrate (7.35 mg/mL), and Water for Injection.  The pH 
is 6.5.     
9.5.1.3.2 Method of Procurement 
Commercially available rituximab will be provided by the study sites from their usual 
suppliers or may be provided by the Sponsor. 
9.5.1.3.3 Dose and Administration 
Subjects will receive rituximab on Day 2 only (treatment arm) or on Day 1 OR Day 2 (+1; 
control arm) of each 21-day treatment cycle for a maximum of 6 cycles.  Rituximab 
(375 mg/m2) will be administered by IV infusion.  Rituximab administration will be 
performed according to local standard of care. 
9.5.1.3.4 Preparation 
Rituximab will be prepared for IV administration according to the USPI or the EU SmPC and 
local standard of care.   
9.5.1.3.5 Storage and Accountability 
Rituximab must be stored, distributed, and disposed of according to institutional practice and 
the USPI or EU SmPC. 


 
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9.5.1.4 Bendamustine 
Please refer to the approved USPI or EU SmPC for detailed information on bendamustine 
hydrochloride. 
9.5.1.4.1 Description 
Bendamustine hydrochloride is provided as a sterile non-pyrogenic white to off-white 
lyophilized powder in a single-use vial, and it is reconstituted with Sterile Water for 
Injection, USP.  The reconstituted formulation is further diluted according to local standard 
of care.   
9.5.1.4.2 Method of Procurement 
Bendamustine will be provided by the Sponsor. 
9.5.1.4.3 Dose and Administration 
Bendamustine will be administered at a dose of 90 mg/m2 by IV infusion given over 
60 minutes on Days 1 and 2 (+1 day) of each 21-day cycle for a maximum of 6 cycles.   
On days when bendamustine is administered with other study drugs (brentuximab vedotin or 
rituximab), bendamustine will be the last study drug administered, beginning 30-60 minutes 
after completion of the brentuximab vedotin or rituximab infusion. 
9.5.1.4.4 Preparation 
Bendamustine will be prepared for IV administration according to the USPI or the EU SmPC 
and local standard of care.  For sites using bendamustine hydrochloride liquid (TREANDA 
Injection; 45 mg/0.5 mL or 180 mg/2 mL solution):  Do not use closed system transfer 
devices (CSTD), adapters, and syringes containing polycarbonate or acrylonitrile-butadiene-
styrene (ABS), as TREANDA Injection is incompatible with ABS (refer to US FDA Safety 
Alerts for Human Medical Products [MedWatch] dated 10 March 2015). 
9.5.1.4.5 Storage and Accountability 
Bendamustine must be stored, distributed, and disposed of according to institutional practice 
and the USPI or EU SmPC. 
9.5.1.5 Management of Adverse Reactions 
9.5.1.5.1 Management of Infusion Reactions 
Infusion-related reactions may occur during the infusion of study treatment.  The infusions 
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 


 
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throughout the study according to institutional standards.  Supportive measures may include 
extending the infusion time and/or administering medications for infusion-related reactions.  
Subjects who experience a Grade 3 infusion-related reaction may potentially receive 
additional treatment at the discretion of the Investigator after discussion with the medical 
monitor.  Treatment should be discontinued for patients who experience Grade 4 
infusion-related reactions, unless the reaction can be attributed to a single agent, in which 
case the single agent must be discontinued. 
With the combination of bendamustine and brentuximab vedotin, infusion-related reactions 
and delayed-type hypersensitivity reactions have been observed. [37]  To reduce the risk of 
infusion reactions, all patients will be premedicated as described in Section 9.5.1.1. 
Rituximab can cause severe, including fatal, infusion reactions.  Severe reactions typically 
occur during the first infusion with time to onset of 30−120 minutes.  Rituximab-induced 
infusion reactions and sequelae include urticaria, hypotension, angioedema, hypoxia, 
bronchospasm, pulmonary infiltrates, acute respiratory distress syndrome, myocardial 
infarction, ventricular fibrillation, cardiogenic shock, anaphylactoid events, or death. 
Appropriate medical management (eg, glucocorticoids, epinephrine, bronchodilators, and 
oxygen) should be instituted for infusion reactions as needed.  Depending on the severity of 
the infusion reaction and the required interventions, rituximab may be temporarily or 
permanently discontinued.  Infusion may be resumed at a minimum 50% reduction in rate 
after symptoms have resolved.  Closely monitor patients with pre-existing cardiac or 
pulmonary conditions or who experienced prior cardiopulmonary adverse reactions. 
If anaphylaxis occurs, study treatment should be immediately and permanently discontinued. 
9.5.1.5.2 Management of Suspected PML 
Signs and symptoms of PML may include altered mental status, motor deficits such as 
hemiparesis or ataxia, visual disturbances, or higher cortical dysfunction, such as dysphasia 
or agnosia.  See the Investigator’s Brochure for further details.   
If PML is suspected, hold further brentuximab vedotin and rituximab dosing and undertake a 
diagnostic work-up including, but not limited to:  
• Neurologic examinations, as warranted 
• Brain magnetic resonance imaging (MRI) 
• PCR analysis for John Cunningham virus (JCV) in cerebrospinal fluid. 
If PML is confirmed, permanently discontinue study treatment. 


 
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9.5.1.5.3 Dose Modifications 
Brentuximab Vedotin 
At the Investigator’s discretion, the dose of brentuximab vedotin may be reduced as outlined 
in Table 1.  If toxicity is thought to be due specifically to brentuximab vedotin, the 
brentuximab vedotin dose may be reduced prior to reducing the dose of bendamustine.  
Subjects randomized to brentuximab vedotin who discontinue rituximab and/or 
bendamustine for any reason may continue to receive brentuximab vedotin per protocol.   
Doses reduced for treatment-related toxicity should not be re-escalated.  Dose delays of 
greater than 3 weeks are prohibited without approval of the Medical Monitor.  
Table 1: 
Recommended dose modifications for brentuximab vedotin-associated 
toxicity  
Toxicity 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Peripheral 
Neuropathy 
Continue at 
same dose level 
Withhold until toxicity resolves to Grade 1 or 
baseline, then resume treatment at 1.2 mg/kga  
Discontinue 
treatment 
Non-hematologic 
(except peripheral 
neuropathy) 
Continue at 
same 
dose level 
Continue at same 
dose level 
Withhold dose until 
toxicity is ≤ Grade 2 or 
has returned to baseline, 
then resume treatment at 
the same dose levelb. 
Withhold dose until 
toxicity is ≤ Grade 2 
or has returned to 
baseline, then reduce 
dose to 1.2 mg/kg 
and resume 
treatment, or 
discontinue at the 
discretion of the 
Investigatora, b, c. 
Hematologicd 
Continue at 
same dose level 
Continue at same 
dose level 
Withhold until toxicity resolves to ≤ Grade 2 or 
baseline, then resume treatment at the same dose 
levele.  Growth factor support (G-CSF or 
GM-CSF) should be considered for subsequent 
cycles.  If Grade 4 neutropenia recurs despite 
growth factor support, consider discontinuation 
or dose reduction to 1.2 mg/kg. 
G-CSF = granulocyte colony-stimulating factor; GM-CSF = granulocyte-macrophage colony-stimulating factor. 
a 
Dose reductions below 1.2 mg/kg are not allowed, and toxicities should be managed with dose delays. 
b 
Patients who develop Grade 3 or 4 electrolyte laboratory abnormalities may continue study treatment without 
interruption. 
c 
Treatment should be discontinued for patients who experience Grade 4 infusion-related reactions. 
d 
Support with blood product transfusions allowed per institutional standard of care. 
e 
Patients who develop Grade 3 or 4 lymphopenia may continue study treatment without interruption. 
f 
For Grade 3 neuropathy, investigator may withhold dose for 1 cycle and continue other therapy.  After resolution to 
≤ Grade 1, may resume brentuximab vedotin at 1.2 mg/kg 
Rituximab 
Dose modification of rituximab due to toxicity is allowed per institutional standards and 
according to the USPI or SmPC at the discretion of the Investigator, including 
discontinuation of treatment. 


 
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Bendamustine 
With the combination of bendamustine and brentuximab vedotin, an increased incidence of 
infusion-related reactions and delayed-type hypersensitivity reactions have been observed 
compared to each agent alone. [37]  Thus, all patients require premedication as described in 
Section 9.5.1.1. 
Permanently discontinue bendamustine if CrCL is <40 mL/min; use bendamustine with 
caution in lesser degrees of renal impairment.  
Dose modification of bendamustine due to toxicity is allowed per institutional standards and 
according to the USPI or SmPC at the discretion of the Investigator.  In general, 
bendamustine administration should be delayed for Grade 4 hematologic toxicity or clinically 
significant Grade ≥2 nonhematologic toxicity until sufficient recovery or resolution 
(Grade ≤1 or baseline for nonhematologic toxicity; ANC ≥1 × 109/L or platelets 
≥75 × 109/L).  Bendamustine can then be reinitiated at the discretion of the treating physician.  
Following Grade 4 hematologic toxicity or Grade ≥3 nonhematologic toxicity, the 
bendamustine dose should be decreased from 90 mg/m2 to 70 mg/m2, and, if toxicity recurs, 
the dose can be further decreased to 50 mg/m2.  Doses lower than 50 mg/m2 are not allowed. 
For patients receiving brentuximab vedotin, if the toxicity is thought to be due specifically to 
bendamustine, the bendamustine dose may be reduced prior to reducing the dose of 
brentuximab vedotin.   
9.5.2 
Blinding of Study Medication 
Not applicable; this is an open-label study. 
9.5.3 
Prior and Concomitant Therapy 
Subjects must not receive live vaccines (in particular yellow fever vaccination) or bleomycin 
while on treatment; subjects requiring these treatments will be discontinued from study.  Live 
vaccines must not be administered within 1 month of starting study treatment. 
Any other treatment (not explicitly excluded) considered necessary for the subject’s welfare 
may be given at the discretion of the Investigator.  Administration of concomitant 
medications must be reported in the appropriate section of the eCRF along with dates of 
administration and reasons for use.  
The use of corticosteroids to treat conditions other than DLBCL or follicular NHL grade 3b is 
permitted per institutional standard.  Systemic corticosteroids may be used to keep DLBCL 
symptoms under control prior to Cycle 1 Day 1 as long as the duration of steroid use is no 
longer than 14 days. 
Routine infectious prophylaxis per the NCCN 2015 guideline for the prevention and 
treatment of cancer-related infections is recommended. 


 
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The use of transfusions per institutional practice is permitted.  The use of white blood cell 
growth factors (eg, G-CSF) is recommended for all patients.  Intrathecal prophylactic 
treatment for cerebral/meningeal disease is permitted at the discretion of the Investigator.  
Prophylactic antiemetics should be administered according to institutional standard. 
Subjects may be eligible for allogenic SCT or ASCT following study treatment.  Subjects 
receiving these treatments should continue in study follow-up. 
All subjects who discontinue the study medication should be offered alternative treatment if 
applicable.  Treatment should be given according to normal clinical practice, after a 
termination visit (see Section 10.3). 
Contraception 
Acceptable methods of contraception include: hormonal (birth control pills, injections, 
implants), intrauterine device (IUD), intrauterine hormone-releasing system (IUS), vasectomy 
(for males), barrier methods (male and female condoms, diaphragms, and spermicides), 
bilateral tubal ligation, and complete abstinence.  Complete abstinence is acceptable when 
this is in line with the preferred and usual lifestyle of the patient.  (Periodic abstinence [eg, 
calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not 
acceptable methods of contraception.)  
9.5.4 
Treatment Compliance 
Brentuximab vedotin, rituximab, and bendamustine will be administered by qualified study 
site staff, and administration information will be recorded in the eCRF. 
9.5.5 
Assignment to Treatment 
After eligibility is determined and within 1 business day of planned first dose of study 
treatment, subjects will be randomized to treatment by a centralized interactive voice and 
web recognition system (IXRS).  Patients will be stratified at randomization by sAAIPI score 
(0 vs 1 vs 2–3) and disease status after initiation of frontline therapy (refractory or relapse 
<12 months vs relapse ≥12 months). 
9.6 
Efficacy and Safety Variables 
9.6.1 
Efficacy and Safety Measurements Assessed 
9.6.1.1 Efficacy Measurements 
Primary Efficacy Criteria: 
The primary efficacy endpoint of this study is ORR. 


 
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Subjects will undergo CT/PET (or CT and PET) at baseline, Cycle 2, and Cycle 6 or EOT for 
patients who do not have an assessment at the end of Cycle 6 or who do not complete 
6 cycles of treatment.  PET is no longer required after documented postbaseline 
FDG-negative PET.  Disease status will be assessed according to the 2014 Lugano 
Classification. [38]  Detailed response definitions are presented in Appendix 18.6. 
Secondary Efficacy Criteria: 
Secondary efficacy endpoints will be the following:  
• Progression-free survival (PFS) 
• Complete response (CR) rate   
• Best clinical response 
• Duration of response (DOR) 
• Overall survival (OS) 
See Section 13.6.4 for definitions. 
9.6.1.2 Pharmacokinetic/Pharmacodynamic Measurements 
Blood will be collected from subjects assigned to receive brentuximab vedotin (treatment 
arm) for measurement of ATA to brentuximab vedotin and both brentuximab vedotin and 
MMAE exposures, and pharmacodynamic (soluble CD30 and other chemokines/cytokines of 
interest) assessments (Section 11.8).  Tumor samples will be collected from all subjects for 
assessment of CD30 antigen expression, mRNA levels of CD30 and related genes, and COO 
classification.  
9.6.1.3 Safety Measurements 
Safety measurements will include type, incidence, severity, seriousness, and relatedness of 
AEs and laboratory abnormalities. 


 
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10. 
STUDY EVALUATIONS BY VISIT 
A full schedule of study procedures for the screening and treatment periods is provided in 
Table 2, and a schedule of follow-up assessments is provided in Table 3. 
 


 
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Table 2: 
Study Schedule 
 
Baseline/ 
Screening 
Enroll-
ment 
Cycles 1 
and 2 
Cycle 2 
only 
Cycles  
3-6 
Cycle 6 
only 
Cycles  
7+ g 
EOT  
visit 
Long-term 
Follow-up 
Visit Window 
D -28 
to 1 
D -7  
to 1 
D -7  
to 1 
D1(±1D) 
to D2 
D7- 
D14 
Day 15-21 
(+2D) 
D1(±1D) 
to D2 
Day 15-21 
(+2D) 
D1(±1D) 
to D2 
30-37 days 
post last dosea  
Screening/ 
Baseline and 
Safety 
Assessments 
Informed consent 
X 
 
Eligibility documentation submitted to Sponsor prior to 
 study start; randomizationd 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
Physical exam (incl. neuro. exam) 
 
X 
X 
Xo 
 
X 
 
X 
X 
 
Tumor specimen/CD30/histologyb,c 
X 
 
 
 
 
 
 
 
 
 
Height  
 
X 
 
 
 
 
 
 
 
 
Weight 
 
X 
X 
 
 
X 
 
X 
 
 
sAAIPI scoree 
X 
 
 
 
 
 
 
 
 
 
Electrocardiogram 
 
X 
X 
 
 
X 
 
X 
 
 
HBsAg / HBcAb  
 
X 
 
 
 
 
 
 
 
 
Pregnancy test 
 
X 
X 
 
 
X 
 
X 
X 
 
Treatment 
Combination treatmentf 
 
 
X 
 
 
X 
 
 
 
 
Single-agent brentuximab vedoting 
 
 
 
 
 
 
 
X 
 
 
ATA/PK/PD 
PK samplesh (treatment arm only) 
 
 
X 
 
 
X 
 
 
 
 
ATA samplesi (treatment arm only) 
 
 
X 
 
 
X 
 
 
X 
 
Pharmacodynamic samplesi 
 
 
X 
 
 
X 
 
 
X 
 
Response 
Assessment 
Lymphoma assessmentj 
 
 
X 
 
 
X 
 
X 
X 
See Table 3 
CT (chest, neck, abdomen, pelvis)k 
X 
 
 
 
X 
 
X 
 
Xa 
PETk,l 
X 
 
 
 
X 
 
X 
 
Xa 
Safety 
Assessments 
ECOG performance status 
 
X 
Xp 
X 
 
X 
 
X 
X 
 
Serum chemistry 
 
X 
X 
 
 
X 
 
X 
X 
 
Creatinine clearancem 
 
Xn 
Xn 
 
 
Xn 
 
 
 
 
Hematology 
 
X 
X 
X 
 
X 
 
X 
X 
 
Concomitant medications & 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 
 
AEs = adverse events; ATA = antitherapeutic antibodies; CT = computed tomography; D = Day; ECOG = Eastern Cooperative Oncology Group; EOT = end of 
treatment; HBsAg = hepatitis B surface antigen; HBcAb = hepatitis B core antibody; PD = pharmacodynamics; PET = positron emission tomography; 
PK = pharmacokinetics; sAAIPI = second-line age-adjusted International Prognostic Index. 
 


 
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Note:  All Day 1 procedures are before treatment unless otherwise specified. 
a. 
Response assessments and pregnancy test at EOT not required if 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. 
b. 
Centrally or locally assessed to enable enrollment.  Submission of the tumor block or approximately 15 unstained slides from a biopsy of relapsed 
disease (or initial diagnostic specimen if refractory) is required for subsequent central pathology disease confirmation and further evaluation of 
additional molecular biomarkers.   
c. 
Biopsy material will also be collected if available to evaluate changes in molecular biomarkers by different treatments.  No additional procedures will be 
conducted to obtain these research tissues; only available tissue will be used. 
d. 
Randomization to occur after eligibility is determined and within 1 business day of planned first dose of study treatment.  The site will contact the 
interactive voice and web recognition system (IXRS) for randomization assignment. 
e. 
ECOG performance status, lactate dehydrogenase (LDH), and disease stage must be recorded on the eCRF; historical values collected within 30 days of 
determination of the sAAIPI are acceptable. 
f 
Brentuximab vedotin, rituximab, and bendamustine OR rituximab and bendamustine. 
g. 
Patients who are responding to combination treatment with brentuximab vedotin and not experiencing excessive toxicity may receive single-agent 
brentuximab vedotin treatment following combination therapy.   
h. 
Predose (within 24 hours before the start of the brentuximab vedotin infusion) and postdose (within 30 minutes after the end of the infusion; samples for 
ADC and MMAE levels only). 
i 
Predose (within 24 hours before the start of the first infusion on Day 1). 
j. 
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.   
k. 
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; PET scan not required after documented postbaseline FDG-negative PET 
scan is obtained. 
l. 
Obtain until patient experiences progressive disease per Investigator assessment, death, or study closure, whichever comes first.  
m. 
Calculated using the Cockcroft-Gault formula. 
n. 
Creatinine clearance must be ≥40 mL/min and checked Day 1 of each cycle prior to infusion of bendamustine. 
o. 
At these visits the physical examination may be a brief, targeted examination, at the discretion of the investigator, to identify changes from baseline. 
p. 
Not required for Cycle 1. 
 


 
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Table 3: 
Schedule of Follow-up Assessments 
 
Time Point (relative to Cycle 1, Day 1) 
Annually after 
Month 36a 
(± 1 week) 
Visit Window 
Month 6 
(± 1 week) 
Month 9 
(± 1 week) 
Month 12 
(± 1 week) 
Month 15 
(± 1 week) 
Month 18 
(± 1 week) 
Month 21 
(± 1 week) 
Month 24 
(± 1 week) 
Month 30 
(± 1 week) 
Month 36 
(± 1 week) 
Response 
Assessment 
Lymphoma assessmentb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
CT (chest, neck, abdomen, pelvis) 
Xc,d 
 
Xc,d 
 
 
 
Xc,d 
 
Xc,d 
Xc,d 
PET 
Xc,d 
 
Xc,d 
 
 
 
Xc,d 
 
Xc,d 
Xc,d 
Survival status 
Xe 
Xe 
Xe 
Xe 
Xe 
Xe 
Xe 
Xe 
Xe 
Xe 
CT = computed tomography; PET = positron emission tomography. 
 
a. 
Long-term response assessments should continue annually after 36 months until death or study closure. 
b. 
Consists of the following:  physical examination, including neurological examination, patient medical history, including a thorough review of the 
patient’s current signs and symptoms, B symptoms, and concomitant medications.   
c. 
Obtain until patient experiences progressive disease per Investigator assessment, death, or study closure, whichever comes first.  
d. 
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; PET scan not required after documented postbaseline FDG-negative PET 
scan is obtained. 
e. 
Once a patient experiences progressive disease per Investigator assessment, survival status should be assessed until death or study closure, whichever 
comes first.  Collect information regarding subsequent anticancer therapies. 
 
 


 
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10.1 
Screening (Day -28 to 1) 
The following procedures will be performed within 28 days before beginning treatment: 
• Informed consent 
• Study eligibility per inclusion/exclusion criteria 
• Medical history, including lymphoma history (Section 11.1) 
• Collection / acquisition of tumor specimen for histology and CD30 assessment 
(Section 11.2) 
• sAAIPI score (see Section 11.3) 
• Baseline disease assessment (Section 11.9). 
The following procedures will be performed within 7 days before beginning treatment: 
• Height and weight (Section 11.5) 
• Standard 12-lead electrocardiogram (ECG; Section 11.4) 
• Physical examination (including neurologic assessment; Section 11.5) 
• Serum pregnancy test (women of childbearing potential only) 
• ECOG performance status (Section 11.5) 
• Clinical laboratory tests (hematology, serum chemistry, CrCL [calculated using the 
Cockcroft-Gault formula], HBsAg, and HBcAb; Section 11.7). 
From the time of informed consent through the day prior to study Day 1, only study protocol-
related AEs should be recorded, as well as any concomitant medications given for the 
treatment of these AEs.  
Within one business day of the planned start of treatment, the study site will contact the IXRS 
as directed in the study manual.  Contact information for the IXRS is provided in the study 
manual. 
10.2 
Treatment Period 
The subject will receive treatment in repeated 21-day cycles of rituximab and bendamustine 
with or without brentuximab vedotin (Section 9.5.1).  In addition, the following procedures 
will be performed at the indicated time points: 


 
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• Cycles 1 and 2, Day 1, pretreatment: 
o For subjects on the treatment arm (brentuximab vedotin) only: 
Pharmacokinetic (PK) and ATA sample collection (within 24 hours before 
beginning the brentuximab vedotin infusion; Section 11.8) 
o For all subjects: 
Pharmacodynamic sample collection (within 24 hours before beginning study 
treatment ; Section 11.8) 
o Weight (Section 11.5)  
o Lymphoma assessment (Section 11.6) 
o Standard 12-lead ECG (Section 11.4) 
o Serum pregnancy test (women of childbearing potential only) 
o Physical examination (including neurologic assessment; Section 11.5) 
o ECOG performance status (not required in Cycle 1; Section 11.5) 
o Pre-dose clinical laboratory tests (CrCL [calculated using the Cockcroft-Gault 
formula], hematology, and serum chemistry; Section 11.7). 
• Cycles 1 and 2, Day 1, posttreatment:   
o For subjects on the treatment arm (brentuximab vedotin) only: 
PK sample collection (within 30 minutes after completion of the brentuximab 
vedotin infusion; Section 11.8). 
• Cycles 1 and 2, Day 7-14:   
o Physical examination (Section 11.5) 
o Clinical laboratory tests (hematology; Section 11.7) 
o ECOG performance status (Section 11.5) 
• Cycle 2 only, Days 15-21: 
o Disease assessment (Section 11.9). 
• Cycles 3 – 6, Day 1, pretreatment: 
o For subjects on the treatment arm (brentuximab vedotin) only: 
PK and ATA sample collection (within 24 hours before beginning the 
brentuximab vedotin infusion; Section 11.8) 


 
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o For all subjects: 
Pharmacodynamic sample collection (within 24 hours before beginning study 
treatment; Section 11.8) 
o Weight (Section 11.5) 
o Lymphoma assessment (Section 11.6) 
o Standard 12-lead ECG (Section 11.4) 
o Serum pregnancy test (women of childbearing potential only) 
o Physical examination (including neurologic assessment; Section 11.5) 
o ECOG performance status (Section 11.5) 
o Pre-dose clinical laboratory tests (CrCL [calculated using the Cockcroft-Gault 
formula], hematology, and serum chemistry; Section 11.7). 
• Cycles 3 – 6, Day 1, posttreatment:   
o For subjects on the treatment arm (brentuximab vedotin) only: 
PK sample collection (within 30 minutes after completion of the brentuximab 
vedotin infusion; Section 11.8). 
• Cycle 6 only, Days 15-21: 
o Disease assessment (Section 11.9). 
• Cycles ≥7, Day 1, pretreatment: 
o Weight (Section 11.5) 
o Lymphoma assessment (Section 11.6) 
o Standard 12-lead ECG (Section 11.4) 
o Serum pregnancy test (women of childbearing potential only) 
o Physical examination (including neurologic assessment; Section 11.5) 
o ECOG performance status (Section 11.5) 
o Pre-dose clinical laboratory tests (hematology and serum chemistry; Section 11.7). 
Any AEs (Section 12.1) and serious adverse events (SAEs; Section 12.1.1), reported or 
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Section 12.1.4.  Any changes in concomitant medications will be recorded at each visit or as 
they are reported.   
10.3 
End of Treatment 
An EOT visit will be performed 30 – 37 days after the last dose of study treatment 
(brentuximab vedotin, rituximab, and/or bendamustine).  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.  At the EOT visit, the following assessments/procedures will be performed: 
• Pharmacodynamic sample collection (Section 11.8) 
• Serum pregnancy test (women of childbearing potential only; not required if 
performed at the last cycle of treatment) 
• Lymphoma assessment (Section 11.6) 
• Physical examination (including neurologic assessment; Section 11.5) 
• Disease assessment (Section 11.9) 
• ECOG performance status (Section 11.5) 
• Clinical laboratory tests (hematology and serum chemistry; Section 11.7). 
Response assessments and pregnancy test at EOT not required if performed at last cycle of 
treatment.  
Any AEs (Section 12.1) and SAEs (Section 12.1.1), reported or observed, will be reported on 
the eCRF, and SAEs will be reported as indicated in Section 12.1.4.  End-of-treatment 
evaluations should be obtained before the initiation of non-protocol therapy.  If the EOT visit 
occurs less than 30 days after the last treatment with brentuximab vedotin, the subject will be 
contacted by telephone 30 to 37 days after the last treatment with brentuximab vedotin to 
assess any AEs or changes in concomitant medications that may have occurred since the EOT 
visit. 
10.4 
Follow-Up 
At the times indicated in Table 3 until disease progression or study closure, subjects will 
undergo a follow-up visit.  Follow-up visits will include lymphoma assessments (all follow-
up visits; Section 11.6) and, at Months 6, 12, 24, 36, and annually thereafter, disease 
assessments (Section 11.9). 
After documented disease progression, the study site will contact the subject to assess 
survival and disease status (Section 11.10) on the same schedule.  In addition, the status of 


 
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any AEs of special interest ongoing at the time of last contact will be assessed at follow-up 
contacts.  Follow-up will continue until death or until the study is closed.  
10.5  End of Study/End of Follow-up 
The date the subject met criteria for study discontinuation and the reason for study 
discontinuation will be collected.   
 


 
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11. 
METHODS OF ASSESSMENT 
11.1 
Medical History 
A full medical history, including demographic information and history of DLBCL or 
follicular NHL grade 3b and prior treatments, will be performed at screening.  Any AEs 
(Section 12.1) occurring after screening and before the first dose of study drug will be 
included as medical history. 
11.2 
Histology / CD30 Assessment 
Histologically confirmed DLBCL or follicular NHL grade 3b must be determined by local 
pathology assessment.  CD30 expression will be determined by local or central laboratory 
visual assessment using IHC (anti-CD30 BerH2 antibody) to determine eligibility.   
If adequate tissue is not available or if disease has relapsed and the patient has not had a 
biopsy since the relapse was documented, a new biopsy must be obtained.  A new biopsy is 
not required for patients with refractory disease, provided a biopsy was obtained prior to the 
initiation of the most recent therapy.  
Submission of the tumor block or approximately 15 unstained slides from a biopsy of 
relapsed disease (or initial diagnostic specimen if refractory) is required for subsequent 
central pathology disease confirmation and further evaluation CD30 expression, and 
additional molecular biomarkers.   
Biopsy material will also be collected from patients who provided consent if available from 
biopsies performed anytime while the subject is on study to evaluate changes in molecular 
biomarkers by different treatments.  The tumor tissue will be used to conduct exploratory 
correlative studies.  Tumor based molecular biomarkers may include, but are not limited to 
COO, prognostic markers for lymphoma, and CD30 pathway related markers.  These will be 
conducted on the following tissues if available: 
• Leftover unstained slides or tumor tissue from a diagnostic biopsy will be obtained at 
baseline if available 
• Unstained slides or leftover tissue from a core biopsy obtained as part of standard-of-
care clinical intervention 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.  
Biospecimen Samples for Future Research 
In the United States, remaining de-identified unused blood and tissue will be retained by 
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future research includes, but is not limited to, the identification of targets for novel ADCs, the 
biology of ADC sensitivity and resistance mechanisms, and the identification of predictive 
pharmacodynamic biomarkers of response to ADCs.  Blood and tissue samples donated for 
future research will be retained for 25 years.  Outside the US 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. 
11.3 
Second-line Age-adjusted International Prognostic Index 
The sAAIPI is a score of 0, 1, 2, or 3, determined by adding 1 for each of the following risk 
factors present (see Appendix 18.5): 
• ECOG ≥2  
• LDH > ULN 
• Stage III or IV disease. 
ECOG performance status, LDH, and disease stage must be recorded on the eCRF; historical 
values collected within 30 days of determination of the sAAIPI are acceptable.  
11.4 
Electrocardiograms 
ECG recordings will be obtained.  A copy of all ECGs will be retained on site. 
For the purposes of screening, the Investigator or a designee will evaluate whether the ECG is 
normal or abnormal and whether it is clinically acceptable for inclusion, if abnormal. 
ECGs may be repeated for quality reasons, and additional ECGs may be collected by the 
Investigator for safety reasons.  Any posttreatment clinically relevant abnormal ECG findings 
will be reported as AEs. 
11.5 
Physical Examination, ECOG Performance Status, and Weight 
Physical examinations will be performed at the time points indicated in Table 2 and include 
assessments of the following body parts/systems: HEENT (head, ears, eyes, nose, and throat), 
neck, cardiovascular and respiratory systems, lymph nodes, abdomen, extremities, skin, and 
neurological.  
At the Day 7-14 visits in Cycles 1 and 2, the physical examination may be a brief, targeted 
examination, at the discretion of the investigator, to identify changes from baseline. 
ECOG performance status (Appendix 18.3) will be assessed at the time points indicated in 
Table 2 and recorded on the eCRF. 
Body weight (kg) will be measured and recorded at Day 1 of each study cycle.  Height (cm) 
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11.6 
Lymphoma Assessment 
The lymphoma assessment includes physical examination (see Section 11.5), patient medical 
history (including a thorough review of the patient’s current signs and symptoms), 
B symptoms, and concomitant medications.   
In the absence of radiological examination (Section 11.9), disease progression can be 
determined based on lymphoma assessment alone. 
11.7 
Clinical Laboratory Tests 
Blood samples will be taken for central and local laboratory analyses.  Local laboratory 
testing will include institutional standard tests for evaluating safety and making clinical 
decisions.  Hematology and serum chemistry assessments will be performed by the central 
laboratory to evaluate safety at the times indicated in Table 2.  The following parameters will 
be determined: 
Hematology:  White blood cell count with five-part differential (neutrophils, lymphocytes, 
monocytes, eosinophils, and basophils), red blood cell count, platelet count, and 
hemoglobin/hematocrit. 
Serum chemistry:  Albumin, alkaline phosphatase, ALT, AST, blood urea nitrogen, calcium, 
creatinine, chloride, LDH, phosphorus, potassium, sodium, total bilirubin, uric acid, lipase, 
amylase, glucose, and hemoglobin A1c (HbA1c; at screening only). 
Creatinine clearance will be calculated using the Cockcroft-Gault [39] formula: 
Male subjects 
Creatinine clearance (mL/min)  
= 
[140 – Age (years)] × body weight (kg) 
72 × serum creatinine 
Female subjects 
Creatinine clearance  (mL/min) = 
0.85 × 
[140 – Age (years)] × body weight (kg) 
 
72 × serum creatinine 
 
Pregnancy will be determined as indicated in Table 2 by serum β-hCG for females of 
childbearing potential.  
Baseline screening for hepatitis B infection by HBsAg and HBcAb.   
Additional laboratory assessments may be performed by certified local laboratories.   
Documentation of certification and laboratory normal ranges will be filed with study 
documentation. 
Additional and repeat laboratory safety testing may be performed at the discretion of the 
Investigator.   
11.8 
Pharmacokinetic, Pharmacodynamic, and Immunogenicity Samples 
Blood will be collected from subjects assigned to receive brentuximab vedotin (treatment 
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MMAE exposures.  PK samples will be collected during Cycles 1 – 6 within 24 hours before 
the start of the Day 1 brentuximab vedotin infusion (predose) and within 30 minutes after the 
end of the Day 1 brentuximab vedotin infusion (postdose).  Samples for ATA will be 
collected within 24 hours before the brentuximab vedotin infusion on Day 1 of each cycle 
(Cycles 1 – 6) and at EOT.  
Blood will be collected for pharmacodynamic assessments from all subjects.  Potential 
pharmacodynamics biomarkers include but are not limited to soluble CD30, inflammatory 
cytokines, and circulating tumour DNA.  Samples for pharmacodynamic studies will be 
collected from patients on both treatment arms within 24 hours before the first infusion on 
Day 1 of each cycle (Cycles 1 – 6) and at EOT.  
Sample handling and shipping information will be provided in the study manual.   
11.9 
Imaging/Response Assessment 
Response will be assessed according to the 2014 Lugano Classification [38] as outlined in 
Section 13.6.4.1 and Appendix 18.6.  Imaging studies will be performed at the time points 
indicated in Table 2 and Table 3.  Imaging will include: (1) diagnostic quality CT of neck, 
chest, abdomen, and pelvis and (2) PET.  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.  Additional 
PET scan is not required if a documented postbaseline FDG-negative PET scan has been 
obtained.  Specific imaging requirements will be outlined in a separate manual.  For PET 
scans performed while patients are receiving study therapy, Deauville scores of 1, 2, and 3 
will be regarded as negative, indicative of complete metabolic response (CMR), while scores 
of 4 and 5 will be regarded as positive. 
In the absence of radiological examination, disease progression can be determined based on 
lymphoma assessment (Section 11.6) alone. 
11.10 Long-term and Survival Status Follow-up 
At the times indicated in Table 3, lymphoma assessment and imaging will be performed until 
disease progression (for subjects who discontinued treatment for reasons other than disease 
progression); after disease progression, follow-up contact may be limited to telephone 
contact.  Follow-up data will include survival status, disease status, and poststudy treatment 
for lymphoma.  In addition, the status of any AEs will be assessed as specified in 
Section 12.1.3. 


 
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12. 
SAFETY MEASUREMENTS AND VARIABLES 
12.1 
Adverse Events  
12.1.1 Definitions  
Adverse Events 
According to the ICH E2A guideline Definitions and Standards for Expedited Reporting, and 
21 CFR 312.32, IND Safety Reporting, an AE is any untoward medical occurrence in a 
subject or clinical investigational subject administered a medicinal product and which does 
not necessarily have a causal relationship with this treatment. 
The following information should be considered when determining whether or not to record a 
test result, medical condition, or other incident on the Adverse Events and Pre-existing 
Conditions eCRF: 
• From the time of informed consent through the day prior to study Day 1, only study 
protocol-related AEs should be recorded.   
• All medical conditions present or ongoing predose on study Day 1 should be 
recorded.   
• All AEs (regardless of relationship to study drug) should be recorded from study 
Day 1 (during and postdose) through the end of the safety reporting period (see 
Section 12.1.3).  Complications that occur in association with any procedure (eg, 
biopsy) should be recorded as AEs whether or not the procedure was protocol 
mandated.  
• Changes in medical conditions and AEs, including changes in severity, frequency, or 
character, during the safety reporting period should be recorded. 
• In general, an abnormal laboratory value should not be recorded as an AE unless it is 
associated with clinical signs or symptoms, requires an intervention, results in an 
SAE, or results in study termination or interruption/discontinuation of study 
treatment.  When recording an AE resulting from a laboratory abnormality, the 
resulting medical condition rather than the abnormality itself should be recorded (eg, 
record “anemia” rather than “low hemoglobin”). 


 
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Serious Adverse Events 
An AE should be classified as an SAE if it meets one of the following criteria: 
Fatal: 
AE resulted in death 
 
Life threatening: 
The AE placed the patient at immediate risk of death.  This classification does not 
apply to an AE that hypothetically might cause death if it were more severe. 
 
Hospitalization: 
The AE required or prolonged an existing inpatient hospitalization.  Hospitalizations 
for elective medical or surgical procedures or treatments planned before the signing 
of informed consent in the study or routine check-ups are not serious AEs 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 AE 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 NCI CTCAE, Version 4.03 (Appendix 18.4).  These 
criteria are provided in the study manual. 
AE severity and seriousness are assessed independently.  ‘Severity’ characterizes the intensity 
of an AE.  ‘Serious’ is a regulatory definition and serves as a guide to the Sponsor for 
defining regulatory reporting obligations (see definition for SAEs). 
Relationship of the Adverse Event to Study Treatment 
The relationship of each AE to each study drug (brentuximab vedotin, rituximab, or 
bendamustine) should be evaluated by the Investigator using the following criteria: 


 
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Related: 
There is evidence to suggest a causal relationship between the drug and the AE, such 
as: 
• 
An event that is uncommon and known to be strongly associated with drug 
exposure (eg, 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 (eg, tendon 
rupture) 
Unrelated: 
Another cause of the AE is more plausible (eg, due to underlying disease or occurs 
commonly in the study population), or a temporal sequence cannot be established 
with the onset of the AE and administration of the study treatment, or a causal 
relationship is considered biologically implausible 
12.1.2 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 eCRF 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 eCRF: 
• 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 of individual symptoms.  
Grouping of symptoms into a diagnosis should only be done if each component sign and/or 
symptom is a medically confirmed component of a diagnosis as evidenced by standard 
medical textbooks.  If any aspect of a sign or symptom does not fit into a classic pattern of 
the diagnosis, report the individual symptom as a separate AE. 
Important exceptions for this study are adverse reactions associated with the infusion of study 
drug.  For infusion-related reactions, do not use the NCI CTCAE terms of ‘cytokine release 
syndrome,’ ‘acute infusion reaction,’ or ‘allergic or hypersensitivity reaction.’  Instead, record 
each sign or symptom as an individual AE.  If multiple signs or symptoms occur with a given 
infusion-related event, each sign or symptom should be recorded separately with its level of 
severity. 


 
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Recording Serious Adverse Events 
For SAEs, record the primary event on both the eCRF 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 eCRF. 
• 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 (eg, ‘malignant 
pleural effusion’, ‘spinal bone metastases’, ‘lymphadenopathy from underlying non-Hodgkin 
lymphoma’, ‘brain metastases’). 
Pregnancy 
Notification to Drug Safety:  Complete a Pregnancy Report Form for all pregnancies that 
occur from the time of first study drug dose until 6 months after the last dose of study 
drug(s), including any pregnancies that occur in the partner of a male study patient.  Only 
report pregnancies that occur in a male patient’s partner if the estimated date of conception is 
after the male patient’s first study drug dose.  Fax or email the Sponsor’s Drug Safety 
Department within 48 hours of becoming aware of a pregnancy. 
All pregnancies will be monitored for the full duration; all perinatal and neonatal outcomes 
should be reported.  Infants should be followed for a minimum of 8 weeks. 
Collection of data on the eCRF:  All pregnancies (as described above) that occur within 
30 days of the last dose of study drug(s) will also be recorded on the Adverse Events and 
Pre-Existing Conditions eCRF. 
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 12.1.1) should be reported as SAEs. 
12.1.3 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 
30 days after the last dose of study treatment (brentuximab vedotin, rituximab, and/or 


 
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bendamustine).  However, all study protocol-related AEs are to be collected from the time of 
informed consent.   
All SAEs that occur after the end of safety reporting period (ie, more than 30 days after the 
last dose of study treatment) 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, or study closure.  All non-serious AEs will be followed 
through the safety reporting period.  Ongoing non-serious AEs of interest (including but not 
limited to neuropathy) may be followed until resolution, return to baseline, or study closure. 
12.1.4 Serious Adverse Events Require Immediate Reporting 
Within 24 hours of observing or learning of an SAE, Investigators are to report the event to 
the Sponsor, regardless of the relationship of the event to the study treatment regimen. 
For initial SAE reports, available case details are to be recorded on an SAE form.  At a 
minimum, the following should be included: 
• 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 or emailed to the Drug 
Safety Department within 24 hours.  Refer to the contact information for the US and Europe 
provided on the SAE report form. 
Relevant follow-up information is to be submitted to the Sponsor as soon as it becomes 
available. 
12.1.5 Sponsor Safety Reporting Requirements 
According to the final rule amending the IND safety reporting requirements under 21 CFR 
312.32 and the FDA’s final guidance Safety Reporting Requirements for INDs and BA/BE 
Studies (December 2012), 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, the SAEs that do not require individual IND safety reports are disease 
progression events.   
These anticipated SAEs will be reviewed periodically by Seattle Genetics’ Drug Safety 
Department.  If, upon review, an SAE is occurring at a higher rate than that which would be 


 
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expected for the study population, then an IND safety report for the SAE will be submitted to 
the FDA. 
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.   
The Sponsor or its designee will report relevant SAEs to the relevant regulatory authorities 
and participating investigators, in accordance with FDA regulations (21 CFR 312.32), ICH 
guidelines, European Clinical Trials Directive (Directive 2001/20/EC), and/or local 
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on the details provided in the protocol.  Additional analyses may be added.  Table, listing, 
and figure shells will also be provided. 
13.4 
Randomization 
Patients will be randomized in a 1:1 manner to receive rituximab plus bendamustine with or 
without brentuximab vedotin stratified by sAAIPI score (0 vs 1 vs 2–3) and duration of 
remission after initiation of frontline therapy (refractory or relapse <12 months vs relapse 
≥12 months).  Randomization will be performed by an IXRS. 
13.5 
Analysis Populations 
13.5.1 Intent-to-Treat Population 
The intent-to-treat (ITT) Population will include all subjects who are randomized.  Subjects 
will be grouped according to their randomized treatment group assignment regardless of the 
treatment they actually received. 
13.5.2 Safety Population 
The safety population will include all subjects who are enrolled and received at least 1 dose 
of study treatment (brentuximab vedotin, rituximab, or bendamustine). 
13.5.3 Efficacy Evaluable Population  
The efficacy evaluable population will include all subjects who received at least 2 cycles of 
combination treatment at the recommended dose level and had a baseline tumor assessment 
and at least 1 postbaseline tumor assessment, or who had documented disease progression at 
any time after the first dose of combination therapy at the recommended dose level. 
13.5.4 Per-Protocol Population 
A per-protocol population may be defined in the SAP. 
13.6 
Statistical Methods 
13.6.1 Missing Data 
Missing data will not be imputed, with the exception of missing or partial dates; imputation 
rules for missing or partial dates will be specified in the SAP. 
Time-to-event data will be censored as outlined in Section 13.6.4.2.  All other missing data 
will be treated as missing. 


 
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13.6.2 Demographic and Baseline Data 
Demographic and baseline data will be summarized descriptively by treatment arm.  For 
continuous variables, descriptive statistics will include the mean, standard deviation (or 
standard error), median, range, and interquartile range.  For categorical variables, descriptive 
statistics will include the number and percent.  All demographic and baseline data will be 
listed. 
13.6.3 Subject Disposition 
The number and percent of subjects who complete combination treatment (6 cycles), who 
discontinue early, and the reasons for discontinuation will be summarized.  Disposition by the 
number of cycles of treatment will be summarized by treatment arm. 
13.6.4 Efficacy 
13.6.4.1 Response to Treatment 
Subjects will be assigned a response status based on imaging and lymphoma assessments at 
each visit as indicated in Table 2 and Table 3.  The response criteria are based upon the 2014 
Lugano Classification [38] and are summarized in Appendix 18.6.  
ORR will be analyzed based on the ITT population.  ORR is defined as the proportion of 
patients who achieve a CR (including CMR) or PR (including partial metabolic response, or 
PMR) as best response to combination therapy on study.  The final analysis of ORR between 
the 2 treatment arms, which is planned to occur after all patients have completed combination 
therapy or discontinued therapy, will be compared and tested at a 1-sided 0.05 alpha level 
using a Cochran-Mantel-Haenszel (CMH) test stratified by the randomization strata.  A 
statistically significant improvement of 22%, assuming a 50% ORR in the control arm and 
72% in the brentuximab vedotin arm, would be considered clinically meaningful. 
If fewer than 5 subjects have sAAIPI score of 0 or 1, then these groups will be combined for 
analyses.  If fewer than 5 subjects have sAAIPI score of 2-3, then this group will be 
combined with sAAIPI score of 1 for analyses. 
13.6.4.2 Secondary Efficacy Endpoints 
Time-to-event variables (DOR, PFS, and OS) will be summarized descriptively using the 
Kaplan-Meier estimate.  Additional details will be provided in the SAP.  Secondary 
endpoints will be assessed in the ITT population (except as indicated below).   
CR Rate and Best Clinical Response:  Response (CR/CMR, PR/PMR, ORR 
[CR/CMR+PR/PMR], stable disease [SD] or no metabolic response [NMR], and 
PD/progressive metabolic disease [PMD]) will be summarized descriptively by treatment 
arm.  CR rate will be summarized with 95% confidence intervals.  Best clinical response is 


 
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defined as the best response (ordered from best to worst as CR/CMR, PR/PMR, SD/NMR, or 
PD/PMD) observed during the treatment period.   
DOR (for PR/CR and CR): DOR is defined as the time from first observation of response 
(PR/PMR+CR/CMR or CR/CMR) to disease progression/relapse, receipt of subsequent 
lymphoma chemotherapy other than the components of the study treatment regimen (excludes 
post-treatment consolidative radiotherapy, post-treatment chemotherapy for the purpose of 
mobilizing peripheral blood stem cells, and consolidative autologous or allogeneic SCT), or 
death from any cause, whichever occurs first.  Durations will be assessed in the ITT 
population with a PR or CR and calculated separately for subjects with CR/CMR and those 
with PR/PMR+CR/CMR combined.  For subjects with a remission without subsequent 
disease progression/relapse or death on study, DOR will be censored at the time of the last 
disease assessment demonstrating a lack of disease progression/relapse.  If more than one 
date of progression is available, the earliest date will be used to determine DOR.  Full 
censoring rules will be provided in the SAP.  Subjects who receive SCT in remission will 
continue to be followed for DOR. 
Progression-free Survival: PFS is defined as the time from randomization to first 
documentation of disease progression/relapse, death due to any cause, or receipt of 
subsequent lymphoma chemotherapy other than the components of the study treatment 
regimen (excludes post-treatment consolidative radiotherapy, post-treatment chemotherapy 
for the purpose of mobilizing peripheral blood stem cells, and consolidative autologous or 
allogeneic SCT), whichever occurs first.  For subjects without disease progression/relapse or 
death on study, PFS will be censored at the time of the last on-study disease assessment 
demonstrating a lack of disease progression/relapse.  If more than one date of progression is 
available, the earliest date will be used to determine PFS.  Full censoring rules will be 
provided in the SAP.  Subjects who receive SCT in remission will continue to be followed 
for PFS. 
Overall Survival: OS is defined as the time from randomization to death due to any cause. 
For subjects not known to have died at the conclusion of the study, OS will be censored at the 
time the subject was last known to be alive (including follow-up data). 
13.6.5 Pharmacokinetics and Pharmacodynamics 
Pharmacokinetic (brentuximab vedotin ADC and MMAE) and ATA to brentuximab vedotin 
results will be summarized.  Pharmacodynamic results (eg, CD30 expression, mRNA levels 
of CD30 and related genes, COO classification, and soluble CD30 and other 
chemokines/cytokines of interest) will be summarized by study arm.  
13.6.6 Safety 
Safety data will be summarized for the safety population.   
Exposure to treatment will be summarized separately for brentuximab vedotin, rituximab, 
and bendamustine.  Summaries will include the duration of treatment, number of doses 




 
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The IDMC will review unblinded safety data after the first 20 patients have completed 
2 cycles of therapy and then every 6 months thereafter and as needed.  The IDMC may 
recommend changes such as, but not limited to, lowering the starting dose level of 
bendamustine to 70 mg/m2 in the case of unacceptable toxicity at the proposed starting dose.  
In addition, the IDMC will communicate major safety concerns and recommendations 
regarding study modification or termination to Seattle Genetics, Inc. senior management at 
any time during the conduct of the study.  
The safety analysis will evaluate the overall safety of the treatment regimens including, but 
not limited to, the following parameters: 
• Type, incidence, severity, seriousness, and relatedness of AEs 
• Incidence of Grade ≥3 neuropathy 
• Type, incidence, and severity of laboratory abnormalities 
• Incidence and severity of infusion-related and hypersensitivity reactions. 
Details of the safety reviews will be provided in the IDMC charter. 
In addition, a formal interim analysis for futility will be performed after 50% of patients have 
completed the Cycle 2 response assessment (Section 13.6.8).  The primary efficacy endpoint 
(ORR) will be used to assess futility.  The IDMC will provide recommendations to the 
Sponsor’s Data Review Board as to appropriate study direction. 


 
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14. 
MONITORING PROCEDURES (QUALITY ASSURANCE) 
The Sponsor has ethical, legal, and scientific obligations to conduct this study in accordance 
with established research principles and ICH GCP guidelines.  As such, in order to fulfill 
these obligations and to maintain current of study progress, the Sponsor's monitors or 
representatives will visit the investigative sites during study conduct, in addition to 
maintaining telephone and written communication.  On-site visits, telephone calls, and 
regular inspection of the eCRFs will be conducted in order to assess subject enrollment, 
compliance with protocol procedures, completeness and accuracy of data entered on the 
eCRFs, verification of eCRF data against original source documents, and occurrence of AEs.  
The Investigator must provide the monitor with full access to all source and study documents. 
14.1 
Routine Monitoring 
Sponsor assigned monitors will conduct regular site visits to the investigational facilities for 
the purpose of monitoring various aspects of the study.  The Investigator must agree to 
Sponsor-authorized personnel having direct access to the clinical (or associated) files and 
clinical study supplies (dispensing and storage areas) for all study subjects considered for 
study entry for the purpose of verifying entries made in the eCRF, and assist with their 
activities, if requested.  Adequate time and space for monitoring visits should be made 
available by the Investigator. 
The site must complete the eCRFs in a timely manner and on an ongoing basis to allow 
regular review by the study monitor. 
Whenever a subject name is revealed on a document that is to be collected for the Sponsor, 
the name must be blacked out permanently by the site personnel, leaving the initials visible, 
and annotated with the subject number as identification. 
14.2 
Inspections and Auditing Procedures 
The Sponsor or its representative may conduct audits at the investigative sites including, but 
not limited to, drug supply, presence of required documents, the informed consent process, 
and comparison of eCRFs with source documents.  All medical records (progress notes) must 
be available for audit.  The Investigator agrees to participate with audits conducted at a 
convenient time in a reasonable manner. 
Government regulatory authorities may also inspect the Investigator during or after the study.  
The Investigator or designee should contact the Sponsor/CRO immediately if this occurs.  
The Investigator must cooperate fully with regulatory authorities or other audits conducted at 
a convenient time in a reasonable manner. 
The purpose of an audit is to assess whether ethics, regulatory, and quality requirements are 
fulfilled. 


 
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15. 
STUDY MANAGEMENT AND MATERIALS 
15.1 
Electronic Case Report Forms 
An eCRF will be used to store and transmit subject information.  The file structure and 
format for the eCRF will be provided by the Sponsor or their representative and should be 
handled in accordance with the instructions provided. 
The eCRF must be reviewed, electronically signed, and dated by the Investigator. 
Access to the eCRF will be strictly password protected and limited to personnel directly 
participating in the study.  Data should be entered into the eCRF completely by examining 
personnel or the study coordinator.  The eCRF must be completed as soon as possible after 
any subject evaluation or communication.  If data is to be changed due to erroneous input or 
other reason, an electronic audit trail will track these changes.  The eCRFs and computers 
that store them must be accessible to study monitors and other regulatory auditors. 
15.2 
Data Collection 
During each study visit, a physician participating in the study will maintain medical records 
to document all significant observations.  At a minimum, these notes will contain: 
• The date of the visit and the corresponding day or visit in the study schedule (eg, 
screening, Cycle 1, Day 1, etc.). 
• General condition and status remarks by the subject, including any significant medical 
findings.  The severity, frequency, duration, and resolution of any reported AE, and 
the Investigator's assessment as to whether or not the reported AE is study drug-
related. 
• Changes in concomitant medications or dosages. 
• A general reference to the procedures completed. 
• The signature or initials of all physicians making an entry in the medical record 
(progress notes). 
In addition, any contact with the subject via telephone or other means that provides 
significant clinical information will also be documented in the medical record (progress 
notes), as described above.  
Information from the medical records (progress notes) and other source documents will be 
promptly transcribed to the appropriate section of the eCRF. 
Changes to information in the medical record (progress notes), eCRF, and other source 
documents will be initialed and dated on the day the change is made by the Investigator or 


 
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designee.  If the reason for the change is not apparent, a brief explanation for the change will 
be written adjacent to the change. 
15.3 
Source Documents Maintenance 
Source documents contain the results of original observations and activities of a clinical 
investigation.  Source documents include, but are not limited to, medical records (progress 
notes), computer printouts, screening logs and recorded data from automated instruments.  
All source documents from this study will be maintained by the Investigator and made 
available for inspection by authorized persons.  The original signed informed consent for 
each subject shall be filed with records kept by the Investigator and a copy shall be given to 
the subject. 
15.4 
Record Maintenance 
All data derived from the study will remain the property of Seattle Genetics, Inc. 
Records must be retained in accordance with the current ICH Guidelines on GCP.  All 
essential study documents including records of subjects, source documents, eCRFs, and study 
drug inventory must be kept on file. 
US FDA regulations (21 CFR 312.62[c]) require that records and documents pertaining to the 
conduct of this study and the distribution of investigational drug, including eCRFs, consent 
forms, laboratory test results, and medical inventory records, must be retained by the 
Principal Investigator for 2 years after marketing application approval.  If no application is 
filed, these records must be kept for 2 years after the investigation is discontinued and the US 
FDA and the applicable national and local health authorities are notified.  The Sponsor or 
their representative will notify the Principal Investigator of these events. 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region, or until at least 2 years have elapsed since the 
formal discontinuation of clinical development of the investigational products.  However, 
essential documents may be retained for a longer period if required by the applicable 
regulatory requirements or by agreement with the Sponsor.  The Sponsor is responsible for 
informing the Investigator when these documents need no longer be retained. 
The Investigator will not dispose of any records relevant to this study without written 
permission from the Sponsor and will provide the Sponsor the opportunity to collect such 
records.  The Investigator shall take responsibility for maintaining adequate and accurate 
source documents of all observations and data generated during this study.  Such 
documentation is subject to inspection by the Sponsor, its representatives, and regulatory 
authorities. 


 
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If an Investigator moves, withdraws from an investigation or retires, the responsibility for 
maintaining the records may be transferred to another person who will accept responsibility.  
Notice of transfer must be made to and agreed on by the Sponsor. 
15.5 
Confidentiality 
All information obtained during the conduct of the study with respect to the subject’s state of 
health will be regarded as confidential.  For disclosure of any such information, an agreement 
will be obtained in writing.  
The Investigator must ensure that each subject’s anonymity is maintained.  On eCRFs and 
other documents submitted to the Sponsor or the CRO, subjects must not be identified by 
name.  Instead, subjects will only be known by their initials and by the unique subject number 
allocated to them in order to ensure confidentiality on all study documentation.  Subjects will 
retain this unique number throughout the study.  The Investigator will keep a separate log of 
these codes. 
In order to comply with government regulatory guidelines and to ensure subject safety, it may 
be necessary for the Sponsor and its representative, the CRO personnel, the local research 
review board, or the US FDA to review subjects’ medical records as they relate to this study.  
Only the subject’s unique number on the eCRF will identify him/her, but their full names 
may be made known to a drug regulatory authority or other authorized government or health 
care officials, if necessary, and to personnel designated by the Sponsor. 
Documents that are not for submission to the Sponsor or the CRO (eg, consent forms) will be 
maintained by the Investigator in strict confidence, except to the extent necessary to allow 
monitoring by the Sponsor and the CRO and auditing by regulatory authorities.  No 
documents identifying subjects by name will leave the investigative site, and subject identity 
will remain confidential in all publications related to the study. 


 
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16. 
ADMINISTRATION PROCEDURES 
16.1 
Regulatory Approval 
Seattle Genetics, Inc., or their appointed agents, will be responsible for ensuring that 
appropriate regulatory authority approvals are obtained, according to local country 
requirements. 
16.2 
Protocol Amendments 
In accordance with ICH Topic E6 (R1) Guideline for GCP, the Investigator should not 
implement any deviation from or changes to the protocol without agreement by the Sponsor 
and documented approval from the IRB/IEC of a protocol amendment, except where 
necessary to eliminate an immediate hazard(s) to study subjects, or when the change(s) 
involves only logistical or administrative aspects of the study (eg, change in monitor[s] or 
change of telephone number[s]). 
Any change to the protocol must be handled as a protocol amendment.  Any potential 
amendment must be approved by the Sponsor.  A written amendment must be submitted to 
the appropriate regulatory authorities and to the IRB/IEC assuming this responsibility.  The 
Investigator must await IRB/IEC approval of protocol amendments before implementing the 
changes, except where necessary to eliminate apparent immediate hazard to subjects.  In these 
cases, the IRB/IEC must be notified within 5 days of the change. 
All amendments to the protocol must be approved in writing by both the appropriate 
regulatory authorities and the IRB/IEC, except for administrative amendments, which require 
notification but not written approval.  Once approved, the protocol amendment will be 
distributed to all recipients of the original protocol, with instructions to append the 
amendment to the protocol. 
If, in the judgment of the local IRB/IEC, the Investigator and/or Sponsor, the protocol 
amendment alters the study design, procedures and/or increases the potential risk to the 
subject, the currently approved written informed consent form will require modification.  The 
modified informed consent form must also be reviewed and approved by the Sponsor, 
appropriate regulatory authorities, and the IRB/IEC.  In such cases, repeat informed consent 
must be obtained from subjects enrolled in the study before participation continues. 
16.3 
Protocol Adherence and Deviations 
The protocol must be read thoroughly, and the instructions must be followed.  However, 
exceptions will be made in emergency situations when the protection, safety, and well-being 
of the subject requires immediate intervention based on the judgment of the Investigator or a 
responsible, appropriately trained, and credentialed professional(s) designated by the 
Investigator as a sub-Investigator.  


 
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In the event of a significant protocol deviation due to an emergency, accident, or error, the 
Investigator or designee must contact the Medical Monitor at the earliest possible time by 
telephone.  This allows for an early joint decision to be made as to whether or not the subject 
should continue study treatment.  The Investigator, the Sponsor, and the Medical Monitor 
will document this decision. 
16.4  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, 
the Investigator will provide the Sponsor, its licensees and collaborators, applicable 
regulatory agencies, and the 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 be 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. 
16.5 
Publication Policy 
The details of the processes of producing and reviewing publications and presentations based 
on the data from this study will be described in the Clinical Trial Agreement between Seattle 
Genetics, Inc., and the institution of the Investigator. 
16.6 
Clinical Study Report 
A final clinical study report will be prepared according to the ICH guideline on Structure and 
Contents of Clinical Study Reports.  A final clinical study report will be prepared regardless 
of whether the study is completed or prematurely terminated.   


 
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16.7 
Contractual and Financial Details 
The Investigator (and/or, as appropriate, the hospital administrative representative) and the 
Sponsor will sign a clinical study agreement prior to the start of the study, outlining overall 
Sponsor and Investigator responsibilities in relation to the study.  The contract should 
describe whether costs for pharmacy, laboratory and other protocol-required services are 
being paid directly or indirectly.   
16.8 
Insurance, Indemnity, and Compensation 
Seattle Genetics, Inc., undertakes to maintain an appropriate clinical study insurance policy. 
Deviations from the study protocol - especially the prescription of a dose other than that 
scheduled in the study protocol, other modes of administration, other indications, and longer 
treatment periods - are not permitted and shall not be covered by the statutory subject 
insurance scheme. 
16.9 
Discontinuation of the Study 
This study may be terminated by the Sponsor.  The study may also be terminated prematurely 
at any time when agreed to by both the Investigator and the Sponsor as being in the best 
interests of subjects and justified on either medical or ethical grounds.  In terminating the 
study, Seattle Genetics, Inc., the CRO (PRA Health Sciences), and the Investigator will 
ensure that adequate consideration is given to the protection of the subjects’ interests. 
16.10 Study Center File Management 
The Investigator is responsible for assuring that the Study Center File is maintained.  The 
Study Center File will contain, but will not be limited to, the information listed below: 
1. Investigator’s Brochure; 
2. Current, signed version of the protocol and any previous versions of the protocol; 
3. Protocol amendments (if applicable); 
4. Operations Manual (if applicable); 
5. Current informed consent form (blank) and any previous versions of the informed 
consent form; 
6. Curricula Vitae of Investigator(s) and sub-Investigator (s) and photocopy of their 
respective license(s) where required by law; Original US FDA Form 1572 (for all 
studies conducted under US Investigational New Drug [IND] regulations), signed by 
all Principal Investigators.  The names of any sub-Investigators must appear on this 
form.  Investigators must also complete all regulatory documentation as required by 
ICH GCP and by local or national regulations; 


 
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7. Documentation of IRB/IEC approval of the protocol, the informed consent form, any 
protocol amendments, and any informed consent form revisions; 
8. All correspondence between the Investigator, IRB/IEC, and the Sponsor/CRO relating 
to study conduct; 
9. Laboratory certification(s); 
10. Monitoring log; 
11. Study drug invoices; 
12. Signature list of all staff completing eCRFs; and 
13. Signature list of all staff completing drug accountability summaries. 
 


 
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37. LaCasce A, Bociek RG, Matous J, et al.  Brentuximab vedotin in combination with 
bendamustine for patients with Hodgkin lymphoma who are relapsed or refractory after 
frontline therapy.  56th ASH Annual Meeting and Exposition, San Francisco, CA USA.  
Abstract 293; 8 December 2014. 


 
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38. Cheson BD, Fisher RI, Barrington SF, et al.  Recommendations for initial evaluation, 
staging, and response assessment of Hodgkin and non-Hodgkin Lymphoma: The Lugano 
Classification.  J Clin Oncol 32(27): 3059-67, 2014. 
39. Cockcroft DW and Gault MH.  Prediction of creatinine clearance from serum creatinine.  
Nephron 16 (1): 31-41, 1976. 


 
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18. APPENDICES 
18.1 
Appendix 1: Declaration of Helsinki 
 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
Ethical Principles for Medical Research Involving Human Subjects 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
53th WMA General Assembly, Washington 2002 (Note of Clarification on paragraph 29 added) 
55th WMA General Assembly, Tokyo 2004 (Note of Clarification on Paragraph 30 added) 
59th WMA General Assembly, Seoul, October 2008 
64th WMA General Assembly, Fortaleza, Brazil, October 2013 
 
A. Preamble 
 
1. 
The World Medical Association (WMA) has developed the Declaration of Helsinki as a 
statement of ethical principles for medical research involving human subjects, including 
research on identifiable human material and data. 
 
 
The Declaration is intended to be read as a whole and each of its constituent paragraphs 
should be applied with consideration of all other relevant paragraphs. 
 
2. 
Consistent with the mandate of the WMA, the Declaration is addressed primarily to 
physicians.  The WMA encourages others who are involved in medical research 
involving human subjects to adopt these principles.  
 
General Principles 
3. 
The Declaration of Geneva of the WMA binds the physician with the words, “The 
health of my patient will be my first consideration,” and the International Code of 
Medical Ethics declares that, “A physician shall act in the patient's best interest when 
providing medical care.” 
 
4. 
It is the duty of the physician to promote and safeguard the health, well-being and rights 
of patients, including those who are involved in medical research.  The physician's 
knowledge and conscience are dedicated to the fulfilment of this duty. 
 
5. 
Medical progress is based on research that ultimately must include studies involving 
human subjects. 
 


 
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6. 
The primary purpose of medical research involving human subjects is to understand the 
causes, development and effects of diseases and improve preventive, diagnostic and 
therapeutic interventions (methods, procedures and treatments).  Even the best proven 
interventions must be evaluated continually through research for their safety, 
effectiveness, efficiency, accessibility and quality. 
 
7. 
Medical research is subject to ethical standards that promote and ensure respect for all 
human subjects and protect their health and rights. 
 
8. 
While the primary purpose of medical research is to generate new knowledge, this goal 
can never take precedence over the rights and interests of individual research subjects. 
 
9. 
It is the duty of physicians who are involved in medical research to protect the life, 
health, dignity, integrity, right to self-determination, privacy, and confidentiality of 
personal information of research subjects.  The responsibility for the protection of 
research subjects must always rest with the physician or other health care professionals 
and never with the research subjects, even though they have given consent. 
 
10. Physicians must consider the ethical, legal and regulatory norms and standards for 
research involving human subjects in their own countries as well as applicable 
international norms and standards.  No national or international ethical, legal or 
regulatory requirement should reduce or eliminate any of the protections for research 
subjects set forth in this Declaration. 
 
11. Medical research should be conducted in a manner that minimises possible harm to the 
environment. 
 
12. Medical research involving human subjects must be conducted only by individuals with 
the appropriate ethics and scientific education, training and qualifications.  Research on 
patients or healthy volunteers requires the supervision of a competent and appropriately 
qualified physician or other health care professional. 
 
13. Groups that are underrepresented in medical research should be provided appropriate 
access to participation in research. 
 
14. Physicians who combine medical research with medical care should involve their 
patients in research only to the extent that this is justified by its potential preventive, 
diagnostic or therapeutic value and if the physician has good reason to believe that 
participation in the research study will not adversely affect the health of the patients 
who serve as research subjects. 
 
15. Appropriate compensation and treatment for subjects who are harmed as a result of 
participating in research must be ensured. 
 


 
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Risks, Burdens and Benefits  
16. In medical practice and in medical research, most interventions involve risks and 
burdens. 
 
 
Medical research involving human subjects may only be conducted if the importance of 
the objective outweighs the risks and burdens to the research subjects. 
 
17. All medical research involving human subjects must be preceded by careful assessment 
of predictable risks and burdens to the individuals and groups involved in the research 
in comparison with foreseeable benefits to them and to other individuals or groups 
affected by the condition under investigation. 
 
 
Measures to minimise the risks must be implemented.  The risks must be continuously 
monitored, assessed and documented by the researcher.  
 
18. Physicians may not be involved in a research study involving human subjects unless 
they are confident that the risks have been adequately assessed and can be satisfactorily 
managed. 
 
 
When the risks are found to outweigh the potential benefits or when there is conclusive 
proof of definitive outcomes, physicians must assess whether to continue, modify or 
immediately stop the study. 
   
 
Vulnerable Groups and Individuals 
19. Some groups and individuals are particularly vulnerable and may have an increased 
likelihood of being wronged or of incurring additional harm. 
 
 
All vulnerable groups and individuals should receive specifically considered protection. 
 
20. Medical research with a vulnerable group is only justified if the research is responsive 
to the health needs or priorities of this group and the research cannot be carried out in a 
non-vulnerable group.  In addition, this group should stand to benefit from the 
knowledge, practices or interventions that result from the research. 
 
Scientific Requirements and Research Protocols  
21. Medical research involving human subjects must conform to generally accepted 
scientific principles, be based on a thorough knowledge of the scientific literature, other 
relevant sources of information, and adequate laboratory and, as appropriate, animal 
experimentation.  The welfare of animals used for research must be respected. 
 
22. The design and performance of each research study involving human subjects must be 
clearly described and justified in a research protocol. 
 
• The protocol should contain a statement of the ethical considerations involved and 
should indicate how the principles in this Declaration have been addressed.  The 


 
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protocol should include information regarding funding, Sponsors, institutional 
affiliations, potential conflicts of interest, incentives for subjects and information 
regarding provisions for treating and/or compensating subjects who are harmed as a 
consequence of participation in the research study. 
 
• In clinical trials, the protocol must also describe appropriate arrangements for post-
trial provisions. 
 
Research Ethics Committees 
23. The research protocol must be submitted for consideration, comment, guidance and 
approval to the concerned research ethics committee before the study begins.  This 
committee must be transparent in its functioning, must be independent of the 
researcher, the Sponsor and any other undue influence and must be duly qualified.  It 
must take into consideration the laws and regulations of the country or countries in 
which the research is to be performed as well as applicable international norms and 
standards but these must not be allowed to reduce or eliminate any of the protections for 
research subjects set forth in this Declaration.  
 
 
The committee must have the right to monitor ongoing studies.  The researcher must 
provide monitoring information to the committee, especially information about any 
serious adverse events.  No amendment to the protocol may be made without 
consideration and approval by the committee.  After the end of the study, the 
researchers must submit a final report to the committee containing a summary of the 
study’s findings and conclusions.  
 
Privacy and Confidentiality  
24. Every precaution must be taken to protect the privacy of research subjects and the 
confidentiality of their personal information. 
 
Informed Consent  
25. Participation by individuals capable of giving informed consent as subjects in medical 
research must be voluntary.  Although it may be appropriate to consult family members 
or community leaders, no individual capable of giving informed consent may be 
enrolled in a research study unless he or she freely agrees. 
 
26. In medical research involving human subjects capable of giving informed consent, each 
potential subject must be adequately informed of the aims, methods, sources of funding, 
any possible conflicts of interest, institutional affiliations of the researcher, the 
anticipated benefits and potential risks of the study and the discomfort it may entail, 
post-study provisions and any other relevant aspects of the study.  The potential subject 
must be informed of the right to refuse to participate in the study or to withdraw 
consent to participate at any time without reprisal.  Special attention should be given to 
the specific information needs of individual potential subjects as well as to the methods 
used to deliver the information. 
 


 
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After ensuring that the potential subject has understood the information, the physician 
or another appropriately qualified individual must then seek the potential subject’s 
freely-given informed consent, preferably in writing.  If the consent cannot be expressed 
in writing, the non-written consent must be formally documented and witnessed. 
 
 
All medical research subjects should be given the option of being informed about the 
general outcome and results of the study. 
 
27. When seeking informed consent for participation in a research study the physician must 
be particularly cautious if the potential subject is in a dependent relationship with the 
physician or may consent under duress.  In such situations the informed consent must 
be sought by an appropriately qualified individual who is completely independent of 
this relationship. 
 
28. For a potential research subject who is incapable of giving informed consent, the 
physician must seek informed consent from the legally authorised representative.  These 
individuals must not be included in a research study that has no likelihood of benefit for 
them unless it is intended to promote the health of the group represented by the 
potential subject, the research cannot instead be performed with persons capable of 
providing informed consent, and the research entails only minimal risk and minimal 
burden. 
 
29. When a potential research subject who is deemed incapable of giving informed consent 
is able to give assent to decisions about participation in research, the physician must 
seek that assent in addition to the consent of the legally authorised representative.  The 
potential subject’s dissent should be respected. 
 
30. Research involving subjects who are physically or mentally incapable of giving consent, 
for example, unconscious patients, may be done only if the physical or mental condition 
that prevents giving informed consent is a necessary characteristic of the research 
group.  In such circumstances the physician must seek informed consent from the 
legally authorised representative.  If no such representative is available and if the 
research cannot be delayed, the study may proceed without informed consent provided 
that the specific reasons for involving subjects with a condition that renders them 
unable to give informed consent have been stated in the research protocol and the study 
has been approved by a research ethics committee.  Consent to remain in the research 
must be obtained as soon as possible from the subject or a legally authorised 
representative. 
 
31. The physician must fully inform the patient which aspects of their care are related to the 
research.  The refusal of a patient to participate in a study or the patient’s decision to 
withdraw from the study must never adversely affect the patient-physician relationship. 
 
32. For medical research using identifiable human material or data, such as research on 
material or data contained in biobanks or similar repositories, physicians must seek 


 
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informed consent for its collection, storage and/or reuse.  There may be exceptional 
situations where consent would be impossible or impracticable to obtain for such 
research.  In such situations the research may be done only after consideration and 
approval of a research ethics committee. 
 
Use of Placebo 
33. The benefits, risks, burdens and effectiveness of a new intervention must be tested 
against those of the best proven intervention(s), except in the following circumstances: 
 
• Where no proven intervention exists, the use of placebo, or no intervention, is 
acceptable; or 
 
• Where for compelling and scientifically sound methodological reasons the use of any 
intervention less effective than the best proven one, the use of placebo, or no 
intervention is necessary to determine the efficacy or safety of an intervention  
 
• and the patients who receive any intervention less effective than the best proven one, 
placebo, or no intervention will not be subject to additional risks of serious or 
irreversible harm as a result of not receiving the best proven intervention.  
 
• Extreme care must be taken to avoid abuse of this option. 
 
Post-Trial Provisions 
34. In advance of a clinical trial, Sponsors, researchers and host country governments 
should make provisions for post-trial access for all participants who still need an 
intervention identified as beneficial in the trial.  This information must also be 
disclosed to participants during the informed consent process. 
 
Research Registration and Publication and Dissemination of Results 
35. Every research study involving human subjects must be registered in a publicly 
accessible database before recruitment of the first subject. 
 
36. Researchers, authors, Sponsors, editors and publishers all have ethical obligations with 
regard to the publication and dissemination of the results of research.  Researchers have 
a duty to make publicly available the results of their research on human subjects and are 
accountable for the completeness and accuracy of their reports.  All parties should 
adhere to accepted guidelines for ethical reporting.  Negative and inconclusive as well 
as positive results must be published or otherwise made publicly available.  Sources of 
funding, institutional affiliations and conflicts of interest must be declared in the 
publication.  Reports of research not in accordance with the principles of this 
Declaration should not be accepted for publication. 
 
Unproven Interventions in Clinical Practice 
37. In the treatment of an individual patient, where proven interventions do not exist or 
other known interventions have been ineffective, the physician, after seeking expert 


 
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advice, with informed consent from the patient or a legally authorised representative, 
may use an unproven intervention if in the physician's judgement it offers hope of 
saving life, re-establishing health or alleviating suffering.  This intervention should 
subsequently be made the object of research, designed to evaluate its safety and 
efficacy.  In all cases, new information must be recorded and, where appropriate, made 
publicly available. 


 
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18.2 
Appendix 2: Elements of Informed Consent 
 
ELEMENTS OF INFORMED CONSENT 
 
Both the informed consent discussion and the written informed consent form and any other 
written information to be provided to subjects should include explanations of the following: 
 
• That the study involves research. 
• The purpose of the study. 
• The study treatment(s) and the probability for random assignment to each treatment. 
• The study procedures to be followed including all invasive procedures. 
• The subject’s responsibilities. 
• Those aspects of the study that are experimental. 
• The reasonably foreseeable risks or inconveniences to the subject and, when applicable, 
to an embryo, fetus, or nursing infant. 
• The reasonably expected benefits.  When there is no intended clinical benefit to the 
subject, the subject should be made aware of this. 
• The alternative procedure(s) or course(s) of treatment that may be available to the subject, 
and their important potential benefits and risks. 
• The compensation and/or treatment available to the subject in the event of study-related 
injury. 
• The anticipated prorated payment, if any, to the subject for participating in the study. 
• The anticipated expenses, if any, to the subject for participating in the study. 
• That the subject’s participation in the study is voluntary and that the subject may refuse to 
participate or withdraw from the study, at any time, without penalty or loss of benefits to 
which the subject is otherwise entitled. 
• That the monitor(s), the auditor(s), the IRB/IEC, and the regulatory authority(ies) will be 
granted direct access to the subject’s original medical records for verification of clinical 
study procedures and/or data, without violating the confidentiality of the subject, to the 
extent permitted by the applicable laws and regulations and that, by signing a written 
informed consent form, the subject or the subject’s legally acceptable representative is 
authorizing such access. 
• That records identifying the subject will be kept confidential and, to the extent permitted 
by the applicable laws and/or regulations, will not be made publicly available.  If the 
results of the study are published, the subject’s identity will remain confidential. 
• That the subject or the subject’s legally acceptable representative will be informed in a 
timely manner if information becomes available that may be relevant to the subject’s 
willingness to continue participation in the study. 


 
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• The person(s) to contact for further information regarding the study and the rights of 
study subjects, and whom to contact in the event of study-related injury. 
• The foreseeable circumstances and/or reasons under which the subject’s participation in 
the study may be terminated. 
• The expected duration of the subject’s participation in the study. 
• The approximate number of subjects involved in the study. 


 
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18.3 
Appendix 3: Eastern Cooperative Oncology Group Performance Status 
Grade 
Criterion 
0 
Fully active, able to carry on all pre-disease activities without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, for example light housework or office work. 
2 
Ambulatory and capable of all self-care but unable to carry out work activities.  Up and about 
more than 50% of waking hours. 
3 
Capable of only limited self care, confined to bed or chair 50% or more of waking hours. 
4 
Completely disabled, cannot carry on any self-care, totally confined to bed or chair. 
5 
Death 
 
 
 


 
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18.4 Appendix 4: Common Terminology Criteria for Adverse Events (CTCAE; v 
4.03) 
The current version of the NCI CTCAE (Version 4.03) can be viewed on-line at the NCI web 
site: 
http://ctep.cancer.gov/reporting/ctc.html 


 
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18.5 
Appendix 5: Second-line Age-adjusted International Prognostic Index  
Add 1 for each of the following risk factors present: 
• ECOG ≥2  
• LDH > ULN 
• Stage III or IV disease 
A score of 0 (no risk factors present) indicates low risk, 1 (any 1 risk factor present), 
indicates low-intermediate risk, 2 (any 2 risk factors present), indicates high-intermediate 
risk, and 3 (all 3 risk factors present), indicates high risk. 
 
From:  Hamlin PA, Zelenetz AD, Kewalramani T, et al.  Age-adjusted International 
Prognostic Index predicts autologous stem cell transplantation outcome for patients with 
relapsed or primary refractory diffuse large B-cell lymphoma.  Blood 102 (6): 1989-96, 2003.  


 
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18.6 
Appendix 6: Response Assessment – The Lugano Classification 
Response and Site  
PET-CT–Based Response  
CT-Based Response 
Complete Response 
Complete metabolic response  
Complete radiologic response (all of the following) 
Lymph nodes and extralymphatic 
sites 
Score 1, 2, or 3* with or without a residual mass on 5PS† 
It is recognized that in Waldeyer’s ring or extranodal sites with high 
physiologic uptake or with activation within spleen or marrow (eg, with 
chemotherapy or myeloid colony-stimulating factors), uptake may be 
greater than normal mediastinum and/or liver.  In this circumstance, 
complete metabolic response may be inferred if uptake at sites of initial 
involvement is no greater than surrounding normal tissue even if the 
tissue has high physiologic uptake 
Target nodes/nodal masses must regress to ≤1.5 cm in LDi 
No extralymphatic sites of disease 
Nonmeasured lesion 
Not applicable 
Absent 
Organ enlargement 
Not applicable 
Regress to normal 
New lesions 
None 
None 
Bone marrow 
No evidence of FDG-avid disease in marrow 
Normal by morphology; if indeterminate, IHC negative 
Partial Response 
Partial metabolic response  
Partial remission (all of the following) 
Lymph nodes and extralymphatic 
sites 
Score 4 or 5† with reduced uptake compared with baseline and residual 
mass(es) of any size 
At interim, these findings suggest responding disease 
When a lesion is too small to measure on CT, assign 5 mm × 
5 mm as the default value 
When no longer visible, 0 × 0 mm 
For a node >5 mm × 5 mm, but smaller than normal, use actual 
measurement for calculation 
Nonmeasured lesion 
Not applicable 
Absent/normal, regressed, but no increase 
Organ enlargement 
Not applicable 
Spleen must have regressed by >50% in length beyond normal 
New lesions 
None 
None 
Bone marrow 
Residual uptake higher than uptake in normal marrow but reduced 
compared with baseline (diffuse uptake compatible with reactive changes 
from chemotherapy allowed).  If there are persistent focal changes in the 
marrow in the context of a nodal response, consideration should be given 
to further evaluation with MRI or biopsy or an interval scan 
Not applicable 
No Response or Stable Disease 
No metabolic response  
Stable disease 
Target nodes/nodal masses, 
extranodal lesions 
Score 4 or 5 with no significant change in FDG uptake from baseline at 
interim or end of treatment 
>50% decrease from baseline in SPD of up to 6 dominant, 
measurable nodes and extranodal sites; no criteria for 
progressive disease are met 
Nonmeasured lesion 
Not applicable 
No increase consistent with progression 
Organ enlargement 
Not applicable 
No increase consistent with progression 
New lesions 
None 
None 
Bone marrow 
No change from baseline 
Not applicable 
continued 


 
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Appendix 6: Response Definitions (continued) 
Progressive Disease 
Progressive metabolic disease  
Progressive disease requires at least 1 of the following 
Individual target nodes/nodal 
masses 
Score 4 or 5 with an increase in intensity of uptake from baseline  
and/or 
PPD progression 
Extranodal lesions 
New FDG-avid foci consistent with lymphoma at interim or EOT 
assessment 
An individual node/lesion must be abnormal with:  
LDi >1.5 cm  
and 
Increase by ≥50% from PPD nadir  
and 
An increase in LDi or SDi from nadir 
0.5 cm for lesions ≤2 cm 
1.0 cm for lesions >2 cm 
In the setting of splenomegaly, the splenic length must increase 
by >50% of the extent of its prior increase beyond baseline (eg, 
a 15-cm spleen must increase to >16 cm).  If no prior 
splenomegaly, must increase by at least 2 cm from baseline 
Nonmeasured lesion 
None 
New or clear progression of preexisting nonmeasured lesions 
New lesions 
New FDG-avid foci consistent with lymphoma rather than another 
etiology (eg, infection, inflammation).  If uncertain regarding etiology of 
new lesions, biopsy or interval scan may be considered 
Regrowth of previously resolved lesions 
A new node >1.5 cm in any axis 
A new extranodal site >1.0 cm in any axis; if <1.0 cm in any 
axis, its presence must be unequivocal and must be attributable 
to lymphoma 
Assessable disease of any size unequivocally attributable to 
lymphoma 
Bone marrow 
New or recurrent FDG-avid foci 
New or recurrent involvement  
Abbreviations: 5PS, 5-point scale; CT, computed tomography; FDG, fluorodeoxyglucose; IHC, immunohistochemistry; LDi, longest transverse diameter of a lesion; MRI, 
magnetic resonance imaging; PET, positron emission tomography; PPD, cross product of the LDi and perpendicular diameter; SDi, shortest axis perpendicular to the LDi; SPD, 
sum of the product of the perpendicular diameters for multiple lesions. 
* 
A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the time of an interim scan.  However, in trials involving PET where de-
escalation is investigated, it may be preferable to consider a score of 3 as inadequate response (to avoid undertreatment).  Measured dominant lesions: Up to 6 of the largest 
dominant nodes, nodal masses, and extranodal lesions selected to be clearly measurable in two diameters.  Nodes should preferably be from disparate regions of the body and 
should include, where applicable, mediastinal and retroperitoneal areas.  Non-nodal lesions include those in solid organs (eg, liver, spleen, kidneys, lungs), gastrointestinal 
involvement, cutaneous lesions, or those noted on palpation.  Nonmeasured lesions: Any disease not selected as measured, dominant disease and truly assessable disease should be 
considered not measured.  These sites include any nodes, nodal masses, and extranodal sites not selected as dominant or measurable or that do not meet the requirements for 
measurability but are still considered abnormal, as well as truly assessable disease, which is any site of suspected disease that would be difficult to follow quantitatively with 
measurement, including pleural effusions, ascites, bone lesions, leptomeningeal disease, abdominal masses, and other lesions that cannot be confirmed and followed by imaging.  
In Waldeyer’s ring or in extranodal sites (eg, gastrointestinal tract, liver, bone marrow), FDG uptake may be greater than in the mediastinum with complete metabolic response, but 
should be no higher than surrounding normal physiologic uptake (eg, with marrow activation as a result of chemotherapy or myeloid growth factors). 
† 
PET 5PS: 1, no uptake above background; 2, uptake ≤ mediastinum; 3, uptake > mediastinum but ≤ liver; 4, uptake moderately > liver; 5, uptake markedly higher than 
liver and/or new lesions; X, new areas of uptake unlikely to be related to lymphoma (see Barrington SF, Mikhaeel NG, Kostakoglu L, et al.  Role of Imaging in the Staging and 
Response Assessment of Lymphoma: Consensus of the International Conference on Malignant Lymphomas Imaging Working Group.  J Clin Oncol 32(27): 3048-58, 2014). 
From 38. Cheson BD, Fisher RI, Barrington SF, et al.  Recommendations for Initial Evaluation, Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: 


 
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The Lugano Classification.  J Clin Oncol 32(27): 3059-67, 2014. 




 
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18.8 
Appendix 8: Summary of Changes in V02 
RATIONALE: 
 
The protocol was updated to add the EudraCT number to the cover page. 
 
SUMMARY OF CHANGES: 
Section:  Cover page: 
Replace: 
Protocol Number: 
SGN35-023 
 
IND number:  
71634 
Study Phase:  
2  
 
 
 
With: 
Protocol Number: 
SGN35-023 
 
IND number:  
71634 
Study Phase:  
2  
 
 
EudraCT Number: 2015-001671-51 
 
 
Section:  Global 
Replace: 
Version 01 Date 01 June 2015 
 
With: 
Version 02, Date 17 June 2015 


 
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18.9 
Appendix 9: Summary of Changes in V03 
RATIONALE: 
 
The protocol was amended for the following reasons: 
• To provide additional detail in the study objective and endpoints. 
• To exclude patients unable to give consent by removing the option for a legally 
acceptable representative to consent. 
• Revise the entry criteria to 
o Increase the required platelet count for study entry to ≥75,000/μL  
o Require females of childbearing potential and males who have partners of 
childbearing potential to use 2 effective contraceptive methods and to specify 
which methods are considered effective 
o Exclude subjects with  
 major surgery less than 30 days prior to first dose of study drug 
 live vaccines within 1 month of first dose of study drug 
 current severe immunodeficiency 
 history of recurring or chronic infections or with underlying conditions 
which may further predispose patients to serious infection 
 concomitant use of bleomycin. 
• Require study discontinuation in the case of pregnancy. 
o Require pretreatment assessment for hepatitis B (HBsAg and HBcAb). 
o Require electrocardiogram assessment at each cycle. 
o Require pregnancy testing (for women of childbearing potential only) at each 
cycle and require that pregnancy testing be by serum β-hCG 
• Clearly specify the requirement for physical examinations and require physical 
examination to include neurological examination at all time points where physical 
examination is required, including where it is required as part of the lymphoma 
assessment. 
• To clarify that sampling for brentuximab and MMAE exposure was only required for 
subjects on the treatment arm (brentuximab vedotin) and to extend this sampling to 
all combination treatment cycles (up to Cycle 6). 
• To limit ATA sampling to the treatment arm (brentuximab vedotin). 
• Clarify that safety reporting is required in all regions of study conducted as required 
by local and international standards. 
• To update the reference to the NCCN guideline for the prevention and treatment of 
cancer-related infections. 
• To require physical examination at screening. 


 
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• To correct an error in the Table of Events (extraneous footnote), add physical 
examination, add clarification regarding CT and PET, and make updates consistent 
with the other changes contained in this amendment. 
• To provide additional details regarding the collection, handling, and storage of 
biological samples. 
• To add glucose to the required battery of clinical laboratory tests. 
• To update and add additional details regarding safety reporting contacts. 
o To specify that subjects may become eligible for transplant (allogenic HCT or 
ASCT) on study. 
• To make minor editorial and formatting corrections. 
 
SUMMARY OF CHANGES: 
Section:  Synopsis, Objectives, Primary Objective, page 4 
Replace:  
• To compare the objective response rate (ORR) between the 2 arms 
 
With: 
• To compare the objective response rate (ORR) among subjects with relapsed or 
refractory CD30-positive diffuse large B-cell lymphoma (DLBCL) receiving 
rituximab and bendamustine plus brentuximab vedotin (treatment arm) with 
that among subjects receiving rituximab and bendamustine alone (control arm) 
 
 
Section:  Synopsis, Objectives, Secondary Objectives, page 4 
Replace:  
• To compare progression-free survival (PFS) between the 2 arms 
• To compare the complete remission (CR) rate between the 2 arms  
• To compare duration of response (DOR) between the 2 arms  
• To compare overall survival (OS) between the 2 arms  
• To evaluate the safety and tolerability of the 2 arms  
With: 
• To compare progression-free survival (PFS) among subjects with relapsed or 
refractory CD30-positive DLBCL receiving rituximab and bendamustine plus 


 
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brentuximab vedotin (treatment arm) with that among subjects receiving 
rituximab and bendamustine alone (control arm) 
• To compare the complete remission (CR) rate between the 2 arms of the study 
• To compare duration of response (DOR) between the 2 arms of the study 
• To compare overall survival (OS) between the 2 arms of the study 
• To evaluate the safety and tolerability of the 2 arms of the study 
 
 
Section:  Synopsis, Objectives, Exploratory Objectives, page 4; 8.3, Exploratory Objectives, 
page 24 
Add:  
• To characterize the incidence of antitherapeutic antibodies (ATA) to brentuximab 
vedotin among subjects with relapsed or refractory CD30-positive DLBCL 
receiving rituximab and bendamustine plus brentuximab vedotin  
 
 
Section:  Synopsis, Study Design and Methodology, page 4 
Add:  
…for the treatment of patients with relapsed or refractory CD30-positive diffuse large B-cell 
lymphoma (DLBCL) and follicular NHL grade 3b after failure of second-line … 
 
 
Section:  Synopsis, Inclusion Criteria, page 5; 9.4.1, Inclusion Criteria, page 28-29;  
Criterion 6b: 
Replace:  
b. 
Platelet count ≥50,000/µL (unless documented bone marrow involvement) 
With: 
b. 
Platelet count ≥75,000/µL (unless documented bone marrow involvement) 
 
Criterion 7: 
Replace:  
7. 
Females of childbearing potential must have a negative serum or urine beta human 
chorionic gonadotropin (β-hCG) pregnancy test result within 7 days prior to the first 
dose of study drug. 


 
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With: 
7. 
Females of childbearing potential must have a negative serum beta human chorionic 
gonadotropin (β-hCG) pregnancy test result within 7 days prior to the first dose of 
study drug. 
 
Criterion 8: 
8. 
Females of childbearing potential and 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 brentuximab vedotin or 12 months following the 
last dose of rituximab, whichever is later. 
With: 
8. 
Females of childbearing potential and males who have partners of childbearing 
potential must agree to use 2 effective contraceptive methods during the study and 
for 6 months following the last dose of brentuximab vedotin or 12 months following 
the last dose of rituximab, whichever is later. 
 
Criterion 9: 
Replace:  
9. 
Patients or their legally authorized representative must provide written informed 
consent. 
With: 
9. 
Patients must be willing and able to provide written informed consent. 
 
 
Section:  Synopsis, Exclusion Criterion, page 6; 9.4.2, Exclusion Criteria, page 29-30 
Criterion 5: 
Add:  
5. 
Chemotherapy, radiotherapy, biologics, and/or other antitumor treatment with 
immunotherapy that is not completed 4 weeks prior to first dose of study drug.  
Concomitant use of other systemic antineoplastic agents (including bleomycin) 
while on study is excluded. 
 


 
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New criteria: 
18. 
Major surgery less than 30 days prior to first dose of study drug.  Major surgery 
is any invasive operative procedure in which a more extensive resection is 
performed, eg, a body cavity is entered, organs are removed, or normal anatomy 
is altered. 
19. 
Live vaccines (in particular yellow fever vaccination) within 1 month prior to the 
first dose of study drug. 
20. 
Current severe immunodeficiency, or history of recurring or chronic infections, 
or with underlying conditions which may further predispose patients to serious 
infection. 
 
 
Section:  Synopsis, Study Evaluations, Primary Efficacy Criteria, page 7;  
Replace:  
The primary efficacy endpoint of this study is ORR 
With: 
The primary efficacy endpoint of this study is objective response rate (ORR) as assessed by 
the 2014 Lugano Classification.   
 
 
Section:  Synopsis, Study Evaluations, Secondary Efficacy Criteria, page 7; 8.4.2, Secondary 
Endpoints, page 25; 9.6.1.1, Efficacy Measurements, page 41 
Replace:  
• PFS 
• CR rate  
… 
• DOR 
• OS 
With: 
• Progression-free survival (PFS)  
• Complete response (CR) rate  
… 
• Duration of response (DOR) 
• Overall survival (OS) 


 
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Section:  Synopsis, Study Evaluations, Pharmacokinetic/Pharmacodynamic Measurements, 
page 7; 8.4.3, Pharmacokinetic / Pharmacodynamic Measurements, page 25; 9.6.1.2, 
Pharmacokinetic/Pharmacodynamic Measurements, page 41 
Replace:  
Blood will be collected for ATA to brentuximab vedotin, brentuximab vedotin and MMAE 
exposures, and pharmacodynamic (soluble CD30 and other chemokines/cytokines of interest) 
assessments.  Tumor samples will be collected for assessment of CD30 antigen expression, 
mRNA levels of CD30 and related genes, and cell of origin classification.  
With: 
Blood will be collected from subjects assigned to receive brentuximab vedotin (treatment 
arm) for measurement of ATA to brentuximab vedotin, and both brentuximab vedotin and 
MMAE exposures, and. 
Blood will be collected from all subjects for pharmacodynamic (soluble CD30 and other 
chemokines/cytokines of interest) assessments.  Tumor samples will be collected from all 
subjects for assessment of CD30 antigen expression, mRNA levels of CD30 and related 
genes, and cell of origin classification.  
 
 
Section:  4, List of Abbreviations and Definition of Terms, page 15 
Add: 
PMD  
Progressive metabolic disease  
 
 
Section:  5.3, Subject Information and Consent, page 17-18 
Delete: 
The Investigator will explain the benefits and risks of participation in the study to each 
subject or the subject’s legally acceptable representative and obtain written informed 
consent… 
 
Each subject’s original consent form, personally signed and dated by the subject or by the 
subject’s legally acceptable representative, and by the person who conducted the informed 
consent discussion, will be retained by the Investigator.   
 
Change: 
The consent form may need to be revised during the study should important new information 
become available that may be relevant to the safety of the subject.  In this instance approval 
should always be given by the IRB/IEC and existing subjects should be informed of the 
changes and reconsented.  This is documented in the same way as previously described. 


 
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To: 
The consent form may need to be revised during the study should important new information 
become available that may be relevant to the safety of the subject.  In this instance approval 
should always be given by the IRB/IEC.  Subjects on treatment should be informed of 
the changes and reconsented if the consent was updated for safety reasons.  This is 
documented in the same way as previously described. 
 
 
Section:  6, Investigators and Study Administrative Structure, page 19 
Replace: 
Contact information for the central pathologist will be provided in the study manual. 
 
With: 
Ventana Medical Systems, Inc. 
1910 E. Innovation Park Drive 
Tucson, Arizona 85755 USA 
+1 (520) 887 2155 
(800) 227 2155 
 
 
Section:  8.1, Primary Study Objective, page 24 
Replace:  
• To compare the ORR between the 2 arms 
With: 
• To compare the objective response rate (ORR) among subjects with relapsed or 
refractory CD30-positive DLBCL receiving rituximab and bendamustine plus 
brentuximab vedotin (treatment arm) with that among subjects receiving 
rituximab and bendamustine alone (control arm) 
 
 
Section:  8.2, Secondary Study Objective, page 24 
Replace:  
• To compare PFS between the 2 arms 
• To compare the CR rate between the 2 arms 
• To compare duration of response (DOR) between the 2 arms  


 
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• To compare OS between the 2 arms 
• To evaluate the safety and tolerability of the 2 arms 
 
With: 
• To compare progression-free survival (PFS) among subjects with relapsed or 
refractory CD30-positive DLBCL receiving rituximab and bendamustine plus 
brentuximab vedotin (treatment arm) with that among subjects receiving 
rituximab and bendamustine alone (control arm) 
• To compare the complete remission (CR) rate between the 2 arms of the study 
• To compare duration of response (DOR) between the 2 arms of the study 
• To compare overall survival (OS) between the 2 arms of the study 
• To evaluate the safety and tolerability of the 2 arms of the study 
 
Section:  8.4.1, Primary Endpoint, page 25 
Replace:  
The primary efficacy endpoint of this study is ORR 
With: 
The primary efficacy endpoint of this study is objective response rate (ORR) as assessed by 
the 2014 Lugano Classification. [38, Appendix 18.6]    
 
 
Section:  9.1, Overall Study Design and Plan, page 26 
Add: 
for the treatment of patients with relapsed or refractory CD30-positive DLBCL and 
grade 3b follicular lymphoma after failure of second-line salvage  
 
Add 
Once stained for CD30 expression by the central pathology laboratory, slides may be 
retained to support future research efforts by the sponsor.  
 
 


 
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Section:  9.4.3.1, Discontinuation of Study Drug, page 31: 
Add: 
Study drug must be discontinued in the case of pregnancy. 
 
 
Section:  9.5.1.1, Required Premedication and Postmedication, page 33 
Replace: 
…NCCN 2012 guideline for the prevention and treatment of cancer-related infections is 
recommended… 
With: 
…NCCN 2015 guideline for the prevention and treatment of cancer-related infections is 
recommended…  
 
 
Section:  9.5.1.3.3 
Dose and Administration, page 35 
Add: 
Subjects will receive rituximab on Day 2 only (treatment arm) or on Day 1 OR Day 2 (+1; 
control arm) of each 21-day treatment cycle for a maximum of 6 cycles. 
 
 
Section:  9.5.3, Prior and Concomitant Therapy, page 39-40 
Add: 
Subjects must not receive live vaccines (in particular yellow fever vaccination) or 
bleomycin while on treatment; subjects requiring these treatments will be discontinued 
from study.  Live vaccines must not be administered within 1 month of starting study 
treatment. 
 
Replace: 
…NCCN 2012 guideline for the prevention and treatment of cancer-related infections is 
recommended… 
With: 
…NCCN 2015 guideline for the prevention and treatment of cancer-related infections is 
recommended…  
 
Add: 
Subjects may be eligible for allogenic SCT or ASCT following study treatment.  
Subjects receiving these treatments should continue in study follow-up. 
 


 
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Add: 
Contraception 
Acceptable methods of contraception include: hormonal (birth control pills, injections, 
implants), intrauterine device (IUD), intrauterine hormone-releasing system (IUS), 
vasectomy (for males), barrier methods (male and female condoms, diaphragms, and 
spermicides), bilateral tubal ligation, and complete abstinence. Complete abstinence is 
acceptable when this is in line with the preferred and usual lifestyle of the patient. 
(Periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] 
and withdrawal are not acceptable methods of contraception).  
 
 
Section:  Table 2:  Study Schedule, page 43-44 
Add (new row): 
Physical Examination (incl. neuro exam)  (with indicators at Screening/Baseline [Day -7 to 
1], Day 1 of each cycle, and EOT) 
 
Add to the row labeled Electrocardiogram: 
(indicators at Day 1 of each cycle). 
 
Add (new row): 
HBsAg / HBcAb (with indicator at Screening/Baseline [Day -7 to 1]). 
 
Add to the row labeled Pregnancy test: 
(indicators at Day 1 of each cycle). 
 
Add (to title of row previously called PK samplesh): 
PK samplesh (treatment arm only) 
and add additional indicator at Cycles 2-6 [D1(±1D) to D2]. 
 
Change the row labeled ATA/pharmacodynamic samplesi to 2 rows, labeled  
ATA/ samplesi (treatment arm only) 
and Pharmacodynamic samplesi 
(indicators at Day 1 of Cycles 1 – 6 and at EOT for both rows). 
 
Add to the list of abbreviations: 
HBsAg = hepatitis B surface antigen; HBcAb = hepatitis B core antibody;   
 
Add: 
Note:  All Day 1 procedures are before treatment unless otherwise specified. 


 
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Delete:  
Footnote a:  Long term response assessments should continue annually after 24 months until 
death or study closure. 
 
Add: 
To footnote b:  Locally assessed to enable enrollment.  Submission of the tumor block or 
approximately 15 unstained slides from a biopsy of relapsed disease obtained within 
1 year prior to screening (or initial diagnostic specimen if refractory) is required for 
subsequent central pathology disease confirmation and further evaluation of additional 
molecular biomarkers. 
 
Add: 
New footnote c (for “Optional tumor specimen”):  Biopsy material will also be collected if 
available to evaluate changes in molecular biomarkers by different treatments.  No 
additional procedures will be conducted to obtain these research tissues; only available 
tissue will be used. 
 
Change (footnotes h and i): 
h. 
Predose (within 24 hours before the start of the brentuximab vedotin infusion) and 
within 30 minutes after the end of the infusion (samples for ADC and MMAE levels 
only). 
i 
Predose (within 24 hours before the start of the infusion). 
To: 
h. 
Predose (within 24 hours before the start of the brentuximab vedotin infusion) and 
postdose (within 30 minutes after the end of the infusion; samples for ADC and 
MMAE levels only). 
i 
Predose (within 24 hours before the start of the first infusion on Day 1). 
 
Add: 
New footnote k (for “CT (chest, neck, abdomen, pelvis)”):  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; PET scan not required after documented postbaseline 
FDG-negative PET scan is obtained. 
 
Revise footnote indicators to accommodate changes. 
 
 


 
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Section:  Table 3:  Study Schedule, page 45 
Add (to footnote b): 
Consists of the following:  physical examination, including neurological examination, 
patient medical history,…  
 
 
Section:  10.1, Screening (Day -28 to 1), page 46 
Add: 
HBsAg and HBcAb;  
 
 
Section:  10.1, Screening (Day -28 to 1), page 46; 10.3, End of Treatment, page 48: 
Delete: 
● 
Serum or urine pregnancy test… 
 
 
Section:  10.1, Screening (Day -28 to 1), page 46; 10.2, Treatment Period (Cycle 1, Day 1 
pretreatment, Cycles 2 – 6, Day 1 pretreatment, Cycles ≥7, Day 1 pretreatment), page 47-48; 
10.3, End of Treatment, page 48: 
Add: 
● 
Physical examination (including neurologic assessment; Section 11.5)  
 
 
Section:  10.2, Treatment Period, page 47-48;  
Under Cycle 1;  
Replace 
● 
Pharmacokinetic (PK) sample collection (within 24 hours before beginning the 
brentuximab vedotin infusion; Section 11.8) 
With: 
● 
For subjects on the treatment arm (brentuximab vedotin) only: 
Pharmacokinetic (PK) and ATA sample collection (within 24 hours before 
beginning the brentuximab vedotin infusion; Section 11.8) 
● 
For all subjects: 
Pharmacodynamic sample collection (within 24 hours before beginning the 
brentuximab vedotin infusion; Section 11.8) 
 


 
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Under Cycle 1, Day 1, posttreatment; 
Add: 
● 
For subjects on the treatment arm (brentuximab vedotin) only: 
PK sample collection (within 30 minutes after completion of the brentuximab vedotin 
infusion; Section 11.8). 
 
 
Under Cycle 1, pretreatment; Cycles 2 – 6, Day 1, pretreatment; Cycles ≥7, Day 1, 
pretreatment;  
Add: 
● 
Standard 12-lead ECG (Section 11.4) 
● 
Serum pregnancy test (women of childbearing potential only) 
 
Under Cycles 2 – 6, Day 1, pretreatment;  
Add: 
● 
For subjects on the treatment arm (brentuximab vedotin) only: 
PK and ATA sample collection (within 24 hours before beginning the 
brentuximab vedotin infusion; Section 11.8) 
● 
For all subjects: 
Pharmacodynamic sample collection (within 24 hours before beginning the 
brentuximab vedotin infusion; Section 11.8) 
 
Add (new top level bullet): 
● 
Cycles 2 – 6, Day 1, posttreatment:   
● 
For subjects on the treatment arm (brentuximab vedotin) only: 
PK sample collection (within 30 minutes after completion of the 
brentuximab vedotin infusion; Section 11.8). 
 
 
Section:  11.2, Histology / CD30 Assessment, page 50 
Add: 
…Submission of the tumor block or approximately 15 unstained slides from a biopsy of 
relapsed disease obtained within 1 year prior to screening (or initial diagnostic specimen 
if refractory) is required for subsequent central pathology disease confirmation and further 
evaluation of additional molecular biomarkers. 
Optional diagnostic bBiopsyies material will also be collected if available from biopsies 
performed anytime while the subject is on study to evaluate changes ofin molecular 
biomarkers by different treatments.  The tumor tissue will be used to conduct exploratory 
correlative studies. Tumor based molecular biomarkers may include, but are not limited to 


 
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COO, prognostic markers for DLBCL and CD30 pathway related markers.  These will be 
conducted on the following tissues if available: 
• Leftover unstained slides or tumor tissue from a diagnostic biopsy will be 
obtained at baseline if available 
• Unstained slides or leftover tissue from a core biopsy obtained as part of 
standard-of-care clinical intervention 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.  
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 consent.  The 
planned future research includes, but is not limited to, the evolution of targets for novel 
ADCs, the biology of ADC sensitivity and resistance mechanisms, and to identify 
predictive pharmacodynamic biomarkers of ADCs. Blood and tissue samples donated 
for future research may be retained for 25 years. Outside the US 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. 
 
 
Section:  11.5, ECOG Performance Status and Weight, page 51: 
Change Section Heading to: 
Physical Examination, ECOG Performance Status, and Weight 
 
Add: 
Physical examinations will be performed at the time points indicated in Table 2 and 
include assessments of the following body parts/systems: HEENT (head, ears, eyes, 
nose, and throat), neck, cardiovascular and respiratory systems, lymph nodes, 
abdomen, extremities, skin, and neurological.   
 
Change: 
Body weight (kg) will be measured and recorded at each study cycle visit.   
To: 
Body weight (kg) will be measured and recorded at Day 1 of each study cycle visit.   
 
Section:  11.6, Lymphoma Assessment, page 51: 
Add: 
The lymphoma assessment includes physical examination (see Section 11.5), patient medical 
history…  
 


 
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Section:  11.7, Clinical Laboratory Tests, page 52 
Replace: 
Clinical chemistry:   
With: 
Serum chemistry:   
 
Add: 
glucose 
 
Replace: 
Pregnancy will be determined at screening and EOT by either urine or serum for females of 
childbearing potential.  
With: 
Pregnancy will be determined as indicated in Table 2 by serum β-hCG for females of 
childbearing potential.  
Baseline screening for hepatitis B infection by HBsAg and HBcAb.   
 
 
Section:  11.8 Pharmacokinetic, Pharmacodynamic, and Immunogenicity Samples, page 52 
Change: 
Blood will be collected for PK, immunogenicity, and pharmacodynamic assessments. 
Potential pharmacodynamics markers include but not limited to sCD30 and inflammatory 
cytokines.  It may also include circulating tumour DNA biomarkers. For subjects assigned to 
receive brentuximab vedotin, samples for PK analysis will be collected during Cycle 1 within 
24 hours before the start of the Day 1 brentuximab vedotin infusion and within 30 minutes 
after the end of the Day 1 brentuximab vedotin infusion. 
Samples for pharmacodynamics and ATA will be collected from patients on both treatment 
arms within 24 hours before the infusion on Day 1 of each cycle (Cycles 1 – 6) and at EOT.  
Sample handling and shipping information will be provided in the study manual.   
To: 
Blood will be collected from subjects assigned to receive brentuximab vedotin 
(treatment arm) for measurement of ATA to brentuximab vedotin and both 
brentuximab vedotin and MMAE exposures only from subjects on the treatment arm 
(brentuximab vedotin).  PK samples will be collected during Cycles 1 – 6 within 24 
hours before the start of the Day 1 brentuximab vedotin infusion (predose) and within 
30 minutes after the end of the Day 1 brentuximab vedotin infusion (postdose).  
Samples for ATA will be collected within 24 hours before the brentuximab vedotin 
infusion on Day 1 of each cycle (Cycles 1 – 6) and at EOT.  


 
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Blood will be collected for pharmacodynamic assessments from all subjects.  Potential 
pharmacodynamics biomarkers include but are not limited to soluble CD30, 
inflammatory cytokines, and circulating tumour DNA.  Samples for pharmacodynamic 
studies will be collected from patients on both treatment arms within 24 hours before 
the first infusion on Day 1 of each cycle (Cycles 1 – 6) and at EOT.  
Sample handling and shipping information will be provided in the study manual.   
 
 
Section:  12.1.4, Serious Adverse Events Require Immediate Reporting, page 58 
Change: 
The completed SAE form and SAE Fax Cover Sheet are to be faxed to the Sponsor’s Drug 
Safety Department at (425) 527-4308 or 1-866-333-6227 (toll free US only) or within 
24 hours.  
To: 
The completed SAE form and SAE Fax Cover Sheet are to be faxed to the Drug Safety 
Department within 24 hours.  Refer to the contact information for the US and Europe 
provided on the SAE report form. 
 
 
Section:  12.1.5, Sponsor Safety Reporting Requirements, page 58-59: 
Delete (from the section title): 
in the United States 
Delete: 
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.  
Add: 
The Sponsor or its designee will report relevant SAEs to the relevant regulatory 
authorities, and participating investigators, in accordance with FDA regulations (21 
CFR 312.32), ICH guidelines, European Clinical Trials Directive (Directive 
2001/20/EC), and/or local regulatory requirements. 
 
Section:  13.6.4.2, Secondary Efficacy Endpoints, page 62-63;  
Add: 
CR Rate and Best Clinical Response: Response (CR/CMR, PR/PMR, ORR 
[CR/CMR+PR/PMR], stable disease [SD] or no metabolic response [NMR], and 
PD/progressive metabolic disease [PMD]) will be summarized descriptively by treatment 
arm. CR rate will be summarized with 95% confidence intervals. Best clinical response is 


 
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defined as the best response (ordered from best to worst as CR/CMR, PR/PMR, 
SD/NMR, or PD/PMD) observed during the treatment period.  
Add: 
…Subjects who receive SCT in remission will continue to be followed for DOR. 
 
…Subjects who receive SCT in remission will continue to be followed for PFS. 
 
 
Section:  13.6.5, Pharmacokinetics and Pharmacodynamics, page 63;  
Change: 
Pharmacokinetic (brentuximab vedotin ADC and MMAE), ATA to brentuximab vedotin, and 
pharmacodynamic (CD30 expression, mRNA levels of CD30 and related genes, COO 
classification, and soluble CD30 and other chemokines/cytokines of interest) results will be 
summarized by treatment arm.  
To: 
Pharmacokinetic (brentuximab vedotin ADC and MMAE) and ATA to brentuximab 
vedotin results will be summarized.  Pharmacodynamic results, (eg, CD30 expression, 
mRNA levels of CD30 and related genes, COO classification, and soluble CD30 and 
other chemokines/cytokines of interest) results will be summarized by study arm.  
 
 
Section:  15.4, Record Maintenance, page 68: 
Delete: 
The Investigator shall take responsibility for maintaining adequate and accurate hard copy 
source documents of all observations and data generated during this study.   
 
 
Section:  Global 
Replace: 
study arm 
With: 
treatment arm 
 
Replace: 
Version 02, Date 17 June 2015 
With: 
Version 03, Date 10 November 2015 


 
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18.10 Appendix 10: Summary of Changes in V04 
RATIONALE: 
 
The protocol was amended to  
• Clarify that the objectives of the study were to investigate the effects of study 
treatment both in patients with DLCBL and those with follicular NHL grade 3b 
• Allow a second dose reduction of bendamustine (to 50 mg/m2) 
• Recommend prophylactic growth factor support and clarified that transfusions and 
intrathecal prophylactic treatment for cerebral/meningeal disease are permitted  
• Correct an error regarding timing of posttreatment assessments:  The timing of all 
posttreatment assessments is relative to Cycle 1 Day 1 (not the end of treatment) 
• Add an additional safety assessment visit during the second week of Cycles 1 and 2 
• To change the definition of PFS and OS to begin at randomization (rather than date of 
first treatment) and to include subsequent treatment for lymphoma (other than post-
treatment consolidative radiotherapy, post-treatment chemotherapy for the purpose of 
mobilizing peripheral blood stem cells, and consolidative autologous or allogeneic 
SCT) as an event in the progression analyses to reflect current statistical planning 
• Remove the requirement that biopsy samples be obtained within than 1 year before 
screening 
• Clarify that tumor samples are only to be collected from archival samples; no tumor 
biopsies are required to be performed for this study 
• Make minor editorial and formatting changes throughout the protocol 
 
SUMMARY OF CHANGES: 
Note:  Editorial and formatting changes are not included below. 
Section:  Synopsis, Objectives, Primary Objective, page 4 
Add: 
• To compare the objective response rate (ORR) among subjects with relapsed or 
refractory CD30 positive diffuse large B-cell lymphoma (DLBCL) or follicular non-
Hodgkin lymphoma (NHL) grade 3b receiving rituximab and bendamustine plus 
brentuximab vedotin (treatment arm) with that among subjects receiving rituximab 
and bendamustine alone (control arm)  
 
 


 
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Section:  Synopsis, Objectives, Secondary Objectives, page 4; 8.2, Secondary Study 
Objectives, page 24 
Add: 
• To compare progression-free survival (PFS) among subjects with relapsed or 
refractory CD30-positive DLBCL or follicular NHL grade 3b receiving rituximab 
and bendamustine plus brentuximab vedotin (treatment arm) with that among subjects 
receiving rituximab and bendamustine alone (control arm) 
 
 
Section:  Synopsis, Objectives, Exploratory Objectives, page 4; 8.3, Exploratory Objectives, 
page 24 
Add: 
• To characterize the incidence of antitherapeutic antibodies (ATA) to brentuximab 
vedotin among subjects with relapsed or refractory CD30-positive DLBCL or 
follicular NHL grade 3b receiving rituximab and bendamustine plus brentuximab 
vedotin  
 
 
Section: Synopsis, Study Design and Methodology, page 4 
Change:  
…brentuximab vedotin in combination with rituximab and bendamustine for the treatment of 
patients with relapsed or refractory CD30-positive diffuse large B cell lymphoma (DLBCL) 
and grade 3b follicular lymphoma grade 3b after failure… 
 
 
Section: Synopsis, Study Design And Methodology, page 5; 9.1, Overall Study Design and 
Plan, page 26 
Add:  
DLBCL or follicular NHL grade 3b will be histologically…  
 
 
Section: Synopsis, Study Population and Main Criteria for Inclusion/Exclusion, page 5 
Delete: 
1. 
Patients with histologically confirmed CD30-positive DLBCL or follicular non
Hodgkin lymphoma (NHL) grade 3b, defined as any detectable CD30 expression on 
tumor cells based on local pathologic assessment. 
 
 


 
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Page 116 of 126 
 
Section: Synopsis, Number of Subjects, page 6 
Add:  
Approximately 110 patients with relapsed or refractory DLBCL or follicular NHL grade 3b 
will be enrolled in the study (approximately 55 patients in each treatment arm). 
 
 
Section: Synopsis, Primary Efficacy Criteria, page 7; Figure 1, footnote d, page 27 
Replace: 
…the end of combination treatment… 
 
With: 
…the start of combination treatment (Cycle 1 Day 1)… 
 
 
Section: 4, List of Abbreviations and Definition of Terms, page 14-15 
Delete: 
ASCO 
American Society of Clinical Oncology  
 
Add: 
NMR 
No metabolic response  
 
 
Section: 7.1, Disease Review (second paragraph), page 21 
Add:  
…Follicular NHL grade 3b, an aggressive follicular lymphoma, is often treated under 
the same guidelines.  [31] 
 
 
Section: 7.3, Clinical Study Rationale, page 22 
Add:  
In the relapsed or refractory setting, DLBCL and follicular NHL grade 3b patients who… 
 
 


 
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Section:  8.3, Primary Study Objectives, page 24 
Add: 
• To compare the objective response rate (ORR) among subjects with relapsed or 
refractory CD30 positive DLBCL or follicular NHL grade 3b receiving rituximab 
and bendamustine plus brentuximab vedotin (treatment arm) with that among subjects 
receiving rituximab and bendamustine alone (control arm)  
 
 
Section:  8.4.3, Pharmacokinetic / Pharmacodynamic Measurements, page 25 
Add: 
Tumor samples from prior biopsies/aspirates will be collected from all subjects for 
assessment  
 
Section:  9.1, Overall Study Design and Plan, page 26 
Change: 
…CD30-positive DLBCL and or grade 3b follicular lymphoma grade 3b after failure of 
second-line salvage therapy or greater… 
 
 
Section:  9.5.1.1, Required Premedication and Postmedication, page 33 
Add:  
The use of transfusions per institutional practice is permitted. The use of white blood 
cell growth factors (eg, G-CSF) is recommended for all patients.  Intrathecal 
prophylactic treatment for cerebral/meningeal disease is permitted at the discretion of 
the Investigator.  
 
Section:  9.5.1.3.1, Description, pages 35 
Add: 
Rituximab is marketed as Rituxan® in the US and as MabThera® in Europe and is a 
sterile, clear, colorless, preservative-free liquid concentrate for IV administration. Rituxan is 
and Mabthera are supplied at a concentrations of 10 mg/mL in either 100 mg/10 mL or 500 
mg/50 mL single-use vials .  The product is and are formulated in polysorbate 80 (0.7 
mg/mL), sodium chloride (9 mg/mL), sodium citrate dihydrate (7.35 mg/mL), and Water for 
Injection. The pH is 6.5.     
 
 


 
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Section:  9.5.1.5.3, Dose Modifications, pages 38-39 
Delete: 
Common toxicities including myelosuppression, nausea, gastrointestinal toxicity, fatigue, 
pyrexia, headache, weight decrease, dyspnea, rash, and stomatitis should be managed 
according to institutional standards or accepted guidelines (eg, American Society of Clinical 
Oncology [ASCO] guidelines for the use of white blood cell growth factors [38]).  Growth 
factor support may be administered as needed according to institutional standard of care.   
 
Replace:  
Following Grade 4 hematologic toxicity or Grade ≥3 nonhematologic toxicity, the 
bendamustine dose should be decreased from 90 mg/m2 to 70 mg/m2.  Doses lower than 
70 mg/m2 are not allowed. 
With:  
Following Grade 4 hematologic toxicity or Grade ≥3 nonhematologic toxicity, the 
bendamustine dose should be decreased from 90 mg/m2 to 70 mg/m2 and, if toxicity recurs, 
the dose can be further decreased to 50 mg/m2.  Doses lower than 50 mg/m2 are not 
allowed. 
 
Delete:  
If toxicity recurs following dose reduction, bendamustine should be discontinued.   
 
 
Section:  9.5.3, Prior and Concomitant Therapy, page 39-40 
Add: 
… other than DLBCL or follicular NHL grade 3b is permitted…  
 
Replace: 
The use of transfusions, platelet and/or colony stimulating factors per institutional practice is 
permitted.  In addition, the ASCO guideline for the use of white blood cell growth factors is 
recommended for the management of neutropenia and febrile neutropenia. [38]  Intrathecal 
prophylactic treatment for cerebral/meningeal disease is permitted at the discretion of the 
Investigator.   
With 
The use of transfusions per institutional practice is permitted. The use of white blood cell 
growth factors (eg, G-CSF) is recommended for all patients.  Intrathecal prophylactic 
treatment for cerebral/meningeal disease is permitted at the discretion of the 
Investigator.  
 
 


 
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Page 119 of 126 
 
Section:  Table 2: 
Study Schedule, pages 43-44 
Modify table structure to include a single spanner head for Cycles 1 and 2, including a new 
column for D7-D14, with indicators for physical examination, ECOG performance status, 
and hematology. Add a column for Cycle 2 only, Day 15-21 (+2D), with indicators for CT 
and PET.  Update 2 following columns to indicate Cycles 3-6 and Cycle 6 only, respectively. 
 
Delete: 
From footnote b:  …15 unstained slides from a biopsy of relapsed disease obtained within 1 
year prior to screening (or initial diagnostic specimen if refractory)… 
 
Add: 
New footnotes, o and p, for the physical examination on Days 7-14 of Cycles 1 and 2:   
o. At these visits the physical examination may be a brief, targeted examination, at the 
discretion of the investigator, to identify changes from baseline. 
p. Not required for Cycle 1. 
 
 
Section:  10.1, Screening (Day -28 to 1), page 46 
Replace:  
• Medical history, including DLCBL history… 
With:  
• Medical history, including lymphoma history… 
 
 
Section:  10.2, Treatment Period, pages 46-49 
Update section Structure to reflect changes to structure of Table 2,  
Add:  
• Cycles 1 and 2, Day 1, pretreatment: 
… 
o Pharmacodynamic sample collection (within 24 hours before beginning the 
brentuximab vedotin infusion; study treatment;  
… 
o ECOG performance status (not required in Cycle 1; Section 11.5) 
… 


 
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• Cycles 1 and 2, Day 1, posttreatment: 
… 
• Cycles 1 and 2, Day 7-14:   
o Physical examination (Section 11.5) 
o Clinical laboratory tests (hematology; Section 11.7). 
o ECOG performance status (Section 11.5) 
… 
• Cycle 2 only, Days 15-21: 
o Disease assessment (Section 11.9). 
• Cycles 2 Cycles 3 – 6, Day 1, pretreatment: 
o Pharmacodynamic sample collection (within 24 hours before beginning the 
brentuximab vedotin infusion; study treatment;  
… 
• Cycles 2 Cycles 3 – 6, Day 1, posttreatment: 
… 
• Cycles 2 and 6 only Cycle 6 only, Days 15-21: 
 
Section:  10.3, End of Treatment, page 49 
Add:  
An EOT visit will be performed 30 – 37 days after the last dose of study treatment 
(brentuximab vedotin, rituximab, and/or bendamustine).  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.  At the EOT visit, the following assessments/procedures will be 
performed: 
… 
• Pharmacodynamic sample collection (Section 11.8) 
… 
Response assessments and pregnancy test at EOT not required if performed at last 
cycle of treatment.  
 


 
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Page 121 of 126 
 
 
Section:  11.1, Medical History, page 51 
Add:  
…history of DLBCL or follicular NHL grade 3b and prior treatments… 
 
 
Section:  11.2, Histology / CD30 Assessment, page 51 
Change:  
Histologically confirmed DLBCL or follicular NHL grade 3b and prior treatments 
…15 unstained slides from a biopsy of relapsed disease obtained within 1 year prior to 
screening (or initial diagnostic specimen if refractory)… 
 
Biopsy material will also be collected from patients who provided consent if available… 
markers for DLBCL lymphoma,…  
 
 
Section:  11.5, Physical Examination, ECOG Performance Status, and Weight, page 52 
Add:  
At the Day 7-14 visits in Cycles 1 and 2, the physical examination may be a brief, 
targeted examination, at the discretion of the investigator, to identify changes from 
baseline. 
 
 
Section:  11.10, Long-term and Survival Status Follow-up, page 54 
Change:  
…and poststudy treatment for DLBCL lymphoma and CD30 pathway…  
 
 
Section:  12.1.4, Serious Adverse Events Require Immediate Reporting, page 59 
Add:  
…Cover Sheet are to be faxed or emailed to the Drug Safety Department …  
 
 
Section: 13.6.4.2, Secondary Efficacy Endpoints, page 64 
Add: 
DOR (for PR/CR and CR): DOR is defined as the time from first observation of response 
(PR/PMR+CR/CMR or CR/CMR) to disease progression/relapse, receipt of subsequent 
lymphoma chemotherapy other than the components of the study treatment regimen 
(excludes post-treatment consolidative radiotherapy, post-treatment chemotherapy for 


 
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Page 122 of 126 
 
the purpose of mobilizing peripheral blood stem cells, and consolidative autologous or 
allogeneic SCT), or death from any cause, whichever occurs first.  Durations will be assessed 
in the ITT population with a PR or CR and calculated separately for subjects with CR/CMR 
and those with PR/PMR+CR/CMR combined.  For subjects with a remission without 
subsequent disease progression/relapse or death on study, DOR will be censored at the time 
of the last disease assessment demonstrating a lack of disease progression/relapse.  If more 
than one date of progression is available, the earliest date will be used to determine 
PFS.  Full censoring rules will be provided in the SAP. Subjects who receive SCT in 
remission will continue to be followed for DOR. 
 
Replace: 
Progression-free Survival: PFS is defined as the time from first dose of study medication to 
first documentation of disease progression/relapse, or to death due to any cause, whichever 
occurs first. For subjects without disease progression/relapse or death on study, PFS will be 
censored at the time of the last on-study disease assessment demonstrating a lack of disease 
progression/relapse. If more than one date of progression is available, the earliest date will be 
used to determine PFS.  Subjects who receive SCT in remission will continue to be followed 
for PFS. 
 
With: 
Progression-free Survival: PFS is defined as the time from randomization to first 
documentation of disease progression/relapse, or to death due to any cause, or receipt of 
subsequent lymphoma chemotherapy other than the components of the study treatment 
regimen (excludes post-treatment consolidative radiotherapy, post-treatment 
chemotherapy for the purpose of mobilizing peripheral blood stem cells, and 
consolidative autologous or allogeneic SCT), whichever occurs first. For subjects without 
disease progression/relapse or death on study, PFS will be censored at the time of the last on-
study disease assessment demonstrating a lack of disease progression/relapse. If more than 
one date of progression is available, the earliest date will be used to determine PFS.  Full 
censoring rules will be provided in the SAP. Subjects who receive SCT in remission will 
continue to be followed for PFS. 
 
Replace: 
Overall Survival: OS is defined as the time from first dose of study medication to death due 
to any cause. For subjects not known to have died at the conclusion of the study, OS will be 
censored at the time the subject was last known to be alive (including follow-up data). 
 
With: 
Overall Survival: OS is defined as the time from randomization to death due to any cause. 
For subjects not known to have died at the conclusion of the study, OS will be censored at the 
time the subject was last known to be alive (including follow-up data). 
 


 
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Section: 17, Reference List, page 78 
Delete: 
38. Smith TJ, Khatcheressian J, Lyman GH, et al.  2006 Update of recommendations for the 
use of white blood cell growth factors: An evidence based clinical practice guideline.  J 
Clin Oncol 24(19): 3187 3205, 2006. 
Update subsequent reference number and as appropriate in report body. 
 
Section:  Global 
Replace: 
Version 03, Date 10 November 2015 
With: 
Version 04, Date 19 February 2016 


 
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18.11 Appendix 11: Summary of Changes in V05 
RATIONALE: 
 
The protocol was amended to  
• Reflect that Teva Pharmaceuticals is discontinuing distribution of the bendamustine 
hydrochloride liquid formulation TREANDA, which was being used at all US sites in 
this study.  Investigators may continue to dispense TREANDA until its expiration 
date, as described in previous versions of the protocol and in the pharmacy manual.  
When acquiring new supplies, sites are to acquire bendamustine hydrochloride 
lyophilized powder.   
• Allow the assessment of CD30 for eligibility assessment to be performed either by 
local or central laboratory 
• Clarify that a new biopsy may be required for subjects with relapsed disease if one has 
not been obtained since relapse 
• To correct an inconsistency between the schedule of follow-up assessments and the 
text description of follow-up events 
• Make minor editorial and formatting changes throughout the protocol 
 
SUMMARY OF CHANGES: 
Note:  Editorial and formatting changes are not included below. 
Section:  Synopsis, Study Design and Methodology, page 5; 9.1, Overall Study Design and 
Plan, page 26 
Change: 
DLBCL or follicular NHL grade 3b will be histologically determined by local pathology 
assessment, and CD30 expression will be locally determined by local or central laboratory 
visual assessment of any detectable level of CD30 on tumor cells by immunohistochemistry 
(IHC; using anti-CD30 BerH2 antibody) to determine eligibility for enrollment.  Tissue will 
be sent to a central laboratory for disease confirmation and retrospective evaluation of 
biomarkers including… 
 
Section:  Synopsis, Inclusion Criteria, page 5; 9.4.1, Inclusion Criteria, page 28 
Add (Inclusion Criterion 1): 
• Patients with histologically confirmed CD30-positive DLBCL or follicular NHL 
grade 3b, defined as any detectable CD30 expression on tumor cells based on local or 
central pathologic assessment. 
 
 


 
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Section: 9.5.1.4, Bendamustine, page 36 
Replace: 
Bendamustine hydrochloride is marketed in the US as TREANDA® by Cephalon, Inc., 
(Frazer, PA USA) and in the EU as Levact by Napp Pharmaceuticals, Ltd, Cambridge, 
Cambridgeshire UK.  Please refer to the approved USPI or EU SmPC for detailed 
information. 
9.5.1.4.1 
Description 
In the US, bendamustine hydrochloride is provided as a liquid, 90 mg/mL formulation.  In the 
EU, it is provided as a sterile non-pyrogenic white to off-white lyophilized powder in a 
single-use vial, and it is reconstituted with Sterile Water for Injection, USP.  Both the liquid 
and reconstituted formulations are further diluted according to local standard of care.   
With: 
Please refer to the approved USPI or EU SmPC for detailed information on bendamustine 
hydrochloride. 
9.5.1.4.1 
Description 
Bendamustine hydrochloride is provided as a sterile non-pyrogenic white to off-white 
lyophilized powder in a single-use vial, and it is reconstituted with Sterile Water for 
Injection, USP.  The reconstituted formulation is further diluted according to local standard 
of care.   
 
 
Section:  Table 2: 
Study Schedule, page 43 
Add (footnote b): 
• Centrally or locally assessed to enable enrollment.  Submission of the tumor block…  
 
 
Section:  Table 3: 
Schedule of Follow-up Events, page 44 
Add indicator (‘X’) to “Lymphoma assessment” row under Month 30 
 
 
Section:  11.2, Histology / CD30 Assessment, page 4 
Add: 
• Histologically confirmed DLBCL or follicular NHL grade 3b must be determined by 
local pathology assessment.  CD30 expression will be determined by local or 
central laboratory visual assessment using IHC (anti-CD30 BerH2 antibody) to 
determine eligibility.   
 
If adequate tissue is not available or if disease has relapsed and the patient has 


 
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not had a biopsy since the relapse was documented, a new biopsy must be 
obtained.  A new biopsy is not required for patients with refractory disease, 
provided a biopsy was obtained prior to the initiation of the most recent therapy.  
 
Submission of the tumor block or approximately 15 unstained slides from a biopsy of 
relapsed disease (or initial diagnostic specimen if refractory) is required for 
subsequent central pathology disease confirmation and further evaluation CD30 
expression, and of additional molecular biomarkers.   
 
 
Section:  Global 
Replace: 
Version 04, Date 19 February 2016 
With: 
Version 05, Date 13 July 2016 
 

SAP_001.pdf: 


Statistical Analysis Plan
Effective Date: 19-JUL2018/Version 2.0
Sponsor: Seattle Genetics, Inc
Protocol no: SGN35-023
PRS 005 T 17 E
Page 2of 23
Strictly Confidential.  © 2004-2014, PRA Health Sciences.  All rights reserved.
Table of Contents
Approvals....................................................................................................................................................................................1
Table of Contents.....................................................................................................................................................................2
Introduction.......................................................................................................................................................................4
1.1 Changes from Protocol..............................................................................................................................................4
Study Objectives...............................................................................................................................................................4
2.1 Primary Objective.......................................................................................................................................................4
2.2 Secondary Objectives.................................................................................................................................................4
2.3 Exploratory Objectives..............................................................................................................................................4
Study Design.......................................................................................................................................................................5
3.1 Sample Size Considerations....................................................................................................................................6
3.2 Randomization.............................................................................................................................................................6
3.3 Blinding...........................................................................................................................................................................7
Study Variables and Covariates..................................................................................................................................7
4.1 Primary Variable..........................................................................................................................................................7
4.2 Secondary Variables...................................................................................................................................................7
4.2.1 Efficacy....................................................................................................................................................................7
4.2.2 Pharmacokinetic/Pharmacodynamic Measurements.........................................................................7
4.2.3 Safety........................................................................................................................................................................7
Definitions...........................................................................................................................................................................7
Analysis Populations.......................................................................................................................................................9
6.1 Intent-to-Treat..............................................................................................................................................................9
6.2 Safety................................................................................................................................................................................9
Interim Analyses...............................................................................................................................................................9
Data Review........................................................................................................................................................................9
8.1 Data Handling and Transfer....................................................................................................................................9
8.2 Data Screening..............................................................................................................................................................9
Statistical Methods..........................................................................................................................................................9
9.1 Patient Disposition...................................................................................................................................................10
9.2 Important Protocol Deviations............................................................................................................................10
9.3 Demographic and Baseline Characteristics....................................................................................................10
9.4 Treatments...................................................................................................................................................................10
9.4.1 Extent of Study Drug Exposure...................................................................................................................10
9.4.2 Prior and Concomitant Medications.........................................................................................................11
9.5 Efficacy Analyses.......................................................................................................................................................11
9.5.1 Primary Efficacy Variable..............................................................................................................................11
9.6 Safety Analyses...........................................................................................................................................................11
9.6.1 Adverse Events..................................................................................................................................................11
9.6.2 Deaths and Serious Adverse Events..........................................................................................................12
9.6.3 Adverse Events of Special Interest............................................................................................................12
9.6.4 Laboratory Data.................................................................................................................................................13
9.6.5 Vital Signs.............................................................................................................................................................13
9.6.6 Eastern Cooperative Oncology Group (ECOG) Performance Status............................................13
9.6.7 Electrocardiograms (ECG)............................................................................................................................13
9.6.8 Physical Examinations....................................................................................................................................13
9.7 Pharmacokinetics/Pharmacodynamics, Antitherapeutic Antibodies and Disease 
Characteristics...................................................................................................................................................................13


Statistical Analysis Plan
Effective Date: 19-JUL2018/Version 2.0
Sponsor: Seattle Genetics, Inc
Protocol no: SGN35-023
PRS 005 T 17 E
Page 3of 23
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9.8 Methods for Handling Dropouts and Missing Data.....................................................................................13
9.9 Data Transformations and Derivations............................................................................................................14
Validation........................................................................................................................................................................14
References......................................................................................................................................................................14
Appendix 1 Glossary of Abbreviations.........................................................................................................................15
Appendix 2 Imputation of Partially Unknown Adverse Event Dates...............................................................17
Appendix 3 Treatment Emergent Adverse Event Programming Guide..........................................................20
Appendix 4 CTCAE V4.03 Grading for Laboratory Values....................................................................................21


Statistical Analysis Plan
Effective Date: 19-JUL2018/Version 2.0
Sponsor: Seattle Genetics, Inc
Protocol no: SGN35-023
PRS 005 T 17 E
Page 4 of 23
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Introduction
This statistical analysis plan (SAP) describes the statistical methods to be used during the reporting and 
analyses of data collected under Seattle Genetics Protocol SGN35-023. 
This SAP should be read in conjunction with the study protocol and case report form (CRF). This version 
of the plan has been developed using the protocol dated 24Jun2016 and CRF dated 12Oct2016. Any 
further changes to the protocol or CRF may necessitate updates to the SAP.
The SAP is to be developed in two stages. The purpose is to “finalize” a SAP so that programming can 
start earlier in the process. Versions of the SAP up to initial sponsor approval will be known as SAP1. 
Changes following approval of SAP1 will be tracked in the SAP Change Log and a final version of the 
SAP, known as SAP2, will be issued for sponsor approval prior to database lock.
1.1 Changes from Protocol
Seattle Genetics ended the study early and therefore only a subset of the analyses planned in the 
protocol will be produced, in order to prepare an abbreviated clinical study report (CSR). There will be no 
formal evaluation of the primary or any secondary endpoints. Analyses for the abbreviated CSR will focus 
on patient disposition, demographics, exposure and safety. The primary endpoint, objective response rate 
(ORR), will be summarized descriptively. Secondary efficacy endpoints will not be calculated or 
summarized, and summaries using the efficacy evaluable population will not be presented. Protocol 
deviation data will not be presented as it is not required for an abbreviated CSR. Pharmacokinetic, 
Pharmacodynamic and Immunogenicity samples were not analyzed for this study and thus these data will 
not be presented.
Study Objectives
2.1 Primary Objective

To compare the objective response rate (ORR) among subjects with relapsed or refractory CD30-
positive diffuse large B-cell lymphoma (DLBCL) or follicular non-Hodgkin lymphoma (NHL) grade 3b 
receiving rituximab and bendamustine plus brentuximab vedotin (treatment arm) with that among 
subjects receiving rituximab and bendamustine alone (control arm)
2.2 Secondary Objectives

To compare Progression Free Survival (PFS) among subjects with relapsed or refractory CD30-
positive DLBCL or follicular NHL grade 3b receiving rituximab and bendamustine plus 
brentuximab vedotin (treatment arm) with that among subjects receiving rituximab and 
bendamustine alone (control arm)

To compare Complete Remission (CR) rate between the 2 arms of the study

To compare Duration of Response (DOR) between the 2 arms of the study

To compare Overall Survival (OS) between the 2 arms of the study

To evaluate the safety and tolerability of the 2 arms of the study
2.3 Exploratory Objectives

To characterize the incidence of antitherapeutic antibodies (ATA) to brentuximab vedotin among 
subjects with relapsed or refractory CD30-positive DLBCL or follicular NHL grade 3b receiving 
rituximab and bendamustine plus brentuximab vedotin

To explore the relationship between CD30 expression and clinical responses


Statistical Analysis Plan
Effective Date: 19-JUL2018/Version 2.0
Sponsor: Seattle Genetics, Inc
Protocol no: SGN35-023
PRS 005 T 17 E
Page 5 of 23
Strictly Confidential.  © 2004-2014, PRA Health Sciences.  All rights reserved.

To explore the relationship between potential patient stratification biomarkers and clinical 
responses 

To evaluate brentuximab vedotin (and monomethyl auristatin E [MMAE]) exposures when 
administered in combination with rituxumab and bendamustine

To characterize pharmacodynamic markers such as soluble CD30 in the 2 treatment arms
Study Design
This is a randomized, open-label, multicenter, Phase 2 clinical trial designed to evaluate the efficacy and 
safety of brentuximab vedotin in combination with rituximab and bendamustine for the treatment of 
patients with relapsed or refractory CD30-positive DLBCL or follicular NHL grade 3b after failure of 
second-line salvage therapy or as second-line treatment in patients ineligible for autologous stem cell 
transplant (ASCT). 
DLBCL or follicular NHL grade 3b will be histologically determined by local pathology assessment, and 
CD30 expression will be determined by local or central visual assessment of any detectable level of CD30 
on tumor cells by immunohistochemistry (IHC; using anti-CD30 BerH2 antibody) to determine eligibility for 
enrollment.  
The study arms include the following: 

Treatment arm: Brentuximab vedotin in combination with rituximab and bendamustine. 

Control arm: Rituximab and bendamustine
The study will include the following periods:

Screening: Within 28 days prior to randomization. 

Randomization:  Patients will be randomized in a 1:1 manner to the treatment and control arm. 
Randomization will be stratified by second-line age-adjusted International Prognostic Index
(sAAIPI) score (0 vs 1 vs 2–3) and duration of remission after initiation of frontline therapy 
(refractory or relapse <12 months vs relapse ≥12 months).

Study treatment: Consists of up to six 21-day cycles of combination treatment. 
Patients in the treatment arm who respond to brentuximab vedotin and do not experience 
excessive toxicity may receive additional single-agent brentuximab vedotin (on Day 1 of each 
cycle) following combination treatment, for up to an additional 10 cycles (up to 16 total cycles of 
treatment).  
Study treatment will continue until treatment completion, disease progression, unacceptable 
adverse events (AEs), patient refusal, Investigator decision, study termination by sponsor or other 
non-AE reasons.  All subjects who discontinue treatment will undergo an end of treatment (EOT) 
visit.

Long-Term follow up: All subjects who discontinue treatment will continue to be followed for 
survival and disease status unless they withdraw from the study. 
The planned duration of the study through final primary analysis (ORR is the primary efficacy endpoint) is 
approximately 2 years from randomization of the first patient, with an additional 2 years until the final 
analysis of OS and PFS. The study includes a planned formal interim analysis for futility and a planned 
interim analyses for safety data to be reviewed by the Independent Data Monitoring Committee (IDMC). 
The interim analysis for futility will be performed after 50% of patients have had the Cycle 2 response 
assessment.  The primary efficacy endpoint (ORR) will be used to assess futility. The safety data will be 
reviewed after the first 20 patients have completed 2 cycles of therapy and then every 6 months 
thereafter and as needed.  




Statistical Analysis Plan
Effective Date: 19-JUL2018/Version 2.0
Sponsor: Seattle Genetics, Inc
Protocol no: SGN35-023
PRS 005 T 17 E
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Strictly Confidential.  © 2004-2014, PRA Health Sciences.  All rights reserved.
duration of remission after initiation of frontline therapy (refractory or relapse <12 months vs relapse ≥12 
months). Randomization will be performed using an Interactive Voice and Web Recognition System
(IXRS).
3.3Blinding
This is an open label study.
Study Variables and Covariates
4.1Primary Variable
The primary efficacy endpoint of this study is Objective Response Rate (ORR) as defined by the 2014 
Lugano Classification[1]. ORR is defined as the proportion of patients who achieve a CR (including CMR) 
or PR (including partial metabolic response, or PMR) as best response to combination therapy on study. 
Patients who cannot be assessed for response will be counted as non-responders. 
4.2Secondary Variables
4.2.1Efficacy
Secondary efficacy variables include: progression-free survival,complete responserate, best clinical 
response, duration of response, and overall survival. Thesevariables will not be calculated or presented.
4.2.2Pharmacokinetic/Pharmacodynamic Measurements
Pharmacokinetic, Pharmacodynamic and Immunogenicity samples were not analyzed for this study and 
thus these variables will not be calculated or presented.
4.2.3Safety
Safety endpointswill includethe following:

Type, incidence, severity, seriousness, and relatedness of AEs 

Type, incidence, and severity of laboratory abnormalities.

Incidence and severity of infusion-related and hypersensitivity reactions.
Definitions
Baseline, Change from Baseline
Baselineis definedas the most recent measurement prior to the first dose of study medication.
Change from baseline is defined as (value at post baseline visit –value at baseline).
Percent change from baseline is definedas [(value at postbaseline visit –value at baseline) / value at 
baseline] * 100%.
Post baseline values for tabulations generally will exclude unscheduled visit values, but unscheduled visit 
values will be included in listings.
Best Overall Response
Bestclinical response is defined as the best response (ordered from best to worst as CR/CMR, PR/PMR, 
Stable Disease/NMR, or Progressive Disease(PD)/PMD) observed by end oftreatment.Patients who 
have any non-PD response per Lugano, 2014 at the same visit as investigator claim of clinical 
progression will be counted as a response of disease progression for determination of best response.
Body Mass Index (BMI)


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BMI = weight (kg) / (height (m)2).
Duration of Treatment (Days) 
Duration of treatment is defined for brentuximab vedotin, rituximab and bendamustine, respectively, as
time from the first study dose to 21 days after the last cycle day 1 dose date, i.e., last cycle day 1 dose 
date + 21 – first dose date. If death occurs less than 21 days after the last cycle day 1 dose, duration of 
treatment is defined as Date of death – first dose date + 1.
Enrolled Patients
An enrolled patient is one with a response of “Yes” to the question “If yes, Seattle Genetics or designee 
approval?” on the Eligibility Criteria Summary CRF page.
Randomized Patient
Randomized patients are defined as patients who have a randomization date. All randomized patients
should also have a randomization number corresponding to a treatment arm which assigned by the IXRS.
Screened Patients
A screened patient is one with Screening ID on the Enrollment/Screening CRF page.
Study Drug
In this study, study drug refers to the standard of care medication, rituximab and bendamustine, or the 
investigational or experimental product, brentuximab vedotin.
Patients Disposition

Completion of Combination Treatment 

A patient will be considered completed combination treatment when an End of Treatment CRF 
page is completed indicating “Complete Treatment” as primary reason for discontinuation.

Discontinuation of Study

A patient will be considered discontinued from the study when an End of Study CRF page is 
completed indicating primary reason for discontinuation.

Early Discontinuation of Treatment

A patient will be considered discontinued from the study early when an End of Treatment CRF 
page is completed indicating primary reasons other than “Complete Treatment” for 
discontinuation

In Long Term Follow Up

A patient will be considered in long term follow up if the response of “Will the patient continue on 
study for Follow-up?” on the End of Treatment CRF page is Yes and no reason for study 
discontinuation is provided

On Treatment  

A patient will be considered on treatment if he/she takes at least one dose of study drug and an 
End of Treatment CRF page is not completed.

Off Treatment  

A patient will be considered off treatment if he/she takes at least one dose of study drug and an 
End of Treatment or an End of Study CRF page is completed indicating primary reason for 
discontinuation. 

On Study  


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
A patient will be considered on study if the End of Study CRF page is NOT completed indicating 
primary reason for discontinuation from study.

Off Study

A patient will be considered off study if the End of Study CRF page is completed indicating 
primary reason for discontinuation from study.
Analysis Populations  
6.1 Intent-to-Treat
The intent-to-treat (ITT) Population will include all patients who are randomized.  Patients will be grouped 
according to their randomized treatment group assignment regardless of the treatment they actually 
received.
6.2 Safety
The safety population will include all patients who are enrolled and received at least 1 dose (any amount)
of study treatment (brentuximab vedotin, rituximab, or bendamustine) with treatment assignment based 
on actual treatment received. (Subjects receiving any amount of brentuximab vedotin during the study will 
be counted in the treatment arm for the safety analyses.)
Interim Analyses
Due to the study premature termination, the planned formal interim analysis for futility and the planned 
interim analysis for safety data will not occur.
Data Review
8.1 Data Handling and Transfer
Data handling and transfer specifications will be stated and conducted according to the Data 
Management Plan.
8.2 Data Screening
Beyond the data screening built into the PRA Data Management Plan, the PRA programming of analysis 
datasets, tables, figures, and listings (TFLs) provides additional data screening. 
Review of a TFL dry run on the nearly finalized database will allow for further data review prior to 
finalization. The dry run TFL will be discussed with the sponsor in a data review meeting to identify any 
final data issues and seek corrections prior to database lock. The PRA statistician and the sponsor must 
approve database lock.
Statistical Methods
All data collected during this study for all patients will be displayed in data listings, unless otherwise 
specified. Data listings will be sorted by treatment and patient identifier. Screen failures will be excluded 
from all tables and listings, except for those describing enrollment.  In addition, listings will include all 
relevant derived variables. Tables that are to be produced for both ITT and Safety Populations will only be 
presented if the populations are different. 
Descriptive statistics (mean, median, standard deviations [SDs], minimum and maximum values) for 
continuous variables will be presented. Mean and median will be presented to 1 decimal more than 
original data. SD will be presented to 2 decimals more than original data. Minimum and maximum will 


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match the decimal points in the original data. For categorical variables, summary measures will include 
the frequency and percentage (with 1 decimal place) of patients in each category.
The summary tables will be presented by 2 treatment groups (Brentuximab vedotin/rituximab/ 
bendamustine, rituximab/bendamustine) and overall.
Unless otherwise noted, missing data will not be imputed or carried forward. 
All data summaries and tabulations will be prepared with SASVersion 9.4 or higher.
9.1 Patient Disposition
The number of patients screened, enrolled, and the number and percentage of patients randomized in the 
study will be presented along with the number and percentage of patients in each analysis population for 
each treatment arm and overall. All percentages will be based on the number of patients enrolled in the 
respective treatment arm and overall.
Disposition of patients will be summarized by treatment arm and overall for the ITT and the Safety 
population. The number and percentage of treated patients, number and percentage of patients who 
completed combination treatment (6 cycles), number and percentage of patients who prematurely 
discontinued treatment and who entered long term survival follow up. For patients who had premature 
discontinuations the reasons for study discontinuation will be summarized.  All percentages will be based 
on the number of patients in the respective treatment arm and overall. A by-patient listing of disposition 
will also be provided.
9.2 Important Protocol Deviations 
Protocol deviations data will not be presented.
9.3 Demographic and Baseline Characteristics  
Demographic and baseline data will be summarized and listed for the ITT population. Variables to be 
presented include age (years), weight (kg), height (cm), BMI, gender (male, female), ethnicity (Hispanic or 
Latino, Not Hispanic or Latino), race (American Indian or Alaska Native, Asian, Black or African American, 
Native Hawaiian or Other Pacific Islander, White, Other), Eastern Cooperative Oncology Group (ECOG) 
and sAAIPI. 
By-patient listings will include demographic and baseline characteristics, initial disease diagnosis, and 
general medical history.
9.4 Treatments
9.4.1 Extent of Study Drug Exposure  
Exposure to treatment will be summarized separately for brentuximab vedotin, rituximab, and 
bendamustine for patients in the Safety population.  
The following summary statistics related to drug exposure will be calculated:

Number and percentage of patients with at least 1 dose delay per protocol reasons, and the 
number of doses delayed 

Number and percentage of patients with at least 1 dose reduced per protocol reasons, and the 
number of doses reduced 

Number and percentage of patients with at least 1 unplanned dose adjustment (which includes 
interrupted due to AE, interrupted due to other reason, stopped early due to AE, stopped early 
due to other reason, or dose errors not leading to interruption or stoppage),  by reason for 
unplanned adjustment, and the number of unplanned dose adjustments.


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
Number and percentage of patients with at least 1 infusion-related reaction, and the number of
infusion-related reactions

Number and percentage of patients with at least 1 delayed hypersensitivity reaction (>24 hours 
post last infusion), and the number of delayed hypersensitivity reactions

Duration of treatment (weeks)

Number of doses received

Number of cycles per patient

Frequency count for patients who receive 1 cycle, 2 cycles, and so on.

Cumulative dose (mg/kg and mg)

Average dosage per cycle (mg/kg and mg)
A listing of intended dose regimen, intended dose, actual dose administered, and reasons for dose 
delayed, dose reduced, dose adjustment, and/or infusion-related reactions will be displayed. 
9.4.2 Prior and Concomitant Medications
Prior and concomitant medications will be coded using World Health Organization (WHO) Drug (version: 
September 2007 or more recent).
All medications will be listed by patient, displaying verbatim name and preferred name, indication, and 
start and stop dates.
9.5 Efficacy Analyses
9.5.1 Primary Efficacy Variable
Due to the small number of patients recruited in the study there will be no formal assessment of the 
primary endpoint. The observed ORR (a best response of CR/CMR, PR/PMR) from response 
assessments up to and including the end of treatment visit as defined in section 4.1, will be presented by 
treatment arm for the ITT population along with the corresponding exact 90% and 95% confidence 
intervals (CIs) using the exact binomial method (i.e., Clopper-Pearson method). 
A by-patient listing of Response Assessments will be provided.
9.6 Safety Analyses   
All the safety endpoints will be summarized in tables and listings for the Safety population unless 
otherwise specified.
AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA, Version 18.1 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).  
9.6.1 Adverse Events  
All AEs will be coded by system organ class, MedDRA preferred term, and severity grade using NCI 
CTCAE Version 4.03.  
Treatment-Emergent AEs (TEAEs) are those that first occur or increase in severity from study Day 1 
through the EOT visit or 30 days after the last study treatment, whichever is later. See Appendix 3 
Treatment Emergent Adverse Event Programming Guide for definition of whether an AE is treatment 
emergent. 
AEs will be summarized by descending frequency of 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 


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class or preferred term, the patient will be counted only once for that specific system organ class or 
preferred term.
A related AE is one that is recorded as “Related” to any of the treatment components (brentuximab 
vedotin, rituximab, or bendamustine) on the CRF.
A summary table of number and percentage of the AE categories will be provided by treatment arm and 
total as follows:

Pre-existing AEs (defined as in Appendix 3)

All TEAEs

AEs related to treatment (brentuximab vedotin, rituximab, or bendamustine)

AEs with outcome of death

Serious Adverse Events (SAEs)

SAEs related to treatment (brentuximab vedotin, rituximab, or bendamustine)

AEs leading to dose delay of treatment (brentuximab vedotin, rituximab, or bendamustine)

AEs leading to dose interruption (full dose of brentuximab vedotin, rituximab, or bendamustine
received)

AEs leading to dose being stopped early (full dose of brentuximab vedotin, rituximab, or 
bendamustine not received)

AEs leading to dose reduction of treatment (brentuximab vedotin, rituximab, or bendamustine)

AEs leading to treatment discontinuation (brentuximab vedotin, rituximab, or bendamustine)

Grade 3-5 treatment-emergent AEs

Infusion-related reaction (IRR) AEs

Hypersensitivity Reaction (HSR) AEs

AEs that started during infusion of any study drug

AEs that started within 24 hours post infusion of any study drug

AEs of special interest (see Section 9.6.3)

TEAEs displayed by system organ class and preferred term 

TEAEs displayed by system organ class, preferred term and maximum severity
A listing of all AEs (including non-treatment-emergent AEs) recorded on the CRF will be provided.
9.6.2 Deaths and Serious Adverse Events
SAEs will be summarized as described above and listed.
Deaths, including cause of death and relationship to disease, will be listed. 
9.6.3 Adverse Events of Special Interest
The AEs of special interest will be summarized as described above and are detailed below:

Peripheral Neuropathy: identified using the Standard MedDRA Query (SMQ) “Peripheral 
Neuropathy” broad search.

Pulmonary Toxicity: identified using the SMQ “Interstitial Lung Disease” broad search.


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
Neutropenia: identified by MedDRA preferred term=”Neutropenia”
or “Neutrophil count
decreased”

IRRs: identified by the Investigator as an Infusion-Related reaction on the drug exposure page (of 
any study drug)
9.6.4 Laboratory Data  
Only central safety laboratory data will be summarized. Local safety laboratory data will not be presented. 
Laboratory results and NCI CTCAE grades for hematology, and serum chemistry will be presented in data 
listings. Laboratory data values will be converted to standard units. 
Hematology lab parameters include  red blood cell (RBC) count, white blood cell (WBC) count, 
hemoglobin, hematocrit and platelets, and the differential includes: neutrophils, lymphocytes, monocytes, 
eosinophils, and basophils. 
Serum chemistry tests include:  alanine aminotransferase (ALT), albumin, alkaline phosphatase (ALP), 
amylase, aspartate aminotransferase (AST), bilirubin (total), blood urea nitrogen (BUN), calcium, chloride, 
creatinine, lactate dehydrogenase (LDH), lipase, potassium, phosphorus, sodium, random glucose, 
creatinine clearance using the Cockcroft-Gault formula, and uric acid.
NCI CTCAE grades will be applied for the lab parameters included in Appendix 4 CTCAE V4.03 Grading 
for Laboratory Values. Laboratory measurements that are within their institutional limits of normal and are 
not graded as 1-4, per the CTCAE, will be summarized as “Grade 0,” which is defined as normal. 
The worst post baseline NCI CTCAE v4.03 or higher grade will be presented by treatment arm and total 
for each lab test.  Patients with multiple grades will be counted at their highest grade. Patients with at 
least 1 on-study measurement for each laboratory parameter will be included, regardless of whether or 
not a baseline assessment is present. Unscheduled lab values will also be considered for determining the 
maximum CTCAE grade. 
9.6.5 Vital Signs
Vital signs will be listed including body temperature, heart rate, blood pressure (diastolic and systolic), 
weight, height and body surface area (m2).
9.6.6 Eastern Cooperative Oncology Group (ECOG) Performance Status
A by-patient listing of ECOG performance status will be generated. 
9.6.7 Electrocardiograms (ECG) 
A by-patient listing of ECG assessments will be generated. 
9.6.8 Physical Examinations
Clinically significant findings observed during physical examinations will be recorded on the AE and pre-
existing condition CRFs. No analyses for physical examinations will be performed.
9.7 Pharmacokinetics/Pharmacodynamics, Antitherapeutic Antibodies and 
Disease Characteristics
Pharmacokinetic, Pharmacodynamic and Immunogenicity samples were not analyzed for this study and 
thus these data will not be presented.
9.8 Methods for Handling Dropouts and Missing Data
With the exception of time-related endpoints, missing observations will not be imputed, unless otherwise 
noted.
For missing or partial start and stop AE dates, see Appendix 2 Imputation of Partially Unknown Adverse 
Event Dates for rules.


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Note, for all listings the actual value for date (not imputed) will be presented in all data listings and 
imputed dates will only be used for programming flags, etc.
9.9 Data Transformations and Derivations
Age in years will be calculated with the SAS INTCK function using informed consent date and birth date.  
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. There is no Study 
Day 0. For all calculations of Study Day, the first dose date will be the earliest date of treatment 
administration for study drug.
Other time variables based on two dates, e.g., Start Date and End Date, will be calculated as (End Date –
Start Date + 1) (in days) unless otherwise specified in the planned analysis section.
The following unit conversion will be implemented unless otherwise specified:
Weeks = Days / 7
Months = Days / 30.4375
Years =Days / 365.25 
Validation
PRA seeks to ensure the quality of the results provided for the study in the form of TFLs, and the derived 
datasets used in their creation, through the following processes:
The entire set of TFLs will be checked for completeness and consistency prior to its delivery to the client 
by the lead analysis programmer, and the lead statistician, following PRA processes,.
The PRA validation process will be repeated any time TFLs are redelivered using different data. 
Execution of this validation process will be documented through the study Table of Programs that will be 
provided to Seattle Genetics at study conclusion.
References
[1] Cheson BD, Fisher RI, Barrington SF, et al.  Recommendations for Initial Evaluation, Staging, and 
Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification.  J Clin 
Oncol 32(27): 3059-67, 2014.




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NHL
Non-Hodgkin lymphoma
NMR
No metabolic response
NE
Non evaluable 
ORR
Objective Response Rate
OS
Overall Survival
PET
Positron emission tomography
PFS
Progression Free Survival
PD
Progressive Disease
PMR
Partial metabolic response
RBC
Red blood cell 
sAAIPI
Second-line age-adjusted International Prognostic Index
SAP
Statistical analysis plan
SAE
Serious Adverse Event
SD
Standard deviation
TEAE
Treatment-emergent adverse event
TFL
Tables, figures, and listings 
WBC
White blood cell 
WHO
World Health Organization 


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Appendix 2 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. 
1.
AE day and month are missing:
a.
If the year is the same as the year of first dose of any study treatment (for combination 
studies this implies any component of the regimen) and the onset period indicates that 
the start of the AE was pre-dose:
i.
AE start date will be imputed as the minimum of (AE condition end date*, day 
prior to first dose of any study treatment)
b.
If the year is the same as the year of first dose of any study treatment and the onset 
period indicates that the start of the AE was post-dose:
i.
AE start date will be imputed as the minimum of (AE condition end date*, first 
dose date of any study treatment)
c.
If the year is before the year of first dose of any study treatment:
i.
AE start date will be imputed as the minimum of (AE condition end date*, 
December 31st) - see example 2 below
d.
If the year is after the year of first dose of any study treatment:
i.
AE start date will be imputed as the minimum of (AE condition end date*, 
January 31st) - see example 2 below
2.
AE month only is missing:
a.
Treat day as missing and replace both month and day according to the above procedure
3.
AE day only is missing:
a.
If the month/year is the same as the month/year of first dose of any study treatment and 
the onset period indicates that the start of the AE was pre-dose:
i.
AE start date will be imputed as the minimum of (AE condition end date*, day 
prior to first dose of any study treatment)
b.
If the month/year is the same as the month/year of first dose of any study treatment and 
the onset period indicates that the start of the AE was post-dose:
i.
AE start date will be imputed as the minimum of (AE condition end date*, first 
dose date of any study treatment)
c.
If the month/year is before the month/year of first dose of any study treatment:
i.
AE start date will be imputed as the minimum of (AE condition end date*, last day 
of the month)
d.
If the month/year is after the month/year of first dose of any study treatment:


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i.
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:
1.
The AE records for a condition/event should be sorted by the imputed start dates then record 
position (order of entry into the eCRF). 
a.
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.  
b.
Repeat step 1. 
2.
After sorting the AE records, apply the following rules to partial or missing AE condition end 
dates:
a.
For all records excluding the last chronological record for a condition/event:
i.
AE condition end date will be imputed as the start date of the subsequent record
b.
For the last chronological record for a condition/event:
ii.
If outcome is “recovered/resolved”, ”recovered/resolved with sequelae”, or “fatal”:
1.
AE condition end date will be imputed as the minimum of (last dose date 
+ 30, death date, data extraction date, or last day of month if month and 
year known, or last day of year if only year is known)
iii.
If outcome is “recovering/resolving”, “not recovered/resolved”, “unknown”, or 
blank:
1.
AE condition end date will not be imputed.
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


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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 1stdose
UNAPR2012
04MAY2012
1
recovered/resolved
post 1stdose
15JAN2013
UNUNK2013
2
recovering/resolving
post 1stdose
UNUNK2013
UNFEB2013
2
not recovered/resolved
post 1stdose
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
15JAN2013
31JAN2013
2
recovering/resolving
31JAN2013
UNFEB2013
2
not recovered/resolved
Example 2a:
Prior to imputation:
Start date
Condition end date
Severity
Outcome
Onset
15FEB2013
UNUNK2013
2
recovering/resolving
post 1stdose
UNUNK2013
UNFEB2013
2
not recovered/resolved
post 1stdose
Post imputation:
Start date
Condition end date
Severity
Outcome
15FEB2013
UNUNK2013
2
recovering/resolving
31JAN2013*
15FEB2013
2
not recovered/resolved
*Note: This AE would now precede theother AE withthe same year after sorting.


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Appendix 3 Treatment Emergent Adverse Event Programming Guide
Term
Standard Definition
Treatment 
emergent
Any newly occurring or worsening AE, where newly occurring means an AE that 
was not present at baseline. (E.g., if the patient had a grade 1 headache at 
baseline that resolved and later had another grade 1 headache, that second 
headache would NOT be considered a TEAE. See below for more algorithm 
details.)
Where:
1. Get first dose date/time of study medication
2. Define baseline/pre-existing AEs as AEs with:

An onset period of (“started before the signing of informed consent”, or 
“started after consent but before the first dose of investigational product”.  

If the onset period of the AE is missing, then look for AE start date < first 
dose date or AE start date = first dose date and onset time is ‘Started 
before first infusion or before infusion on any dosing day’. 

If AE start date is missing, use AE start date imputation rule (described 
in Appendix 2). 
<AND>

a stop date that is:

≥first dose date <OR>

missing with outcome equal to

recovering/resolving (this outcome may or may not have 
a date with it), or

not recovered/not resolved, or

unknown

Note: AEs with no outcome and missing stop dates 
should be queried. 

Note:  If the event ended on Day 1 (the day of first dose) it will be 
considered a baseline event.
  
3. Define post-baseline AEs as AEs with an onset period of (“started after the 
first dose of investigational product”.  If the onset period of the AE is missing, 
then look for AE start date >= first dose date (from 1) or AE start date = first dose 
date (from 1) but onset time is NOT ‘Started before first infusion or before 
infusion on any dosing day’. If AE start date is missing, use AE start date 
imputation rule.
4. Compare post-baseline AEs to baseline AEs using lower level term (LLT). 

If terms match from baseline to post-baseline:

compare CTC grades. If post-baseline CTC grade is > baseline 
CTC grade, then TEAE=YES. If post-baseline CTC grade is <= 
baseline CTC grade, then TEAE=NO. 

If there are no matching terms from baseline to post-baseline, then 
TEAE=Yes. 

If post-baseline AEs are uncoded, then TEAE = Yes. 
NOTE: if there isn’t enough information (partial dates, onset period flags) 
to determine TEAE, those events should be counted as TEAE = Yes.


Statistical Analysis Plan
Effective Date: 19JUL2018/Version 2.0
Sponsor: Seattle Genetics, Inc
Protocol no: SGN35-023
PRS 005 T 17 E
Page 21 of 23
Strictly Confidential.  © 2004-2014, PRA Health Sciences.  All rights reserved.
Appendix 4 CTCAE V4.03 Grading for Laboratory Values
CTCAE v4.03 
SOC
CTCAE v4.03 
Term
Grade 1
Grade 2
Grade 3
Grade 4
Investigations
White blood 
cell decreased
<LLN -
3000/mm3; 
<LLN - 3.0 
109/L
<3000 -
2000/mm3; 
<3.0 - 2.0 
109/L
<2000 -
1000/mm3; 
<2.0 - 1.0 109
/L
<1000/mm3; 
<1.0 109/L
Investigations
White blood 
cell increased 
(leukocytosis)
-
-
>100,000 mm3
Clinical 
manifestations 
of leucostasis; 
urgent 
intervention 
indicated
Blood and 
lymphatic 
system 
disorders
Anemia
Hemoglobin 
(Hgb) <LLN -
10.0 g/dL; 
<LLN - 6.2 
mmol/L; <LLN 
- 100 g/L
Hgb <10.0 -
8.0 g/dL; <6.2 
- 4.9 mmol/L;  
<100 - 80g/L
Hgb <8.0 g/dL; 
<4.9 mmol/L;
<80 g/L; 
transfusion 
indicated
Life-
threatening 
consequences; 
urgent 
intervention 
indicated
Investigations
Lymphocyte 
count 
decreased
<LLN -
800/mm3; 
<LLN - 0.8 
x109 /L
<800 -
500/mm3; 
<0.8 - 0.5 109
/L
<500 -
200/mm3; 
<0.5 - 0.2 109
/L
<200/mm3; 
<0.2 109 /L
Investigations
Lymphocyte 
count increased
-
>4000 - 20,000 
mm3
>20,000 mm3
-
Investigations
Neutrophil 
count 
decreased
<LLN -
1500/mm3; 
<LLN - 1.5 
109/L
<1500 -
1000/mm3; 
<1.5 - 1.0 
109/L
<1000 -
500/mm3; <1.0 
- 0.5 109/L
<500/mm3; 
<0.5 109/L
Investigations
Platelet count 
decreased
<LLN -
75,000/mm3; 
<LLN - 75.0 
109/L
<75,000 -
50,000/mm3; 
<75.0 - 50.0 
109/L
<50,000 -
25,000/mm3; 
<50.0 - 25.0 
109/L
<25,000/mm3; 
<25.0 109/L
Investigations
Serum 
amlylase 
increased
>ULN - 1.5 
ULN
>1.5 - 2.0 
ULN
>2.0 - 5.0 
ULN
>5.0 ULN
Metabolism 
and nutrition 
disorders
Hypoalbumine
mia
<LLN - 3 g/dL; 
<LLN - 30 g/L
<3 - 2 g/dL; 
<30 - 20 g/L
<2 g/dL; <20 
g/L
Life-
threatening 
consequences; 
urgent 
intervention 
indicated


Statistical Analysis Plan
Effective Date: 19JUL2018/Version 2.0
Sponsor: Seattle Genetics, Inc
Protocol no: SGN35-023
PRS 005 T 17 E
Page 22 of 23
Strictly Confidential.  © 2004-2014, PRA Health Sciences.  All rights reserved.
CTCAE v4.03 
SOC
CTCAE v4.03 
Term
Grade 1
Grade 2
Grade 3
Grade 4
Investigations
Alkaline 
phosphatase 
increased
>ULN - 2.5 
ULN
>2.5 - 5.0 
ULN
>5.0 - 20.0 
ULN
>20.0 ULN
Investigations
Alanine 
aminotransfera
se increased
>ULN - 3.0 
ULN
>3.0 - 5.0 x 
ULN
>5.0 - 20.0 x 
ULN
>20.0 ULN
Investigations
Aspartate 
aminotransfera
se increased
>ULN - 3.0 
ULN
>3.0 - 5.0 x 
ULN
>5.0 - 20.0 x 
ULN
>20.0 ULN
Investigations
Blood bilirubin
increased
>ULN - 1.5 
ULN
>1.5 - 3.0 
ULN
>3.0 - 10.0 
ULN
>10.0 ULN
Investigations
GGT increased
>ULN – 2.5 x 
ULN
>2.5 - 5.0 
ULN
>5.0 - 20.0 
ULN
>20.0 ULN
Investigations
Hemoglobin 
increased
Increase in >0-
2 gm/dl above 
ULN or above 
baseline if 
baseline is 
above ULN
Increase in >2-
4 gm/dl above 
ULN or above 
baseline if 
baseline is 
above ULN
Increase in >4 
gm/dl above 
ULN or above 
baseline if 
baseline is 
above ULN
-
Investigations
Lipase 
increased
>ULN - 1.5 
ULN
>1.5 - 2.0 
ULN
>2.0 - 5.0 
ULN
>5.0 ULN
Metabolism 
and nutrition 
disorders
Hypercalcemia
Corrected 
serum calcium 
of
>ULN - 11.5 
mg/dL; >ULN 
- 2.9
mmol/L; 
Ionized 
calcium >ULN
- 1.5 mmol/L
Corrected 
serum calcium 
of
>11.5 - 12.5 
mg/dL; >2.9 -
3.1
mmol/L; 
Ionized 
calcium >1.5 -
1.6 mmol/L; 
symptomatic
Corrected 
serum calcium 
of
>12.5 - 13.5 
mg/dL; >3.1 -
3.4
mmol/L; 
Ionized 
calcium >1.6 -
1.8 mmol/L; 
hospitalization
indicated
Corrected 
serum calcium 
of
>13.5 mg/dL; 
>3.4 mmol/L;
Ionized 
calcium >1.8 
mmol/L;
life-threatening 
consequences
Metabolism 
and nutrition 
disorders
Hypocalcemia
Corrected 
serum calcium 
of
<LLN - 8.0 
mg/dL; <LLN 
- 2.0
mmol/L; 
Ionized 
calcium <LLN 
-
1.0 mmol/L
Corrected 
serum calcium 
of
<8.0 - 7.0 
mg/dL; <2.0 -
1.75
mmol/L; 
Ionized 
calcium <1.0 -
0.9 mmol/L; 
symptomatic
Corrected 
serum calcium 
of
<7.0 - 6.0 
mg/dL; <1.75 -
1.5
mmol/L; 
Ionized 
calcium <0.9 -
0.8 mmol/L; 
hospitalization
indicated
Corrected 
serum calcium 
of
<6.0 mg/dL; 
<1.5 mmol/L;
Ionized 
calcium <0.8 
mmol/L;
life-threatening 
consequences


Statistical Analysis Plan
Effective Date: 19JUL2018/Version 2.0
Sponsor: Seattle Genetics, Inc
Protocol no: SGN35-023
PRS 005 T 17 E
Page 23 of 23
Strictly Confidential.  © 2004-2014, PRA Health Sciences.  All rights reserved.
CTCAE v4.03 
SOC
CTCAE v4.03 
Term
Grade 1
Grade 2
Grade 3
Grade 4
Investigations
Creatinine 
increased
>1 - 1.5 
baseline; 
>ULN - 1.5 
ULN
>1.5 - 3.0 
baseline; >1.5 -
3.0 ULN
>3.0 baseline; 
>3.0 - 6.0 
ULN
>6.0 ULN
Metabolism 
and nutrition 
disorders
Hyperglycemia
Fasting glucose 
value >ULN -
160 mg/dL;
Fasting glucose 
value >ULN -
8.9 mmol/L
Fasting glucose 
value >160 -
250 mg/dL;
Fasting glucose 
value >8.9 -
13.9 mmol/L
>250 - 500 
mg/dL; >13.9 -
27.8 mmol/L; 
hospitalization 
indicated
>500 mg/dL; 
>27.8 mmol/L; 
life-threatening 
consequences
Metabolism 
and nutrition 
disorders
Hypoglycemia
<LLN - 55 
mg/dL; <LLN 
- 3.0 mmol/L
<55 - 40 
mg/dL; 
<3.0 - 2.2 
mmol/L
<40 - 30 
mg/dL; 
<2.2 - 1.7 
mmol/L
<30 mg/dL; 
<1.7 mmol/L; 
life-threatening 
consequences; 
seizures
Metabolism 
and nutrition 
disorders
Hypophosphat
emia
<LLN - 2.5 
mg/dL; <LLN 
- 0.8 mmol/L
<2.5 - 2.0 
mg/dL; <0.8 -
0.6 mmol/L
<2.0 - 1.0 
mg/dL; <0.6 -
0.3 mmol/L
<1.0 mg/dL; 
<0.3 mmol/L; 
life-threatening 
consequences
Metabolism 
and nutrition 
disorders
Hyperkalemia
>ULN - 5.5 
mmol/L
>5.5 - 6.0 
mmol/L
>6.0 - 7.0 
mmol/L; 
hospitalization 
indicated
>7.0 mmol/L; 
life-threatening 
consequences
Metabolism 
and nutrition 
disorders
Hypokalemia
<LLN - 3.0 
mmol/L
<LLN - 3.0 
mmol/L; 
symptomatic; 
intervention 
indicated
<3.0 - 2.5 
mmol/L; 
hospitalization 
indicated
<2.5 mmol/L; 
life-threatening 
consequences
Metabolism 
and nutrition 
disorders
Hyponatremia
<LLN - 130 
mmol/L
-
<130 - 120 
mmol/L
<120 mmol/L; 
life-threatening 
consequences
Metabolism 
and nutrition 
disorders
Hypernatremia
>ULN - 150 
mmol/L
>150 - 155 
mmol/L
>155 - 160 
mmol/L; 
hospitalization 
indicated
>160 mmol/L; 
life-threatening 
consequences
Metabolism 
and nutrition 
disorders
Hyperuricemia
>ULN – 10 
mg/dl (0.59 
mmol/L) 
without 
physiologic 
consequences
-
>ULN  - 10 
mg/dl (0.59 
mmol/L) with 
physiologic 
consequences
>10 mg/dl ; 
>0.59 mmol/L; 
life-threatening 
consequences