Clinical trial NCT02592876
Conditions: Lymphoma, B-cell Lymphoma, Large B-Cell, Diffuse Lymphoma, Follicular, Grade 3b Follicular Lymphoma, Grade 3b
Keywords: Antibodies, Monoclonal Antibody-Drug Conjugate Antigens, CD19 Autologous Stem Cell Transplant Drug Therapy Follicular Lymphoma Grade 3b Hematologic Diseases Immune System Diseases Immunoproliferative Disorders Immunotherapy Lymphatic Diseases Lymphoma Lymphoma, B-Cell Lymphoma, Large B-Cell, Diffuse Lymphoma, Non-Hodgkin Monomethylauristatin F Neoplasms Neoplasms by Histologic Type Transformed Lymphoma / DLBCL Rituximab Ifosfamide Carboplatin Etoposide
Sponsor: Seagen Inc.
Start date: 2015-10-01; Completion date: 2018-04-20
Enrollment: 81 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this randomized, open-label study is to evaluate the safety and efficacy of denintuzumab mafodotin plus RICE (rituximab, ifosfamide, carboplatin, and etoposide) when compared to RICE alone in the treatment of patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) or Grade 3b follicular lymphoma. Eligible patients must also be candidates for autologous stem cell transplant. Patients will be randomly assigned in a 1:1 ratio to receive 3 cycles of study treatment with either denintuzumab mafodotin + RICE or RICE alone. The study will assess whether there is a difference between the 2 groups in the side effects that are reported and the number of patients who achieve complete remission at the end of their study treatment.

Detailed description:

Arms: arm 1: Denintuzumab mafodotin plus rituximab, ifosfamide, carboplatin, and etoposide arm 2: Rituximab, ifosfamide, carboplatin, and etoposide
Interventions: intervention 1: denintuzumab mafodotin intervention 2: rituximab intervention 3: ifosfamide intervention 4: carboplatin intervention 5: etoposide
Intervention descriptions: intervention 1: Denintuzumab mafodotin 3 mg/kg by intravenous (IV) infusion, every 3 weeks for up to 3 cycles. intervention 2: 375 mg/m\^2 by IV infusion, every 3 weeks for up to 3 cycles intervention 3: 5000 mg/m\^2 by IV infusion over a 24-hour period, every 3 weeks for up to 3 cycles intervention 4: AUC 5mg/mL x min by IV infusion, every 3 weeks for up to 3 cycles intervention 5: 100 mg/m\^2 per day by IV infusion for 3 days, every 3 weeks for up to 3 cycles

Protocol documents:
Prot_000.pdf: 


Study SGN19A-003  
 Clinical Protocol  
 Amendment 2; 28-Oct-2017 
Denintuzumab mafodotin  
 Seattle Genetics, Inc. - Confidential  
 Page 2 of 83 
PROTOCOL SYNOPSIS 
Protocol Number 
SGN19A-003 
Version 
Amendment 2; 28-Oct-2017 
Phase 
2 
Product Name 
Denintuzumab mafodotin (SGN-CD19A) 
Sponsor 
Seattle Genetics, Inc. 
21823 30th Drive SE 
Bothell, WA 98021, USA 
 
Protocol Title 
A randomized, open-label phase 2 study of denintuzumab mafodotin (SGN-CD19A) plus rituximab, ifosfamide, 
carboplatin, and etoposide (19A+RICE) chemotherapy vs. RICE in the treatment of patients with relapsed or 
refractory diffuse large B-cell lymphoma (DLBCL) who are candidates for autologous stem cell transplant 
Study Objectives 
Primary: 
● To compare the complete remission (CR) rates in patients with relapsed/refractory DLBCL who are 
candidates for autologous stem cell transplant (ASCT) treated with denintuzumab mafodotin plus RICE 
(19A+RICE) versus RICE 
Secondary: 
● To evaluate the safety of denintuzumab mafodotin given in combination with RICE 
● To compare progression-free survival (PFS) between study arms 
● To compare overall survival (OS) between study arms 
● To compare the proportion of patients who are able to adequately mobilize peripheral blood stem cells 
(PBSC) between study arms 
● To compare the proportion of patients receiving ASCT following study treatment between study arms 
● To compare other measures of antitumor activity between study arms 
Additional: 
● To evaluate the pharmacokinetics (PK) of denintuzumab mafodotin (antibody-drug conjugate [ADC] and 
cys-mcMMAF) when denintuzumab mafodotin is given in combination with RICE chemotherapy 
● To evaluate the incidence of antitherapeutic antibodies (ATA) against denintuzumab mafodotin 
● To assess denintuzumab mafodotin-mediated pharmacodynamic (PD) effects and potential biomarkers to 
stratify response 
Study Population 
Eligible patients are aged 18 years and older with histologically confirmed CD20-positive (CD20-positivity 
requirement not applicable to Amendment 2), relapsed or refractory DLBCL (including de novo and 
transformed DLBCL, Grade 3b follicular lymphoma, and patients with DLBCL found to have small-cell 
infiltration of the bone marrow or other diagnostic material), have received frontline treatment with 
CD20-directed immunotherapy with anthracycline- or anthracenedione-based multi-agent chemotherapy, and 
are candidates for high-dose chemotherapy followed by ASCT. All patients must have achieved a response of 
stable disease or better (when compared to the baseline, pre-treatment disease assessment) following the last 
cycle of frontline treatment with multi-agent chemo-immunotherapy regimens delivered with curative intent, 
and for patients enrolled under Amendment 2, patients must have relapsed less than or equal to 6 months from 
the completion of frontline therapy at the time of initial dosing in this clinical trial. A representative tissue 
sample from the most recent biopsy after last therapy must be available, or a fresh biopsy must be obtained at 
baseline. Fluorodeoxyglucose (FDG)-avid disease by positive emission tomography (PET), measurable disease 


Study SGN19A-003  
 Clinical Protocol  
 Amendment 2; 28-Oct-2017 
Denintuzumab mafodotin  
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of >1.5 cm by computed tomography (CT), an Eastern Cooperative Oncology Group (ECOG) performance 
status of ≤2, and adequate renal, hepatic and hematologic function are required at baseline. 
Patients are not eligible if they have previous history of any of the following: indolent lymphoma treated with 
more than 1 multi-agent chemotherapy regimen or previous cancer therapy for recurrent DLBCL or Grade 3b 
follicular lymphoma; autologous or allogeneic stem cell transplant (SCT); another primary invasive cancer, 
hematologic malignancy or myelodysplastic syndrome that has not been in remission for at least 1 year; or 
progressive multifocal leukoencephalopathy (PML). Patients are not permitted in the study if they have any of 
the following: cerebral/meningeal disease related to the underlying malignancy; corneal disorders, monocular 
vision, or certain active ocular disorders requiring treatment; Class III or IV congestive heart failure; active 
Grade 3 or higher (per the NCI CTCAE, Version 4.03 or higher) viral, bacterial, or fungal infection within 
2 weeks of the first dose of study drug; positive polymerase chain reaction (PCR) assay with positive hepatitis 
surface antigen and/or anti-hepatitis B core antibody, known or suspected active hepatitis C infection, or known 
human immunodeficiency virus (HIV) infection; or known urinary tract obstruction. Chemotherapy, 
radiotherapy, biologics, and/or other antitumor treatment with immunotherapy must be completed 4 weeks prior 
to study entry; however, radiotherapy within 4 weeks prior to study entry is acceptable if the underlying disease 
has progressed on treatment. 
Number of Planned Patients 
Approximately 100 patients will be randomized in a 1:1 ratio to 1 of 2 study arms (~50 patients in each arm). If 
dose modification of denintuzumab mafodotin is necessary, up to 50 additional patients (25 in each arm) may be 
randomized. If a subset of patients appears to potentially derive benefit from 19A+RICE versus RICE at a pre-
planned evaluation, the Sponsor may continue enrolling those patients beyond the planned sample size 
(approximately 100 patients), but will not exceed the planned maximum number of patients to be randomized in 
this study (up to approximately 150 patients). 
Study Design 
This is a randomized, open-label phase 2 study designed to compare the CR rates in patients with relapsed or 
refractory DLBCL who are candidates for ASCT. Patients will be randomized in a 1:1 ratio to 1 of 2 study arms: 
1. Control, RICE Arm: 3 cycles (3 weeks per cycle) of RICE 
2. Investigational, 19A+RICE Arm: 3 cycles (3 weeks per cycle) of denintuzumab mafodotin 
administered on Day 1 of every cycle, in conjunction with 3 cycles (3 weeks per cycle) of RICE 
Lymphoma response and progression will be assessed using the Lugano Classification Revised Staging System 
for malignant lymphoma (Cheson 2014). CT scans (neck, chest, abdomen, and pelvis) and PET scans will be 
performed at baseline and at end of treatment (EOT). Follow-up assessments will be performed at 3, 6, 12, 18, 
24 months, and then annually after ASCT or EOT (for patients who don’t receive ASCT). For all follow-up 
assessments, both PET and CT scans are required until disease is PET negative; responses will then be followed 
by CT scans of diagnostic quality. A CT scan of diagnostic quality will also be performed at the time of 
suspected clinical progression. Follow-up assessments will continue until disease progression, initiation of a 
new anticancer treatment (with the exception of a stem cell transplant), or study closure, whichever occurs first. 
Survival status follow-up will continue until patient death or study closure, whichever occurs first. 
A safety monitoring committee (SMC) comprising the study investigators, medical monitor, and study 
biostatistician will monitor the safety of patients at predefined interim safety evaluations and over the course of 
the treatment period. 
Test Product, Dose, and Mode of Administration 
Both arms: RICE administered in 21-day cycles, with rituximab 375 mg/m2 given as the first component of 
RICE via intravenous (IV) infusion on Day 1; and followed by etoposide (100 mg/m2 per day), ifosfamide 
(5000 mg/m2) with mesna, and carboplatin (area under the curve 5 mg/mL x min; maximum dose, 800 mg) 
administered during each cycle in an order as per institutional standard of care. 
19A+RICE Arm only: denintuzumab mafodotin 3 mg/kg administered via IV infusion on Day 1 of every 21-day 
cycle prior to the rituximab component of RICE therapy. The SMC may recommend modification of the dose of 


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 Clinical Protocol  
 Amendment 2; 28-Oct-2017 
Denintuzumab mafodotin  
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denintuzumab mafodotin (e.g., to 2 mg/kg) in subsequently enrolled patients upon evaluation of the data at the 
predefined interim safety evaluations. 
Duration of Treatment 
Patients may receive a maximum of 3 cycles (3 weeks per cycle) of treatment, either 19A+RICE or RICE alone. 
Efficacy Assessments 
Disease response will be assessed by both the investigator and an independent review facility (IRF) based on 
the Lugano classification criteria (Cheson 2014). 
Pharmacokinetic and Antitherapeutic Antibody Assessments 
Patients in both treatment arms will have blood samples collected for pharmacokinetic and antitherapeutic 
antibody (ATA) evaluation at protocol-defined timepoints. 
Biomarker Assessments 
Biomarker evaluation may include but not be limited to baseline measurement and change of circulating B cells 
by flow cytometry. Pre- and post-treatment serum and plasma will be obtained and evaluated for soluble 
mediator quantification. Peripheral blood cell pellets will be collected for assessment of FC gamma receptor 
(FcγR) polymorphisms. In addition, evaluation of tumor biopsies may include but not be limited to therapeutic 
target CD19 and other immune cell marker expression by immunohistochemistry, cell of origin, as well as 
somatic mutations that are prognostic or predictive of denintuzumab mafodotin response. 
Safety Assessments 
Safety assessments will include the surveillance and recording of adverse events (AEs), physical examination 
findings, and laboratory tests. Ophthalmologic exams and ocular health surveys will be conducted at protocol-
specific timepoints. PBSC collection will also be assessed as a measure of safety. Additionally, transplant-
related data following ASCT will be collected and will include, but not be limited to, the time to neutrophil and 
platelet engraftment in each treatment arm. 
Statistical Methods 
Sample Size Considerations 
With approximately 100 patients randomized in a 1:1 ratio to each treatment arm (~50 patients per arm) for the 
primary analysis, the study is designed to have approximately 80% power to detect an increase in the CR rate of 
25% (e.g., from 35% in RICE Arm to 60% in 19A+RICE Arm). This calculation is based on a two-sided χ2 test 
with significance level of α = 0.1 using EAST 5.4. 
If the dose of denintuzumab mafodotin in the investigational 19A+RICE Arm is modified, up to 50 additional 
patients may be randomized (25 in each arm) so that a total of 100 patients will be randomized in a 1:1 ratio to 
either the 19A (modified dose) + RICE arm or the RICE only arm. Up to approximately 150 patients may be 
randomized in this study. If a subset of patients appears to potentially derive benefit from 19A+RICE versus 
RICE at a pre-planned evaluation, the Sponsor may continue enrolling those patients beyond the planned 
sample size (approximately 100 patients), but will not exceed the planned maximum number of patients to be 
randomized in this study (up to approximately 150 patients). 
Randomization 
Stratified block randomization will be performed centrally. Patients will be stratified by 3 factors: 
● Disease status 
● Second-line age-adjusted International Prognostic Index (saaIPI) score or standard IPI score, as appropriate to 
patient age, at randomization 
● Disease type 
Safety Analysis 
The safety analysis will evaluate the type, incidence, severity, seriousness, and relatedness of AEs, the ability to 
mobilize stem cells, and the type, incidence, and severity of laboratory abnormalities. 


Study SGN19A-003  
 Clinical Protocol  
 Amendment 2; 28-Oct-2017 
Denintuzumab mafodotin  
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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ....................................................................................................................................... 2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ......................................................................... 8 
1 
INTRODUCTION ......................................................................................................................................... 10 
1.1 
Diffuse Large B-Cell Lymphoma ....................................................................................................... 10 
1.2 
CD19 .................................................................................................................................................. 11 
1.3 
Denintuzumab Mafodotin ................................................................................................................... 11 
1.3.1 
Mechanism of Action of Denintuzumab Mafodotin ............................................................. 12 
1.3.2 
Experience with Denintuzumab Mafodotin .......................................................................... 12 
1.4 
Rationale for Study ............................................................................................................................. 12 
2 
OBJECTIVES ............................................................................................................................................... 14 
2.1 
Primary Objective ............................................................................................................................... 14 
2.2 
Secondary Objectives ......................................................................................................................... 14 
2.3 
Additional Objectives ......................................................................................................................... 14 
2.4 
Endpoints ............................................................................................................................................ 14 
2.4.1 
Primary Endpoint ................................................................................................................. 14 
2.4.2 
Secondary Endpoints ............................................................................................................ 14 
2.4.3 
Additional Endpoints ............................................................................................................ 15 
3 
INVESTIGATIONAL PLAN ....................................................................................................................... 15 
3.1 
Summary of Study Design .................................................................................................................. 15 
3.1.1 
Dose-Delaying Toxicity ....................................................................................................... 16 
3.1.2 
Interim Safety Evaluations ................................................................................................... 17 
3.2 
Discussion and Rationale for Study Design........................................................................................ 17 
3.2.1 
Method of Assigning Patients to Treatment Groups ............................................................ 18 
3.2.2 
Rationale for Selection of Doses .......................................................................................... 18 
3.2.3 
Blinding ................................................................................................................................ 19 
4 
STUDY POPULATION................................................................................................................................ 19 
4.1 
Inclusion Criteria ................................................................................................................................ 19 
4.2 
Exclusion Criteria ............................................................................................................................... 21 
4.3 
Removal of Patients from Therapy or Assessment ............................................................................. 22 
4.3.1 
Discontinuation of Study Drug ............................................................................................. 22 
4.3.2 
Patient Withdrawal from Study ............................................................................................ 22 
5 
TREATMENTS ............................................................................................................................................ 23 
5.1 
Treatments Administered.................................................................................................................... 23 
5.2 
Investigational Study Drug ................................................................................................................. 23 
5.2.1 
Description ........................................................................................................................... 23 
5.2.2 
Dose and Administration ...................................................................................................... 23 
5.2.3 
Storage and Handling ........................................................................................................... 24 
5.2.4 
Packaging and Labeling ....................................................................................................... 24 
5.2.5 
Preparation ........................................................................................................................... 24 
5.3 
Rituximab, Etoposide, Ifosfamide, and Carboplatin ........................................................................... 24 
5.3.1 
Description ........................................................................................................................... 25 
5.3.2 
Method of Procurement ........................................................................................................ 25 
5.3.3 
Dose and Administration ...................................................................................................... 25 
5.3.4 
Storage and Handling ........................................................................................................... 25 
5.3.5 
Packaging and Labeling ....................................................................................................... 25 
5.3.6 
Preparation ........................................................................................................................... 25 
5.4 
Required Premedication and Postmedication ..................................................................................... 25 
5.4.1 
Prophylactic Ocular Interventions for Denintuzumab Mafodotin ........................................ 26 
5.5 
Concomitant Therapy ......................................................................................................................... 28 
5.5.1 
Required Concomitant Therapy ........................................................................................... 28 
5.5.2 
Allowed Concomitant Therapy ............................................................................................ 28 
5.5.3 
Prohibited Concomitant Therapy ......................................................................................... 29 


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5.6 
Management of Infusion Reactions .................................................................................................... 29 
5.7 
Management of Suspected PML ......................................................................................................... 30 
5.8 
Dose Modifications............................................................................................................................. 30 
5.8.1 
Dose Modifications for Ocular Events ................................................................................. 31 
5.9 
Peripheral Blood Stem Cell Mobilization and Collection .................................................................. 33 
5.10 Treatment Compliance ....................................................................................................................... 33 
6 
STUDY ACTIVITIES ................................................................................................................................... 33 
6.1 
Schedule of Events ............................................................................................................................. 33 
6.2 
Screening Visit (Day –28 to Day 1).................................................................................................... 33 
6.2.1 
Baseline Visit (Day –7 to Day 1) ......................................................................................... 34 
6.3 
Randomization (Day –1 to Day 1) ...................................................................................................... 34 
6.4 
Treatment Period (Day 1 to Day 21) .................................................................................................. 34 
6.4.1 
Cycle 1, Day 1 ...................................................................................................................... 34 
6.4.2 
Cycle 1, Day 1 to Day 3 (+1 day) ......................................................................................... 35 
6.4.3 
Cycle 1, Day 4 ...................................................................................................................... 35 
6.4.4 
Cycle 1, Day 8 (±1 day) ....................................................................................................... 35 
6.4.5 
Cycle 1, Day 15 (±1 day) ..................................................................................................... 35 
6.4.6 
Cycle 1, Day 22 (±3 days) .................................................................................................... 35 
6.4.7 
Cycles 2 and 3: Day 1 (±1 day) ............................................................................................ 35 
6.4.8 
Cycles 2 and 3: Day 1 to Day 3 (±1 day) ............................................................................. 36 
6.4.9 
Cycles 2 and 3: Day 8 (±1 day) ............................................................................................ 36 
6.4.10 
Cycles 2 and 3: Day 15 (±1 day) .......................................................................................... 36 
6.4.11 
Cycle 2, Day 22 (±3 days) .................................................................................................... 37 
6.5 
PBSC Mobilization ............................................................................................................................. 37 
6.6 
End of Treatment Visit ....................................................................................................................... 37 
6.7 
Long-Term Follow-Up Visits ............................................................................................................. 38 
6.8 
End of Study/End of Follow-Up ......................................................................................................... 39 
7 
STUDY ASSESSMENTS ............................................................................................................................. 39 
7.1 
Screening/Baseline Assessments ........................................................................................................ 39 
7.2 
Response/Efficacy Assessments ......................................................................................................... 40 
7.3 
Pharmacokinetic and Antitherapeutic Antibody Assessments ............................................................ 41 
7.4 
Biomarker Analysis ............................................................................................................................ 43 
7.4.1 
B-Cell Subsets Analysis ....................................................................................................... 43 
7.4.2 
Protein Markers in Blood ..................................................................................................... 43 
7.4.3 
Fc-γ Receptor (FcγR) Variants ............................................................................................. 43 
7.4.4 
Characterization of Tumor Tissue ........................................................................................ 44 
7.5 
Biospecimen Repository ..................................................................................................................... 44 
7.6 
Patient-Reported Outcomes ................................................................................................................ 44 
7.6.1 
Ocular Health Survey ........................................................................................................... 44 
7.7 
Safety Assessments............................................................................................................................. 44 
7.7.1 
Adverse Events ..................................................................................................................... 45 
7.7.2 
Vital Signs ............................................................................................................................ 50 
7.7.3 
Clinical Laboratory Tests ..................................................................................................... 50 
7.7.4 
Physical Examination ........................................................................................................... 50 
7.7.5 
Ocular Monitoring Plan ........................................................................................................ 51 
7.7.6 
Monitoring for Tumor Lysis Syndrome ............................................................................... 51 
7.7.7 
ECOG Performance Status ................................................................................................... 51 
7.8 
Appropriateness of Measurements...................................................................................................... 51 
8 
DATA QUALITY CONTROL AND QUALITY ASSURANCE ................................................................ 52 
8.1 
Site Training and Monitoring Procedures ........................................................................................... 52 
8.2 
Data Management Procedures ............................................................................................................ 53 
8.3 
Access to Source Data ........................................................................................................................ 53 
8.4 
Accuracy and Reliability of Data........................................................................................................ 53 
8.5 
Quality Assurance Procedures ............................................................................................................ 54 


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8.6 
Data Handling and Record Keeping ................................................................................................... 54 
8.6.1 
Data Handling ...................................................................................................................... 54 
8.6.2 
Investigator Record Retention .............................................................................................. 54 
9 
DATA ANALYSIS METHODS ................................................................................................................... 54 
9.1 
Determination of Sample Size ............................................................................................................ 54 
9.2 
Study Endpoint Definitions ................................................................................................................ 55 
9.2.1 
Primary Efficacy Endpoint: CR Rate per IRF ...................................................................... 55 
9.2.2 
Secondary Efficacy Endpoints ............................................................................................. 55 
9.3 
Statistical and Analytical Plans .......................................................................................................... 56 
9.3.1 
General Considerations ........................................................................................................ 57 
9.3.2 
Patient Disposition ............................................................................................................... 60 
9.3.3 
Patient Characteristics .......................................................................................................... 60 
9.3.4 
Treatment Compliance ......................................................................................................... 60 
9.3.5 
Efficacy Analyses ................................................................................................................. 60 
9.3.6 
Pharmacokinetic and Antitherapeutic Antibody Analyses ................................................... 61 
9.3.7 
Biomarker Analyses ............................................................................................................. 61 
9.3.8 
Patient-Reported Health Outcome Analyses ........................................................................ 61 
9.3.9 
Safety Analyses .................................................................................................................... 61 
9.3.10 
Interim Analyses .................................................................................................................. 63 
10 INFORMED CONSENT, ETHICAL REVIEW, AND REGULATORY CONSIDERATIONS ................. 63 
10.1 Informed Consent ............................................................................................................................... 63 
10.2 Ethical Review .................................................................................................................................... 64 
10.3 Regulatory Considerations.................................................................................................................. 64 
10.3.1 
Investigator Information ....................................................................................................... 64 
10.3.2 
Protocol Amendments and Study Termination .................................................................... 65 
10.4 Study Documentation, Privacy and Records Retention ...................................................................... 65 
10.5 Clinical Trial Agreement .................................................................................................................... 65 
11 REFERENCES .............................................................................................................................................. 66 
APPENDIX A: SCHEDULE OF EVENTS ......................................................................................................... 68 
APPENDIX B: PERFORMANCE STATUS SCALES CONVERSION ............................................................. 70 
APPENDIX C: NEW YORK HEART ASSOCIATION CLASSIFICATION .................................................... 71 
APPENDIX D: SECOND-LINE AGE-ADJUSTED INTERNATIONAL PROGNOSTIC INDEX (IPI) 
 SCORE AND STANDARD IPI SCORE FOR NHL ................................................................................... 72 
APPENDIX E: MODIFIED* CTCAE V4.03 GRADING SCHEME FOR OCULAR TOXICITY .................... 73 
APPENDIX F: RESPONSE ASSESSMENT – THE LUGANO CLASSIFICATION ........................................ 74 
APPENDIX G: INVESTIGATOR SIGNATURE PAGE .................................................................................... 76 
APPENDIX H: DOCUMENT HISTORY ............................................................................................................ 77 
 
LIST OF IN-TEXT TABLES 
Table 1: 
Prophylactica ocular interventions with denintuzumab mafodotin ................................................ 28 
Table 2: 
Evaluation, treatment, and dose modifications in the event of ocular toxicity .............................. 32 
Table 3: 
Pharmacokinetic, antitherapeutic antibody, and biomarker sampling timepoints.......................... 42 
 
LIST OF IN-TEXT FIGURES 
Figure 1: Study design .......................................................................................................................................... 15 
 


Study SGN19A-003  
 Clinical Protocol  
 Amendment 2; 28-Oct-2017 
Denintuzumab mafodotin  
 Seattle Genetics, Inc. - Confidential  
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
19A 
denintuzumab mafodotin 
19A+RICE 
denintuzumab mafodotin plus RICE 
ADC 
antibody-drug conjugate 
ADCC 
antibody dependent cellular cytotoxicity 
ADL 
activities of daily living 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
ASCT 
autologous stem cell transplant 
AST 
aspartate aminotransferase 
ATA 
antitherapeutic antibodies 
β-hCG 
beta human chorionic gonadotropin  
CBC 
complete blood count 
CHOP 
cyclophosphamide, doxorubicin, vincristine, prednisone 
CI 
confidence interval 
CMH 
Cochran-Mantel-Haenszel 
CMR 
complete metabolic response 
CNS 
central nervous system 
CR 
complete remission 
CRF 
case report form 
CT 
computed tomography 
CYP 
cytochrome P450 
DDT 
dose-delaying toxicity 
DHAP 
dexamethasone, cytarabine, cisplatin 
DLBCL 
diffuse large B-cell lymphoma 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EOT 
end of treatment 
FcγR 
FC gamma receptor 
FDA 
Food and Drug Administration 
FDG 
fluorodeoxyglucose  
FOCBP 
female of childbearing potential 
GCB 
germinal center B cell 
GCP 
good clinical practice 
Hgb A1c 
hemoglobin A1c 
IB 
Investigator’s Brochure 
ICE 
ifosfamide, carboplatin, etoposide 
ICH 
International Council on Harmonization  
IHC 
immunohistochemistry  
IND 
Investigational New Drug 
INR 
international normalized ratio 
IPI 
International Prognostic Index 
IRB 
institutional review board 
IRF 
independent review facility 
ITT 
intent-to-treat 


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IV  
intravenous  
mc 
maleimidocapryol 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified intent-to-treat 
MMAF 
monomethyl auristatin F 
MRD 
minimum residual disease 
MTD 
maximum tolerated dose 
NCCN 
National Comprehensive Cancer Network 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NHL 
non-Hodgkin lymphoma 
NYHA 
New York Heart Association 
OR 
objective response 
ORR 
overall response rate 
OS 
overall survival 
PBSC 
peripheral blood stem cell 
PCR 
polymerase chain reaction 
PD 
pharmacodynamic  
PEG 
polyethylene glycol 
PET 
positive emission tomography 
PFS 
progression-free survival 
P-gp 
P-glycoprotein 
PK 
pharmacokinetics  
PML 
progressive multifocal leukoencephalopathy 
PP 
per-protocol 
PR 
partial remission 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
RICE 
rituximab, ifosfamide, carboplatin, etoposide 
saaIPI 
second-line, age-adjusted International Prognostic Index 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
sc 
subcutaneously 
sCD19 
soluble CD19 
SCT 
stem cell transplant 
SD 
stable disease 
SGN-CD19A 
denintuzumab mafodotin 
SMC 
safety monitoring committee 
TLS 
tumor lysis syndrome 
ULN 
upper limit of normal 
UPC 
urine protein:creatinine 
USPI 
United States Prescribing Information 
VFQ 
Visual Function Questionnaire 
 


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 Amendment 2; 28-Oct-2017 
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1 
INTRODUCTION 
1.1 Diffuse Large B-Cell Lymphoma 
Diffuse large B-cell lymphoma (DLBCL) is a subset of non-Hodgkin lymphomas (NHL) that 
comprises approximately 30% of all newly diagnosed cases of NHL in the United States, 
representing the most common lymphoid neoplasm in adults (Swerdlow 2008). Although the 
majority of patients with newly diagnosed DLBCL achieve long-term remissions with 
rituximab and multi-agent chemotherapy, approximately 30% of patients will experience 
relapse or progression. At the time of relapsed disease, the treatment approach is based on 
whether the patient is a candidate for autologous stem cell transplant (ASCT). In patients 
considered to be transplant eligible, the decision to proceed to ASCT is determined by the 
response to salvage treatment (Ghielmini 2013; NCCN 2015). The goals of salvage therapy 
are typically to minimize disease burden and induce remission, providing the best 
opportunity to benefit from consolidative ASCT. 
Various multi-agent salvage regimens incorporating rituximab have been explored in 
DLBCL patients. A large randomized comparison of the most commonly used salvage 
regimens demonstrated the equivalence of rituximab combined with either ICE (ifosfamide, 
carboplatin, etoposide) or DHAP (dexamethasone, cytarabine, cisplatin) (Gisselbrecht 2010). 
There were no significant differences overall between these regimens, and the combined 
results supported an overall response rate (ORR) of 63%, with 37% of patients achieving a 
complete remission (CR of 25%, unconfirmed CR of 12%). The median progression-free 
survival (PFS) was found to be approximately 1 year, with a 3-year event-free survival of 
31% and 3-year overall survival (OS) of 50%. Patients with chemo-sensitive disease who 
achieved a CR or partial remission (PR) and had adequate stem cell collection were 
candidates to proceed to ASCT; only 50% of patients were able to proceed to ASCT 
following salvage therapy. The most common reason to not proceed to ASCT was induction 
treatment failure to induce remission. Additionally, the study incorporated a second 
randomization to evaluate the benefit of maintenance rituximab following ASCT; 
preliminary results suggested there was no benefit. 
In general, treatment guidelines support ASCT as the treatment of choice for patients with 
chemo-sensitive relapsed or refractory DLBCL (Ghielmini 2013; NCCN 2015). Patients who 
are candidates for ASCT should be treated with multi-agent chemotherapy regimens 
combined with rituximab, such as DHAP, ESHAP, GDP, GCD, GemOx, ICE or MINE; there 
is no clear advantage of one regimen over another. Patients achieving remissions should then 
proceed to consolidative ASCT (Ghielmini 2013; NCCN 2015). 
Obtaining a positive emission tomography (PET)-negative CR following second-line salvage 
therapy has been associated with improvement in outcome in relapsed DLBCL patients who 
proceed to ASCT (Dickinson 2010; Johnston 2008; Terasawa 2010). A meta-analysis, 
including 300 patients with DLBCL, demonstrated that a positive PET scan pre-ASCT was 
associated with a significantly shorter PFS interval (random effects hazard ratio 4.3; 95% CI 
3.1, 6; p<0.0001) (Terasawa 2010). A PET-positive status pre-ASCT resulted in a 4 to 5-fold 


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higher risk for treatment failure versus a PET-negative status. A smaller study evaluating the 
prognostic value of pre-ASCT PET scanning in relapsed DLBCL patients found a striking 
difference in long term outcome, with a 3-year PFS of 81% for patients with a negative scan 
versus 35% for those with a positive scan. This translated into similar 3-year OS findings, 
with 81% of patients alive with a negative scan versus 39% with a positive scan (Dickinson 
2010). 
Recent literature indicates that patients with DLBCL who experience primary treatment 
failure (PTF) have a poor prognosis. PTF includes patients who have progressed while on 
frontline therapy, patients with residual disease at the end of frontline therapy, or patients 
who relapse early (<6 months from end of therapy after achieving a CR). Often, patients with 
PTF are subsequently salvaged in the same way as patients who experience much later 
relapse of disease (Costa 2017; Gisselbrecht 2010). Previous trials, such as the CORAL, 
BMT CTN 04-01, and ORCHARRD studies, have included early relapse patients with the 
later relapsed patients (Gisselbrecht 2009; van Imhoff 2016; Vose 2013). The recently 
published results from the multi-center retrospective study REFINE indicate that the use of 
more refined clinical and genetic characterization in patients with PTF can identify those 
who appear to do poorly with conventional approaches, and thus stand to benefit from 
investigational therapies (Costa 2017). Additionally, preliminary data from the patients with 
PTF enrolled to date on our study (SGN19A-003) suggest that these high-risk patients may 
potentially benefit from combining 19A+RICE relative to RICE alone. 
Novel treatment strategies are needed to improve outcomes for relapsed, transplant-eligible 
DLBCL patients. The goal of treatment in this population is to achieve a high-quality 
remission that enables subsequent ASCT. The primary unmet need is the failure to achieve a 
high rate of CR. Achieving a CR with salvage therapy prior to ASCT has been associated 
with improved long-term outcomes. Chemo-immunotherapy regimens, such as RICE 
(rituximab, ifosfamide, carboplatin, etoposide) or RDHAP, result in less than half of patients 
achieving CR; adding a novel agent with demonstrated activity in relapsed DLBCL to these 
regimens has the potential to improve outcomes. 
1.2 CD19 
CD19 is a member of the immunoglobulin superfamily and is one of the earliest markers of 
B-cell differentiation. B-lineage commitment coincides with surface expression of CD19, and 
thus, CD19 is found on normal and malignant B cells as early as the pro-B cell stage (Bryder 
2010; Del Nagro 2005; Huh 2000). Unlike other markers, such as CD20 and CD21 (Chu 
2002; Echeverri 2002; Gervasi 2004), CD19 is rarely lost during malignant transformation or 
treatment. CD19 is expressed in almost all B-cell malignancies; and accordingly, CD19 is a 
standard marker of B-lineage non-Hodgkin lymphomas such as DLBCL and is found in 
almost all clinical immunohistochemistry (IHC) and flow cytometry diagnostic panels. 
1.3 Denintuzumab Mafodotin 
Denintuzumab mafodotin (SGN-CD19A) is an antibody-drug conjugate (ADC) directed 
against the CD19 antigen. The antibody backbone of denintuzumab mafodotin, hBU12, is a 


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humanized anti-CD19 monoclonal antibody that is chemically conjugated to a synthetic 
analog (monomethyl auristatin F [MMAF]) of the naturally occurring tubulin-disrupting 
drug, dolastatin 10. The maleimidocapryol (mc) linker is used to conjugate MMAF to hBU12 
on the cysteine residues that comprise the interchain disulfide bonds of the antibody. An 
average of 4 MMAF molecules is present on each antibody molecule. 
1.3.1 Mechanism of Action of Denintuzumab Mafodotin 
Subsequent to cell surface binding to CD19, denintuzumab mafodotin is internalized and 
trafficked through the endocytic pathway to reach the lysosomes. Proteolytic degradation of 
the hBU12 in lysosomes releases the cysteine adduct of the drug linker in the form of 
cysteine maleimidocapryol monomethyl auristatin F (cys-mcMMAF) which becomes 
available for tubulin binding. Interaction between cys-mcMMAF and tubulin disrupts the 
cellular microtubule network, arrests cells at the G2/M phase of the cell cycle, prevents cell 
division, and eventually leads to cellular apoptosis. Antitumor activity and 
immunospecificity of denintuzumab mafodotin have been demonstrated in vitro and in vivo 
with animal models representing B-lineage NHL and disseminated leukemia. 
1.3.2 Experience with Denintuzumab Mafodotin 
1.3.2.1 Preclinical Experience 
A complete summary of the nonclinical data relevant to denintuzumab mafodotin 
(SGN-CD19A) and its study in human subjects is provided in the Investigator’s Brochure 
(IB). 
1.3.2.2 Clinical Experience 
The safety and efficacy of denintuzumab mafodotin are being evaluated in an ongoing 
phase 1 dose-escalation tolerability study in patients with relapsed or refractory NHL 
(Protocol SGN19A-002). In the 52 patients treated to date, including 45 patients with 
DLBCL, the maximum tolerated dose (MTD) was not exceeded after escalating to 6 mg/kg 
every 3 weeks. Denintuzumab mafodotin was generally well tolerated, and the most common 
adverse events of any grade included blurred vision, dry eye, fatigue, constipation, and 
keratopathy. Hematopoietic toxicity and peripheral neuropathy were uncommon. Of the 
51 patients evaluable for response, 18 patients (35%) achieved an objective response, 
including 10 patients (20%) with a complete remission (as presented by Moskowitz CH, et al. 
at ASH 2014). Antitumor activity appeared to be higher in relapsed patients. Of the 22 
patients relapsed to their most recent prior therapy, 12 patients (55%) achieved an objective 
response, including 7 patients (32%) with a best response of CR and 5 (23%) with a PR. 
See the IB for complete clinical safety information. 
1.4 Rationale for Study 
As described above, novel treatment strategies are needed to improve outcomes for relapsed, 
transplant-eligible DLBCL patients, where the goal is to achieve a high-quality remission 
that enables subsequent ASCT. The primary unmet need is the failure to achieve a high rate 


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of CR, as achievement of a PET-negative CR following second-line salvage therapy has been 
associated with improvement in outcome in relapsed DLBCL patients who proceed to ASCT 
(Dickinson 2010; Johnston 2008; Terasawa 2010). 
Preliminary activity has been observed with denintuzumab mafodotin monotherapy in 
patients with relapsed or refractory DLBCL after failure of second-line salvage (unless 
transplant-ineligible) and beyond (Moskowitz 2014). Introduction of denintuzumab 
mafodotin into second-line treatment may be both clinically meaningful and associated with 
a favorable risk-benefit ratio. Denintuzumab mafodotin has not previously been combined 
with RICE. However, given the known safety profiles of RICE and denintuzumab mafodotin 
alone, few overlapping toxicities are anticipated. Safety data to date in Protocol 
SGN19A-002 have shown a favorable toxicity profile for denintuzumab mafodotin, with 
hematopoietic toxicity and peripheral neuropathy uncommon (Moskowitz 2014). Although 
myelosuppression is an expected consequence of RICE therapy, only transient 
thrombocytopenia that recovered prior to the subsequent 3-week cycle has been consistently 
associated with treatment with denintuzumab mafodotin in the NHL population. 
Nonclinical studies have been conducted to study the effects of denintuzumab mafodotin 
administered in combination with other single- and multi-agent regimens. The combined 
cytotoxic effects of denintuzumab mafodotin and a set of small molecule drugs with different 
mechanisms of action were evaluated in a panel of transformed B-cell lines. Denintuzumab 
mafodotin was found to be synergistic with several agents, including the DNA alkylating 
agent bendamustine, the DNA cross-linking agent cisplatin, and the DNA topoisomerase 
inhibitor etoposide, as well as the anti-CD20 monoclonal antibody rituximab. Murine in vivo 
studies demonstrated impressive antitumor activity that exceeded that of denintuzumab 
mafodotin alone in NHL lymphoma models when combined with the therapeutic regimens of 
rituximab and RICE. In inherently denintuzumab mafodotin insensitive tumor xenograft 
models, the combined antitumor activity of both denintuzumab mafodotin and rituximab, as 
well as denintuzumab mafodotin and RICE was found to be considerably stronger than either 
agent or regimen alone in follicular lymphoma and diffuse large B-cell lymphoma (DLBCL) 
models, leading to prolonged tumor delay as well as complete remissions. Similarly, the 
combinations of denintuzumab mafodotin and ICE also demonstrated stronger antitumor 
activity in the DLBCL models when compared to denintuzumab mafodotin or ICE alone. In 
vitro studies demonstrated that denintuzumab mafodotin internalizes faster and delivers more 
free drug (cys-mcMMAF) in the presence of rituximab, creating a synergistic combination 
(as presented by VanEpps H, et al. at the Annual Meeting of the American Association for 
Cancer Research, 2015). 
Taken together, these data support further evaluation of incorporating denintuzumab 
mafodotin as part of multi-agent second-line therapy such as RICE and may yield an 
improvement in the CR rate, as well as PFS and OS benefit, in relapsed or refractory, 
transplant-eligible DLBCL patients. 


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2 
OBJECTIVES 
2.1 Primary Objective 
● 
To compare the complete remission (CR) rates in patients with relapsed/refractory 
DLBCL who are candidates for autologous stem cell transplant (ASCT) treated with 
denintuzumab mafodotin plus RICE (19A+RICE) versus RICE 
2.2 Secondary Objectives 
● 
To evaluate the safety of denintuzumab mafodotin given in combination with RICE 
● 
To compare progression-free survival (PFS) between study arms 
● 
To compare overall survival (OS) between study arms 
● 
To compare the proportion of patients who are able to adequately mobilize peripheral 
blood stem cells (PBSC) between study arms 
● 
To compare the proportion of patients receiving ASCT following study treatment 
between study arms 
● 
To compare other measures of antitumor activity between study arms 
2.3 Additional Objectives 
● 
To evaluate the pharmacokinetics (PK) of denintuzumab mafodotin (ADC and 
cys-mcMMAF) when denintuzumab mafodotin is given in combination with RICE 
chemotherapy 
● 
To evaluate the incidence of antitherapeutic antibodies (ATA) against denintuzumab 
mafodotin 
● 
To assess denintuzumab mafodotin-mediated pharmacodynamic (PD) effects and 
potential biomarkers to stratify response 
2.4 Endpoints 
2.4.1 Primary Endpoint 
● 
Complete remission (CR) rate as determined by an independent review facility (IRF) 
following the completion of study treatment 
2.4.2 Secondary Endpoints 
● 
Type, incidence, severity, seriousness, and relatedness of adverse events (AEs) and 
laboratory abnormalities 
● 
Objective response rate (ORR) per IRF following the completion of study treatment 
● 
Duration of response (objective response [OR] and CR) 
● 
Progression-free survival (PFS) 


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● 
Overall survival (OS) 
● 
Proportion of patients achieving PBSC mobilization 
● 
Proportion of patients receiving ASCT 
2.4.3 Additional Endpoints 
● 
Estimates of selected PK parameters of denintuzumab mafodotin and released 
cys-mcMMAF 
● 
Incidence of antitherapeutic antibodies (ATA) 
● 
Exploratory biomarkers of denintuzumab mafodotin-mediated PD effects 
3 
INVESTIGATIONAL PLAN 
3.1 Summary of Study Design 
This is a randomized, open-label phase 2 study designed to compare the CR rates in patients 
with relapsed or refractory DLBCL who are candidates for ASCT. Approximately 
100 patients will be randomized in a 1:1 ratio to 1 of 2 study arms (see Figure 1): 
● 
Control, RICE Arm: 3 cycles (3 weeks per cycle) of rituximab 375 mg/m2 administered 
as the first component of RICE on Day 1 of every cycle; and followed by etoposide 
(100 mg/m2 per day), ifosfamide (5,000 mg/m2) infused continuously with mesna, and 
carboplatin (area under the curve 5 mg/mL x min; maximum dose, 800 mg) administered 
during each cycle in an order as per institutional standard of care 
● 
Investigational, 19A+RICE Arm: 3 cycles (3 weeks per cycle) of denintuzumab 
mafodotin 3 mg/kg on Day 1 of every cycle in conjunction with 3 cycles (3 weeks per 
cycle) of RICE; denintuzumab mafodotin is administered prior to the rituximab 
component of RICE therapy given on Day 1 of each cycle 
Figure 1: Study design 
 
a 
Follow-up PET and CT scans required until disease is PET negative; responses will then be followed by CT scans of 
diagnostic quality. Follow-up assessments continue until disease progression, initiation of a new anticancer treatment 
(with the exception of stem cell transplant), death, or study closure, whichever comes first. Survival status follow-up 
until death or study closure, whichever comes first. 
RICE Arm
3 cycles
19A+RICE Arm
3 cycles
Randomize
End-of-treatment
Follow-up:  
3, 6, 12, 18, 24 months, 
and then annually 
after ASCT or EOTa


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A safety monitoring committee (SMC) comprising the study investigators, medical monitor, 
and study biostatistician will periodically monitor the safety of patients at predefined interim 
safety evaluations and during the treatment period (See Section 3.1.2). Upon its evaluation of 
the data, the SMC may recommend modification of the dose of denintuzumab mafodotin in 
the 19A+RICE Arm (e.g., to 2 mg/kg) in subsequently enrolled patients. If dose modification 
is necessary, up to 50 additional patients may be randomized (25 in each arm) so that a total 
of 100 patients will be randomized in a 1:1 ratio to receive either 19A (modified dose) + 
RICE or RICE alone. 
If a subset of patients appears to potentially derive benefit from 19A+RICE versus RICE at a 
pre-planned evaluation, the Sponsor may continue enrolling those patients beyond the 
planned sample size (approximately 100 patients), but will not exceed the planned maximum 
number of patients to be randomized in this study (up to approximately 150 patients). 
 PET scans and computed tomography (CT) scans of the neck, chest, abdomen, and pelvis, 
will be assessed at baseline and at end of treatment (EOT). CT scans will be of diagnostic 
quality (i.e., contrast-enhanced with IV and oral contrast, unless contrast is medically 
contraindicated). Follow-up assessments will be performed at 3, 6, 12, 18, 24 months, and 
then annually after ASCT or EOT (for patients who don’t receive ASCT). For all follow-up 
assessments, both PET and CT scans are required until disease is PET negative; responses 
will then be followed by CT scans of diagnostic quality. Follow-up assessments will continue 
until disease progression, initiation of a new anticancer treatment (with the exception of a 
stem cell transplant), or study closure, whichever occurs first. 
At screening and/or at any time on study, if a bone marrow biopsy is performed as part of 
standard of care, the results from the biopsy report for the presence of lymphoma will be 
recorded in the case report form (CRF). A CT scan of diagnostic quality will be performed at 
the time of suspected clinical progression. Survival status follow-up will continue until 
patient death or study closure, whichever occurs first. 
Subsequent ASCT is permitted, based on investigator discretion and standard of care, and is 
recommended to occur within 8 weeks of Cycle 3 Day 1 (Philip 1995). Data will be recorded 
to assess adequacy of hematopoietic stem cell collection and transplant. 
3.1.1 Dose-Delaying Toxicity 
A dose-delaying toxicity (DDT) is defined as any study treatment-related toxicity that 
necessitates a delay of >14 days in the start of RICE treatment in the next cycle. With respect 
to hematologic recovery, it is recommended that the next cycle of RICE treatment be given 
once the patient’s absolute neutrophil count (ANC) recovers to ≥1000/µL and the platelet 
count recovers to ≥75,000/µL, as applicable. 
See Section 5.8 for dose delay guidelines for DDTs; dose modifications for ocular events are 
described in Section 5.8.1. 


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3.1.2 Interim Safety Evaluations 
An initial evaluation of the safety data will be conducted by the SMC after approximately 
12 patients (6 patients in the 19A+RICE Arm) have been randomized and evaluated for 
DDTs delaying the Cycle 2 dose. Enrollment will be paused at this initial evaluation while 
the SMC assesses the cumulative safety data, including the incidence of DDTs that are 
associated with denintuzumab mafodotin in combination with RICE. After its review, the 
SMC will make one of the following recommendations to the sponsor regarding further 
conduct of the trial: 
● 
Continue the trial as planned 
● 
Modify the dose of denintuzumab mafodotin (e.g., to 2 mg/kg) in patients 
subsequently enrolled to the 19A+RICE Arm 
● 
Temporarily halt enrollment 
 
A second planned evaluation of the cumulative safety data will be conducted once the first 
12 patients in the 19A+RICE Arm have been randomized and evaluated for DDTs delaying 
the Cycle 2 dose. The SMC will make a recommendation either to continue the trial as 
planned, modify the dose of denintuzumab mafodotin (e.g., to 2 mg/kg, if not already 
modified) in subsequently enrolled patients, or to temporarily halt enrollment. 
A third planned interim evaluation for safety will be conducted once the first 12 patients in 
the 19A+RICE Arm have completed Cycle 3 or EOT. At this assessment, the SMC will 
evaluate safety including DDTs and late toxicities associated with denintuzumab mafodotin 
in combination with RICE, including an assessment of the ability to mobilize PBSC per 
institutional standard of care. 
During the treatment period, the SMC may also recommend conducting additional safety 
analyses or temporarily halting enrollment until an appropriate evaluation of the cumulative 
safety data, including review of unanticipated safety issues, has been completed. 
3.2 Discussion and Rationale for Study Design 
The Food and Drug Administration’s (FDA’s) “Guidance on Clinical Trial Endpoints for the 
Approval of Cancer Drugs and Biologics” (May 2007) was considered prior to the selection 
of primary and secondary endpoints for this study. The primary endpoint for this study is the 
CR rate at the end of treatment as assessed by IRF utilizing the Lugano classification criteria 
(Cheson 2014). In this population where the ability to achieve a CR and proceed to ASCT 
directly influences long-term outcomes, CR is the most appropriate endpoint to assess 
treatment benefit. Complete remission measures the effect of the 2 treatment approaches 
being tested before ASCT is experienced by patients. The decision to proceed to subsequent 
transplant and subtle differences in conditioning regimens applied prior to transplant may 
represent sources of bias. Complete remission as the primary endpoint provides a direct 
comparison of treatment regimen efficacy, is directly correlated with long-term clinical 
benefit, and minimizes potential biases in interpretation. Therefore, CR rate is the most 
appropriate primary endpoint in this phase 2, randomized, open-label clinical trial. 


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3.2.1 Method of Assigning Patients to Treatment Groups 
Following informed consent and screening assessments, patients will be assigned to 1 of 2 
treatment arms in a 1:1 ratio using a central randomization system. Patients will be stratified 
by 3 factors: 
● 
Disease status 
● 
Second-line age-adjusted IPI score (saaIPI) for patients ≤60 years of age or standard 
IPI score for patients >60 years of age, as assessed at randomization 
● 
Disease type 
 
Randomization strata are specified in Section 9.3.1.1. Randomization procedures are detailed 
in the study manual. 
3.2.2 Rationale for Selection of Doses 
In the ongoing phase 1 dose-escalation study in B-lineage NHL (Protocol SGN19A-002), 
denintuzumab mafodotin has been administered at dose levels from 0.5 mg/kg up to 6 mg/kg 
intravenously (IV) every 3 weeks. Denintuzumab mafodotin has been generally well 
tolerated, and MTD was not exceeded at 6 mg/kg. The dose of denintuzumab mafodotin 
selected for this study (3 mg/kg) is half of the maximum dose tested of 6 mg/kg. 
Denintuzumab mafodotin given every 3 weeks has demonstrated antitumor activity in 
51 efficacy-evaluable patients with an ORR of 35% and CR rate of 20% (Moskowitz 2014). 
While responses were seen at all dose levels >0.5 mg/kg, there is very limited experience for 
the 1 mg/kg (n=3) and 2 mg/kg (n=2) dose levels. Following expansion, the patients treated 
at 3 mg/kg (n=14) experienced the same rate of response (CR/PR) as those at the higher dose 
levels (unpublished data). Additionally, the 3 mg/kg dose level was well tolerated with fewer 
Grade 3/4 hematological adverse events than that observed with higher doses. Thus, 3 mg/kg 
is expected to be a safe and efficacious dose of denintuzumab mafodotin for evaluation in 
combination with RICE. 
The dose of rituximab (375 mg/m2) is the standard approved dose for patients with 
previously untreated DLBCL when given in combination with CHOP (cyclophosphamide, 
doxorubicin, vincristine, prednisone) or other anthracycline-based chemotherapy regimens. 
There is no standard dose or schedule for rituximab in the relapsed or refractory setting; 
however, the selected dose and schedule has been safely and effectively employed in 
combination with various single- and multi-agent chemotherapy regimens for this patient 
population (Gisselbrecht 2010; NCCN 2015). In theory, rituximab and denintuzumab 
mafodotin are partly eliminated via binding to CD19/CD20-positive B-cells, internalization, 
and catabolism, therefore changes in this cell population could potentially alter the PK of 
these molecules. However, dose adjustment of rituximab based on pre-treatment CD19 count 
is not necessary (Rituxan Prescribing Information, Genentech, September 2013), while 
denintuzumab mafodotin PK generally did not differ based on baseline CD19 levels in 
relapsed/refractory NHL patients (unpublished data). 


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The doses of ifosfamide (5000 mg/m2), carboplatin (area under the curve 5 mg/mL x min; 
maximum dose, 800 mg), and etoposide (100 mg/m2 per day for 3 days) are the standard 
doses when given in a combination setting. Additionally: 
● 
Ifosfamide is extensively metabolized (70–86% of the dose) by CYP3A4 and 
CYP2B6 (Ifosfamide Prescribing Information, APP Pharmaceuticals, January 2008). 
Cys-mcMMAF is metabolically stable in human microsomal preparations and, at 
concentrations up to 1 μM (roughly 100-fold higher than circulating levels after a 
3 mg/kg dose of denintuzumab mafodotin), was not a direct, time- or metabolism-
dependent inhibitor or inducer of CYP 3A or 2B6 in vitro (denintuzumab mafodotin 
IB). 
● 
Carboplatin is mainly eliminated by renal glomerular filtration (Paraplatin Prescribing 
Information, Bristol-Myers Squibb, July 2010). 
● 
Etoposide is eliminated by multiple mechanisms, including renal and biliary excretion 
and several metabolic pathways (sulfation, glucuronidation, and oxidation by 
CYP3A4) (Etopophos Prescribing Information, Bristol-Myers Squibb, March 2011). 
Based on known metabolism and elimination information for cys-mcMMAF, rituximab, 
ifosfamide, carboplatin, and etoposide, the risk of drug-drug interactions between RICE 
components and denintuzumab mafodotin is considered low, therefore standard RICE doses 
are considered appropriate. 
3.2.3 Blinding 
This study is not blinded. 
4 
STUDY POPULATION 
Patients must meet all of the enrollment criteria to be eligible for this study. Eligibility 
criteria may not be waived by the investigator and are subject to review in the event of Good 
Clinical Practice (GCP) audit and/or health regulatory authority inspection. 
4.1 Inclusion Criteria 
1. Histologically confirmed CD20-positive, relapsed or refractory DLBCL, including de 
novo and transformed DLBCL (from follicular or marginal zone lymphoma), and Grade 
3b follicular lymphoma. This includes patients with DLBCL who are found to have small 
cell infiltration of the bone marrow or other diagnostic material (representing a discordant 
lymphoma). (CD20-positivity requirement not applicable to Amendment 2.) 
2. Available representative tissue from the most recent biopsy after the last therapy; if such 
tissue is not available, a fresh biopsy must be obtained. Archived tumor tissue from the 
initial biopsy, if available, is also required to be submitted during the trial. 
3. Received only frontline CD20-directed immunotherapy with anthracycline- or 
anthracenedione-based multi-agent chemotherapy. Monotherapy rituximab or other 
CD20-directed immunotherapy prior to frontline chemotherapy, as maintenance therapy, 


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and radiotherapy in a limited field or as a part of the frontline treatment plan are 
permitted. 
4. Achieved a response of stable disease (SD), PR, or CR (when compared to the baseline, 
pre-treatment disease assessment) following the last cycle of frontline treatment with 
multi-agent chemo-immunotherapy regimens delivered with curative intent. 
a. Relapsed less than or equal to 6 months from the completion of frontline therapy at 
the time of initial dosing in this clinical trial (applicable only to patients enrolled 
under Amendment 2). 
5. Considered eligible for high-dose chemotherapy followed by ASCT. 
6. FDG-avid disease by PET, and measurable disease of >1.5 cm in the greatest transverse 
diameter by CT, as assessed by the site radiologist. 
7. Age 18 years or older. 
8. An Eastern Cooperative Oncology Group (ECOG) performance status ≤2. 
9. Patients must have the following baseline laboratory data: 
● 
serum bilirubin ≤1.5 x the upper limit of normal (ULN) or ≤3 mg/dL for patients with 
Gilbert's syndrome or documented hepatic involvement with lymphoma 
● 
alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3 x ULN or 
≤5 x ULN for patients with documented hepatic involvement with lymphoma 
● 
serum creatinine of ≤1.5 mg/dL; if creatinine >1.5 mg/dL creatinine clearance must 
be >60 mL/min within 7 days prior to treatment either measured or calculated using a 
standard Cockcroft and Gault formula 
● 
absolute neutrophil count (ANC) ≥1000/µL 
● 
platelet count ≥75,000/µL 
 
10. 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 treatment. Females of non-childbearing potential are those who are post-
menopausal for more than 1 year or who have had a bilateral tubal ligation or 
hysterectomy. 
11. Females of childbearing potential and males who have partners of childbearing potential 
must agree to use 2 effective contraception methods during the study and for 12 months 
following the last dose of study drug. 
12. Patients must provide written informed consent. 


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4.2 Exclusion Criteria 
1. Previous history of indolent lymphoma treated with more than 1 multi-agent 
chemotherapy regimen (including such therapies as rituximab-bendamustine) or previous 
cancer therapy for recurrent DLBCL or Grade 3b follicular lymphoma. 
2. History of autologous or allogeneic stem cell transplant. 
3. History of another primary invasive cancer, hematologic malignancy, or myelodysplastic 
syndrome that has not been in remission for at least 1 year. 
4. History of progressive multifocal leukoencephalopathy (PML). 
5. 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 disease has been definitively treated. 
6. Patients with the following ocular conditions: 
● 
Corneal disorders: corneal dystrophies, history of corneal or limbal stem cell 
transplantation (including endothelial keratoplasty), evidence of limbal stem cell 
deficiency (i.e., deep pannus, poor epithelial healing) 
● 
Monocular vision (i.e., best corrected visual acuity ≥20/200 in one eye) 
● 
Active ocular disorders requiring treatment such as corneal ulcer, herpetic keratitis, 
uncontrolled glaucoma (stable topical medication is allowed), uncontrolled diabetic 
retinopathy, evolving wet macular degeneration, iritis or vitritis, papilledema, or optic 
nerve disorder 
 
7. Congestive heart failure, Class III or IV, by the New York Heart Association (NYHA) 
criteria. 
8. Any active Grade 3 or higher (per the National Cancer Institute Common Terminology 
Criteria for Adverse Events [NCI CTCAE], Version 4.03 or higher) viral, bacterial, or 
fungal infection within 2 weeks prior to the first dose of study treatment. Routine 
antimicrobial prophylaxis is permitted. 
9. Current therapy with other systemic anti-neoplastic or investigational agents. 
10. Chemotherapy, radiotherapy, biologics, and/or other antitumor treatment with 
immunotherapy that is not completed 4 weeks prior to study entry. Note: radiotherapy 
within 4 weeks prior to study entry is acceptable if the underlying disease has progressed 
on treatment. 
11. Acute toxicities from previous chemotherapy, radiotherapy, biologics and/or other 
antitumor treatment must have resolved or returned to baseline. 
12. Females who are breastfeeding. 


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13. Known hypersensitivity to any study treatment or any excipient contained in the drug 
formulations of study treatments. 
14. Patients with a positive polymerase chain reaction (PCR) assay who have also tested 
positive for hepatitis B surface antigen and/or anti-hepatitis B core antibody; patients 
with a negative PCR assay are permitted with appropriate anti-viral prophylaxis. 
15. Known or suspected active hepatitis C infection or known human immunodeficiency 
virus (HIV) infection. 
16. Known urinary tract obstruction. 
4.3 Removal of Patients from Therapy or Assessment 
Seattle Genetics or their designee must be notified if a patient is withdrawn from study 
treatment or from the study. The reason(s) for withdrawal must be documented in the 
patient’s medical records and case report form (CRF). 
4.3.1 Discontinuation of Study Drug 
A patient’s treatment with study drug may be discontinued for any of the following reasons: 
● 
Completed treatment 
● 
Progressive disease 
● 
Adverse event (AE) 
● 
Investigator decision 
● 
Patient decision, Non-AE 
● 
Study termination by sponsor 
● 
Other, Non-AE 
 
Patients who discontinue from study treatment will remain on study for follow-up unless they 
withdraw consent. 
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 


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5 
TREATMENTS 
5.1 Treatments Administered 
Patients will be randomized within 1 business day prior to the planned first dose of Cycle 1 
Day 1. Patients will receive either denintuzumab mafodotin in combination with RICE 
(19A+RICE Arm) or RICE alone. 
5.2 Investigational Study Drug 
Denintuzumab mafodotin (SGN-CD19A), the investigational agent under study in this 
protocol, is an ADC consisting of the anti-CD19 monoclonal antibody hBU12 specific for 
human CD19 conjugated to MMAF, a synthetic analog of the naturally occurring 
microtubule-disrupting drug, dolastatin 10. 
Detailed information describing the preparation, administration, and storage of denintuzumab 
mafodotin is located in the Pharmacy Instructions. 
5.2.1 Description 
Denintuzumab mafodotin is a sterile, preservative-free, white to off-white lyophilized cake or 
powder supplied by Seattle Genetics in single-use glass vials for reconstitution for IV 
administration. Each drug product vial contains
 
Drug product vials are labeled 
with a nominal content of 20 mg/vial. Each vial contains 22.5 mg of denintuzumab 
mafodotin. Enough overfill is included to allow for 20 mg of denintuzumab mafodotin to be 
withdrawn for use. When reconstituted with 4.5 mL Water for Injection (WFI), United States 
Pharmacopeia (USP), the reconstituted product has a concentration of 5 mg/mL. The pH of 
the reconstituted product is approximately 6. Before administration, reconstituted 
denintuzumab mafodotin must be diluted. 
5.2.2 Dose and Administration 
Patients randomized to the 19A+RICE Arm will receive denintuzumab mafodotin (3 mg/kg), 
administered on Day 1 of each 21-day cycle by IV infusion given over approximately 
30 minutes. The dose of denintuzumab mafodotin may be modified (e.g., to 2 mg/kg) upon 
recommendation of the SMC. Dosing of denintuzumab mafodotin is based on patient weight 
obtained according to the institutional standard; however, doses must be adjusted for patients 
who experience a ≥10% change in weight from baseline. If rounding, doses must be rounded 
to the nearest milligram. 
Denintuzumab mafodotin should be given prior to and on the same day as rituximab (the first 
component of RICE). Denintuzumab mafodotin infusion should be completed approximately 
30 to 60 minutes prior to the start of rituximab (see Section 5.3.3). In the absence of infusion 
toxicities, the infusion rate for all patients should be calculated in order to achieve a 
30-minute infusion period (window 20–45 minutes). 


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DENINTUZUMAB MAFODOTIN MUST NOT BE ADMINISTERED AS AN IV PUSH 
OR BOLUS. Denintuzumab mafodotin must be administered through a dedicated IV line 
without an in-line filter. Denintuzumab mafodotin cannot be mixed with other medications. 
The patient should be observed for 60 minutes following the first infusion of denintuzumab 
mafodotin. During this observation period, the IV line should remain to allow administration 
of IV drugs if necessary. All supportive measures consistent with optimal patient care will be 
given throughout the study according to institution standards. 
5.2.3 Storage and Handling 
Single-use vials containing denintuzumab mafodotin must be stored under refrigeration set to 
2 to 8°C in an appropriate locked room accessible only to the pharmacist, investigator, or a 
duly designated person. 
Chemical and physical stability of the reconstituted drug product has been demonstrated for 
24 hours at 2 to 8°C and at room temperature. However, denintuzumab mafodotin drug 
product does not contain preservatives; therefore, from a microbiological standpoint, opened 
and reconstituted vials should be used immediately. After exposure to ambient temperature 
and light conditions, the prepared dosing solution should be administered within 8 hours if 
stored at ambient temperature. If not used immediately, or if it is necessary to extend the 
post-reconstitution hold time, the prepared dosing solution should be stored at 2 to 8°C. The 
in-use storage of opened and reconstituted vials or prepared dosing solution should not be 
longer than 24 hours after initial vial reconstitution under refrigeration set to 2 to 8°C. Drug 
product vials and solutions should be protected from direct sunlight until the time of use. 
Reconstituted vials and solutions must not be shaken. 
Drug accountability instructions are provided in the Pharmacy Binder. 
5.2.4 Packaging and Labeling 
Denintuzumab mafodotin is supplied in single-use vials. Drug product vials may be labeled 
as denintuzumab mafodotin, the United States adopted name (USAN) and the International 
Nonproprietary Name (INN), or as SGN-CD19A, the compound code; the 2 names can be 
used interchangeably. 
5.2.5 Preparation 
Before administration, denintuzumab mafodotin must be reconstituted and diluted. 
Recommended safety measures for handling and preparation include masks, protective 
clothing, gloves, and vertical laminar airflow safety cabinets. Detailed drug preparation 
instructions are provided in the Pharmacy Instructions. 
5.3 Rituximab, Etoposide, Ifosfamide, and Carboplatin 
In this protocol, RICE is administered either in combination with denintuzumab mafodotin 
(19A+RICE Arm) or alone. 


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5.3.1 Description 
RICE is a standard chemo-immunotherapy regimen consisting of rituximab, etoposide, 
ifosfamide, and carboplatin. Rituximab is a CD20-directed cytolytic antibody. Etoposide is a 
topoisomerase inhibitor. Ifosfamide is a nitrogen mustard alkylating agent. Carboplatin is a 
platinum-based antineoplastic agent with a mechanism of action that interacts with DNA to 
interfere with DNA repair. 
5.3.2 Method of Procurement 
Agents contained in the RICE regimen are commercially available and approved by the 
United States FDA for use in treating patients with multiple types of cancer. 
Rituximab, etoposide, ifosfamide, and carboplatin will be supplied by the study site and 
billed to patients and/or their third-party payer (insurance, a healthcare provider, or 
applicable government program). 
5.3.3 Dose and Administration 
Patients in both treatment arms will receive RICE. In the 19A+RICE Arm, rituximab 
administration (as the first component of RICE) should be initiated approximately 30 to 
60 minutes after the completion of denintuzumab mafodotin study drug infusion on Day 1. 
Rituximab 375 mg/m2 should be administered IV on Day 1 as the first component of RICE. 
The remaining RICE components may be administered in an order as per institutional 
standard of care. Typically, etoposide (100 mg/m2 per day) is administered IV on Days 1 
through 3; ifosfamide (5,000 mg/m2) is infused continuously in an inpatient setting for 
approximately 24 hours on Day 2 with mesna; and carboplatin (area under the curve 
5 mg/mL x min; maximum dose, 800 mg) is administered IV on Day 2. 
Dosing for RICE should be based on the patient’s baseline (predose, Cycle 1 Day 1) height 
and weight or per institutional standards at the site. 
5.3.4 Storage and Handling 
Rituximab, etoposide, ifosfamide, and carboplatin should be stored and handled per the 
package insert. 
5.3.5 Packaging and Labeling 
Rituximab, etoposide, ifosfamide, and carboplatin are commercially available in the US. 
5.3.6 Preparation 
Rituximab, etoposide, ifosfamide, and carboplatin should be prepared per the package insert. 
5.4 Required Premedication and Postmedication 
Routine premedication is not necessary for the prevention of infusion-related reactions prior 
to the first dose of denintuzumab mafodotin. However, patients who experience a Grade 1 or 


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Grade 2 infusion-related reaction may receive subsequent denintuzumab mafodotin infusions 
with premedication as described in Section 5.6. 
Acetaminophen and an antihistamine should be given within 15 to 90 minutes prior to 
initiating the rituximab infusion. Additional premedications, including steroids, may be given 
prior to the rituximab infusion in accordance with the rituximab package insert, institutional 
standard of care, or as clinically indicated. Premedications for the rituximab infusion may be 
given during the 30 to 60 minute period between the completion of the denintuzumab 
mafodotin infusion and the start of the rituximab infusion. 
Routine anti-emetic prophylaxis regimen should be administered with each cycle of RICE 
per institutional standard and should include oral or IV dexamethasone at a dose of at least 
12 mg on Day 1, and 8 mg on Days 2 and 3. Omission or discontinuation of steroid 
antiemetic treatment may be allowed under certain circumstances (e.g., in the setting of 
intolerability, contraindication, or toxicity secondary to dexamethasone) upon discussion 
with the medical monitor. 
Patients in both treatment arms should receive prophylactic growth factor support (e.g., 
filgrastim or polyethylene glycol [PEG]-filgrastim, per institutional standard) following each 
cycle of chemotherapy to shorten the duration of neutropenia (see Section 5.8). As per 
National Comprehensive Cancer Network (NCCN) guidelines, it is recommended that: 
● 
PEG-filgrastim be given as 1 dose of 6 mg subcutaneously (sc) per cycle, 
administered the day after completion of chemotherapy 
● 
Filgrastim be given as a daily dose of 5 mcg/kg (total dose rounded to the nearest vial 
size per institutional-defined weight limits) initiated the next day or up to 3–4 days 
after completion of chemotherapy until post-nadir ANC recovery to normal or near 
normal levels by laboratory standards. The preferred route of administration is sc, but 
may also be given IV 
Refer to the United States Prescribing Information (USPI) for the applicable growth factor 
support in order to determine the appropriate administration window for use with cytotoxic 
chemotherapy. 
There are no protocol-required pre- or postmedications for etoposide, ifosfamide, or 
carboplatin, other than those mentioned above. 
See Section 5.5.1 for other required concomitant therapies. 
5.4.1 Prophylactic Ocular Interventions for Denintuzumab Mafodotin 
Prophylactic steroid eye drops must be administered daily for 7 days with each dose of 
denintuzumab mafodotin. Steroid eye drops should consist of prednisolone 1% administered 
four times daily, 1 drop in each eye or equivalent. Prophylaxis is recommended to begin 
1 day prior to each dose of denintuzumab mafodotin. Omission or discontinuation of 
prophylactic steroid eye drops may be allowed under certain circumstances (e.g., in the 
setting of intolerability, contraindication, or toxicity secondary to steroid eye drops) upon 


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discussion with the medical monitor. The use of steroid eye drops for the treatment of ocular 
toxicity and dose modifications of denintuzumab mafodotin for corneal events are described 
in Section 5.8.1, .See Section 7.7.5 for the ocular safety monitoring plan. 
Prophylactic preservative-free artificial tears should be administered twice daily, at least one 
drop in each eye, beginning on Cycle 1 Day 1 until EOT. Allow at least 30 minutes between 
administration of artificial tears and steroid eye drops. In the event of ocular symptoms (i.e., 
dry eyes), the use of artificial tears may be increased up to every 2 hours as needed 
(Section 5.8.1). 
While not yet clinically demonstrated, it is theoretically possible that the application of a 
cooling eye mask during denintuzumab mafodotin administration in the first few hours after 
infusion and the use of vasoconstrictor eye drops may reduce exposure of the eye tissue to 
denintuzumab mafodotin and may subsequently decrease ocular side effects. On the day of 
infusion, the following are recommended: 
● 
Vasoconstrictor eye drops (consisting of tetrahydrozoline 0.05% or naphazoline 
0.012%, or equivalent) should be administered 1 drop in each eye at the following 
time points: (1) start of denintuzumab mafodotin infusion, (2) start of rituximab 
infusion, and (3) end of rituximab infusion. 
● 
Beginning with the start of each denintuzumab mafodotin infusion, it is recommended 
that patients apply cooling eye masks to their eyes for approximately 1 hour, or as 
much as tolerated by the patient. Patients are encouraged to continue using the 
cooling eye mask beyond the first hour for up to 4 hours. Further use beyond 4 hours 
is at the patient’s discretion. 
Patients should avoid use of contact lenses while on denintuzumab mafodotin. 
A summary of prophylactic ocular interventions for patients randomized to the 19A+RICE 
Arm is provided in Table 1. 


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Table 1: 
Prophylactica ocular interventions with denintuzumab mafodotin 
Prophylactic Measure 
Dose and Administration 
Timing 
Steroid eye drops 
Prednisolone 1% administered 
4 times daily, 1 drop in each eye or 
equivalent. 
Begin 1 day prior to each dose of 
denintuzumab mafodotinb. Administer for 
7 days. 
Preservative-free 
artificial tears 
Administer twice daily, at least 
1 drop in each eye. 
Administer daily beginning on Cycle 1 
Day 1 until EOT. Allow at least 30 minutes 
between administration of artificial tears and 
steroid eye drops. 
Vasoconstrictor eye 
drops 
Tetrahydrozoline 0.05% or 
naphazoline 0.012% or equivalent, 
administer 1 drop in each eye. 
At the time of infusion: 
1. At the start of denintuzumab 
mafodotin infusion 
2. At the start of rituximab infusion 
3. At the end of rituximab infusion 
Cooling eye mask 
Apply cooling eye mask to both 
eyes for approximately 1 hour, or 
as much as tolerated by the patient. 
Use beyond the first hour for up to 
4 hours is encouraged. Further use 
beyond 4 hours is at the patient’s 
discretion. 
Begin at the start of each denintuzumab 
mafodotin infusion. 
a 
Dose modifications and treatment for ocular toxicities are discussed in Section 5.8.1. 
b 
In Cycle 1, beginning steroid eye drop prophylaxis on Day 1 is acceptable. 
5.5 Concomitant Therapy 
All concomitant medications and blood products administered will be recorded from Day 1 
(predose) through the safety reporting period, unless the concomitant medication is for an 
event specifically related to ASCT (see Section 6.1). Any concomitant medication given for a 
study protocol-related AE should be recorded from the time of informed consent. 
5.5.1 Required Concomitant Therapy 
Patients with a negative hepatitis PCR assay who tested positive for hepatitis B surface 
antigen and/or hepatitis B core antibody should begin antiviral prophylaxis prior to receiving 
study treatment and for at least 6 months following the completion of study treatment, per 
institutional standard. Patients receiving antiviral prophylaxis should be regularly monitored 
for viral reactivation by PCR per institutional standard. 
All patients should be individually evaluated to assess the need for tumor lysis prophylaxis 
prior to the first dose of study treatment. Patients should receive prophylaxis as appropriate 
per the institutional standards (e.g., treatment with allopurinol or rasburicase, as well as 
adequate hydration (Cairo 2010). 
See Section 5.4 for required pre- and post-medications. 
5.5.2 Allowed Concomitant Therapy 
The use of platelet and/or red blood cell supportive growth factors or transfusions when 
applicable is allowed. 


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The use of corticosteroids to treat conditions other than DLBCL is permitted per institutional 
standard. The use of systemic corticosteroids to palliate DLBCL-related symptoms prior to 
Cycle 1 Day 1 is permitted but recommended not to exceed 14 days. 
Routine antibiotic prophylaxis for Pneumocystis jiroveci pneumonia (PCP) should be 
considered for all patients per standard of care. In addition, the NCCN 2015 guideline for the 
prevention and treatment of cancer-related infections is recommended (NCCN 2015). 
Routine prophylaxis with vaccines that do not contain live micro-organisms is permitted. 
However, the administration of live vaccines (especially yellow fever vaccine) should be 
avoided. 
Intrathecal prophylactic treatment for cerebral/meningeal disease is permitted at the 
discretion of the investigator. 
5.5.3 Prohibited Concomitant Therapy 
Patients may not receive other investigational drugs, immunosuppressive medications, 
radiotherapy, or systemic anti-neoplastic therapy during the treatment phase of the study. 
Exceptions are noted in Section 5.5.2. 
5.6 Management of Infusion Reactions 
Infusion reactions related to rituximab, etoposide, ifosfamide, or carboplatin should be 
managed according to the package insert and/or institutional standard of care. 
Infusion-related reactions may occur during the infusion of denintuzumab mafodotin. The 
infusion should be administered at a site properly equipped and staffed to manage 
anaphylaxis, should it occur. All supportive measures consistent with optimal patient care 
should be given throughout the study according to institutional standards. Supportive 
measures may include extending the infusion time and/or administering medications for 
infusion-related reactions. 
● 
Patients who have experienced a Grade 1 or Grade 2 infusion-related reaction after 
administration of denintuzumab mafodotin should be premedicated for subsequent 
infusions. Premedication may include acetaminophen, an antihistamine, and a 
corticosteroid administered 15–90 minutes prior to each infusion or according to 
institutional standards. 
● 
Patients who experience a Grade 3 infusion-related reaction after denintuzumab 
mafodotin administration may potentially receive additional treatment with 
denintuzumab mafodotin at the discretion of the investigator after discussion with the 
sponsor. 
● 
If anaphylaxis or a Grade 4 infusion-related reaction occurs after denintuzumab 
mafodotin administration, denintuzumab mafodotin should be immediately and 
permanently discontinued. 
See Section 7.7.1 for details regarding recording adverse events. 


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5.7 Management of Suspected PML 
PML has been associated with rituximab treatment (Rituxan Prescribing Information, 
Genentech, September 2013) and has not been observed with denintuzumab mafodotin. 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. 
If PML is suspected, hold further study treatment (RICE and denintuzumab mafodotin) and 
undertake a diagnostic work-up including (but not limited to): 
● 
Neurologic examinations, as warranted 
● 
Brain radiologic features by magnetic resonance imaging (MRI) 
● 
Polymerase chain reaction (PCR) analysis: John Cunningham virus (JCV) DNA 
detectable in cerebrospinal fluid 
 
If PML is confirmed, permanently discontinue study treatment. 
5.8 Dose Modifications 
Dose modifications of rituximab, etoposide, ifosfamide, or carboplatin due to hematologic 
and non-hematologic toxicity are allowed per institutional standards and according to the 
product-specific United States Prescribing Information (USPI), or other country-specific 
package insert, at the discretion of the investigator. Permitted dose modifications include 
discontinuation of a treatment component. 
Myelosuppression is an expected consequence of RICE chemo-immunotherapy and should 
not be used as the basis for dose reduction or elimination of denintuzumab mafodotin. All 
patients should receive growth factor support to shorten the duration of neutropenia (see 
Section 5.4). If adequate myeloid recovery has not occurred per institutional standard of care, 
initiation of the next cycle may be postponed. Cycle 2 and/or Cycle 3 should not begin until 
there has been satisfactory recovery of peripheral blood counts (i.e., recommend that platelets 
≥75,000/µL and ANC ≥1000/µl). 
If RICE chemo-immunotherapy will be delayed at the start of Cycle 2 or Cycle 3 due to 
myelosuppression or other dose-delaying toxicity (DDT), denintuzumab mafodotin infusion 
will be delayed as well. A delay of more than 14 days in starting RICE in Cycles 2 and/or 3 
is discouraged; delays of more than 21 days are not allowed without discussion with the 
sponsor. 
If RICE chemo-immunotherapy is discontinued, no further denintuzumab mafodotin will be 
given and the patient will be discontinued from the treatment phase of the study (see Section 
6.6). 
Denintuzumab mafodotin infusion may be delayed at the start of Cycle 2 or Cycle 3 due to 
ocular toxicity (see Section 5.8.1). Per-patient dose modifications of denintuzumab 
mafodotin are permitted as described in Section 5.8.1. Dose modifications of denintuzumab 
mafodotin must be discussed with the medical monitor. In the absence of myelosuppression 


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or other DDT, RICE chemo-immunotherapy should be administered as planned on a q3week 
(21-day) cycle. 
5.8.1 Dose Modifications for Ocular Events 
Ocular adverse events are assessed as either ocular symptoms or corneal changes observed 
on ocular examination and are graded according to a modified CTCAE version 4.03 scheme 
(see Appendix E). Table 2 describes the recommended evaluations, treatment, and dose 
modifications for denintuzumab mafodotin -associated ocular toxicity. 
Per-patient dose delays and/or reductions of denintuzumab mafodotin are permitted in the 
event of Grade 3 ocular symptoms or Grade 4 corneal changes. Denintuzumab mafodotin 
dosing should be held until ocular symptoms recover to ≤ Grade 2 or corneal changes recover 
to ≤ Grade 3. The more conservative evaluation, treatment, and dose modification should 
apply in cases of simultaneous ocular symptom and corneal change toxicities. Dose 
modifications must be discussed with the medical monitor; deviations from the 
recommended dose modifications must be approved by the medical monitor. 
In the event of ocular symptoms (i.e., dry eyes), the use of preservative-free artificial tears 
may be increased up to every 2 hours, as needed. 
Steroid eye drops administered for the treatment of ≥ Grade 2 ocular symptoms or ≥ Grade 1 
corneal changes should contain prednisolone 1% (or equivalent). The frequency and duration 
of steroid eye drop administration for the treatment of ocular toxicity is per the discretion of 
the treating physician. However, it is recommended that the initial frequency should be at 
least 6 times per day. Treatment can be supplemented with topical steroid ointment applied 
overnight depending on severity. 
See Section 7.7.5 for additional details of the ocular safety monitoring plan. Refer to Section 
7.7.1.2 and Appendix E for information regarding the grading of ocular events related to the 
cornea. 


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Table 2: 
Evaluation, treatment, and dose modifications in the event of ocular toxicity 
CTCAEa 
Evaluation and Treatment 
Dose Modificationsb 
Ocular Symptoms 
Grade 1 
Use of preservative-free artificial tears may 
be increased up to every 2 hours, as needed 
Continue treatment with denintuzumab mafodotin 
without interruption or dose reduction. 
Grade 2 
Obtain ophthalmologic evaluation; change 
from a prophylactic schedule with steroid 
eye drops to a treatment schedule (1% 
prednisolone or equivalent). 
Use of preservative-free artificial tears may 
be increased up to every 2 hours, as needed. 
Continue treatment with denintuzumab mafodotin 
without interruption or dose reduction. 
Grade 3 
Same as Grade 2 
Hold denintuzumab mafodotin and discuss with the 
medical monitor. 
If ocular symptom (in the absence of Grade 4 corneal 
findings) resolves to ≤ Grade 2 within 7 days after the 
start of the current cycle of RICE, denintuzumab 
mafodotin may be resumed at the pre-hold dose level 
or with a dose reduction upon approval of the medical 
monitor. 
If ocular symptom does not resolve to ≤ Grade 2 
within 7 days after the start of the current cycle of 
RICE, skip dose of denintuzumab mafodotin for this 
cycle. Re-evaluate subsequent denintuzumab 
mafodotin dosing at the end-of-cycle ophthalmologic 
evaluation. 
Corneal Changes (diagnosed by ocular exam) 
Grade 1–
3 
Change from a prophylactic schedule with 
steroid eye drops to a treatment schedule 
(1% prednisolone or equivalent). 
Use of preservative-free artificial tears may 
be increased up to every 2 hours, as needed. 
Follow-up per protocol or more frequently 
as suggested by ophthalmologist. 
Continue treatment with denintuzumab mafodotin 
without interruption or dose reduction. 
Grade 4 
Same as Grade 3 
Hold denintuzumab mafodotin and discuss with the 
medical monitor. 
If corneal change resolves to ≤ Grade 3 within 7 days 
after the start of the current cycle of RICE, 
denintuzumab mafodotin may be resumed at the pre-
hold dose level or with a dose reduction upon approval 
of the medical monitor. 
If corneal change does not resolve to ≤ Grade 3 within 
7 days after the start of the current cycle of RICE, skip 
dose of denintuzumab mafodotin for this cycle. Re-
evaluate subsequent denintuzumab mafodotin dosing 
at the end-of-cycle ophthalmologic evaluation. 
a 
Modified CTCAE grading scheme; see Appendix E. 
b 
Discuss dose modifications with the medical monitor; deviations from the recommended dose modifications must be 
approved by the medical monitor. 


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5.9 Peripheral Blood Stem Cell Mobilization and Collection 
Peripheral blood stem cells may be mobilized during study treatment at the discretion of the 
investigator. 
Collection of PBSC for ASCT, if applicable, should occur per institutional standard of care. 
If initial stem cell collection is inadequate, additional collection of peripheral blood stem 
cells for ASCT may be performed per institutional standards. 
5.10 Treatment Compliance 
Study drug administration will be performed by study site staff and documented in source 
documents and the CRF. 
6 
STUDY ACTIVITIES 
6.1 Schedule of Events 
Adverse events (AEs) and concomitant medications will be recorded from Day 1 (predose) 
through the safety reporting period (see Section 7.7.1.3). Any study protocol-related AE 
should be recorded from the time of informed consent as well as any concomitant 
medications given for the treatment of the AE. 
Beyond the safety reporting period, patients may undergo subsequent ASCT. Additional 
transplant-related data will be collected following ASCT and may include, but not be limited 
to, the time to neutrophil and platelet engraftment in each treatment arm. 
A schedule of events is provided in Appendix A. Study activities are listed by visit in this 
section, and descriptions of all study assessments are presented in Section 7. 
6.2 Screening Visit (Day –28 to Day 1) 
● 
Informed consent 
● 
Study eligibility per inclusion/exclusion criteria (see Section 4) 
● 
Medical history; medical history at screening includes a review of inflammatory 
conditions (see Section 7.1) 
● 
Collection/acquisition of tumor specimen for central pathology review (see 
Section 7.1) 
● 
Patient second-line, age-adjusted International Prognostic Index (saaIPI) score for 
patients ≤60 years of age or standard IPI score for patients >60 years of age (see 
Appendix D) 
● 
Serology for hepatitis B surface antigen and anti-hepatitis B core antibody; if either is 
positive, PCR for hepatitis B viremia must also be performed (see Section 5.5.1) 
● 
Blood sample for biomarker assessments (Table 3) 
● 
CT of diagnostic quality of neck, chest, abdomen, and pelvis (see Section 7.2) 
● 
PET scan (Note: a combined CT/PET may be obtained to satisfy the requirements for 
CT and PET scanning, as long as the CT is of diagnostic quality) 


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● 
If a bone marrow biopsy has been performed as part of standard of care, record the 
biopsy result for lymphoma involvement in the CRF (see Section 7.2; a result from a 
biopsy collected within 60 days prior to the first dose of study treatment may be used) 
● 
Ophthalmology exam (see Section 7.7.5) 
○ 
Ocular health survey (±2 days from the ophthalmology exam) 
6.2.1 Baseline Visit (Day –7 to Day 1) 
● 
Physical exam (see Section 7.7.4) 
● 
Height and weight 
● 
B symptom assessment (see Section 7.2) 
● 
ECOG performance status (see Appendix B) 
● 
Electrocardiogram (ECG) 
● 
Pregnancy test for females of childbearing potential 
● 
Serum chemistry panel, including fasting blood glucose (see Section 7.7.3) 
● 
Hemoglobin A1c (Hgb A1c) 
● 
Complete blood count (CBC) with differential (see Section 7.7.3) 
● 
Prothrombin time, partial thromboplastin time, international normalized ratio 
(PT/PTT/INR) 
● 
Spot urine for urine protein:creatinine (UPC) ratio (see Section 7.7.3) 
6.3 Randomization (Day –1 to Day 1) 
Randomization to occur after eligibility is determined and within 1 business day prior to the 
planned first dose of Cycle 1 Day 1. 
● 
For the 19A+RICE Arm: Begin prophylactic steroid eye drop administration. Steroid 
eye drop prophylaxis is recommended to begin 1 day prior to denintuzumab 
mafodotin dose if possible (see Section 5.4.1); however, beginning steroid eye drop 
prophylaxis on Day 1 for the first cycle of treatment is acceptable. 
6.4 Treatment Period (Day 1 to Day 21) 
6.4.1 Cycle 1, Day 1 
All Day 1 assessments should be completed prior to study drug administration. 
● 
Vital signs (see Section 7.7.2) 
● 
Serum chemistry panel 
● 
CBC with differential 
● 
PT/PTT/INR 
● 
Spot urine for UPC ratio 
● 
Blood samples for PK, ATA, and biomarker assessments (see Table 3) 
● 
For the 19A+RICE Arm: 
○ 
Denintuzumab mafodotin administration 


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○ 
Prophylactic steroid eye drop administration starting 1 day before infusion, if not 
already started 
○ 
Recommended prophylactic ocular interventions at the time of infusion: cooling 
eye mask application and vasoconstrictor eye drops administration (see Table 1) 
 
If Baseline Visit activities occur within 1 day prior to Cycle 1, Day 1, the following 
assessments do not need to be repeated at the Cycle 1 Day 1 visit: serum chemistry panel, 
CBC with differential, PT/PTT/INR, and spot urine for UPC calculation. 
6.4.2 Cycle 1, Day 1 to Day 3 (+1 day) 
● 
RICE administration (see Section 5.3.3) 
● 
Days 1 and 2: Blood samples for PK, ATA, and biomarker assessments (see Table 3) 
6.4.3 Cycle 1, Day 4 
● 
Blood samples for PK and biomarker assessments (see Table 3) 
6.4.4 Cycle 1, Day 8 (±1 day) 
● 
Serum chemistry panel 
● 
CBC with differential 
● 
Spot urine for UPC ratio 
○ 
24-hour urine collection if UPC >2 (prior to next cycle dosing, or prior to EOT 
visit if discontinuing study treatment) 
● 
Blood samples for PK and biomarker assessments (see Table 3) 
6.4.5 Cycle 1, Day 15 (±1 day) 
● 
Serum chemistry panel 
● 
CBC with differential 
● 
Spot urine for UPC ratio 
○ 
24-hour urine collection if UPC >2 (prior to next cycle dosing, or prior to EOT 
visit if discontinuing study treatment) 
● 
Blood samples for PK and biomarker assessments (see Table 3) 
6.4.6 Cycle 1, Day 22 (±3 days) 
For patients who do not continue on treatment or do not start the next cycle on Day 22 due to 
dose delay: 
● 
Blood sample for PK (see Table 3) 
6.4.7 Cycles 2 and 3: Day 1 (±1 day) 
● 
Perform the following procedures within 24 hours prior to administration of the first 
component of study treatment 
○ 
Physical exam, including weight 


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○ 
Vital signs (see Section 7.7.2) 
○ 
ECOG performance status 
○ 
B symptom assessment 
○ 
Serum chemistry panel 
○ 
CBC with differential 
○ 
PT/PTT/INR 
○ 
Spot urine for UPC ratio 
̵ 
24-hour urine collection if UPC >2 (prior to next cycle dosing, or prior to 
EOT visit if discontinuing study treatment) 
● 
Blood samples for PK, ATA, and biomarker assessments (see Table 3) 
● 
For the 19A+RICE Arm: 
○ 
Denintuzumab mafodotin administration  
○ 
Prophylactic steroid eye drop administration. Note: Eye drop prophylaxis should 
begin 1 day prior to denintuzumab mafodotin dose (see Section 5.4.1). 
○ 
Recommended prophylactic ocular interventions at the time of infusion: cooling 
eye mask application and vasoconstrictor eye drops administration (see Table 1) 
6.4.8 Cycles 2 and 3: Day 1 to Day 3 (±1 day) 
● 
RICE administration 
6.4.9 Cycles 2 and 3: Day 8 (±1 day) 
● 
Serum chemistry panel 
● 
CBC with differential 
● 
Spot urine for UPC ratio 
○ 
24-hour urine collection if UPC >2 (prior to next cycle dosing, or prior to EOT 
visit if discontinuing study treatment) 
6.4.10 Cycles 2 and 3: Day 15 (±1 day) 
● 
Serum chemistry panel 
● 
CBC with differential 
● 
Spot urine for UPC ratio 
○ 
24-hour urine collection if UPC >2 (prior to next cycle dosing, or prior to EOT 
visit if discontinuing study treatment) 
● 
Ophthalmology exam (performed Day 14 to Day 21 of the treatment cycle, unless 
alternate schedule is approved by the medical monitor; see Section 7.7.5). Review 
exam results prior to next dosing of denintuzumab mafodotin; dose modifications 
should be made based on ocular toxicity grading (see Table 2 and Appendix E). 
○ 
Ocular health survey (±2 days from the ophthalmology exam) 


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6.4.11 Cycle 2, Day 22 (±3 days) 
For patients who do not continue on treatment or do not start the next cycle on Day 22 due to 
dose delay: 
● 
Blood sample for PK (see Table 3) 
6.5 PBSC Mobilization 
PBSC mobilization for ASCT should occur per institutional standard of care. Chemotherapy 
for the mobilization of stem cells is permitted. Information surrounding PBSC mobilization 
and collection, if conducted, will be collected and may include, but not be limited to, the 
following: date of mobilization, number of CD34-positive cells mobilized (cells/kg), and 
mobilization regimen. 
6.6 End of Treatment Visit 
End of Treatment (EOT) visits should occur 14 to 30 days after the start of the last cycle 
(administration of denintuzumab mafodotin in the 19A+RICE Arm, or Day 1 of RICE in the 
control arm), unless delayed due to an AE. However, EOT evaluations must be performed 
before initiation of a new therapy, inclusive of radiotherapy and ASCT. If EOT evaluations 
are completed before 30 days after completion of study treatment, the patient will also be 
contacted 30–37 days following the completion of study treatment to assess for adverse 
events. 
● 
Physical examination 
● 
Review of inflammatory conditions (only for those patients with certain inflammatory 
conditions of interest at Screening/Baseline) 
● 
ECOG performance status 
● 
B symptom assessment 
● 
ECG 
● 
Ophthalmology exam (not required if an exam was performed within 4 weeks prior to 
the EOT visit, and following the last dose of study treatment) 
○ 
Ocular health survey (±2 days from the ophthalmology exam) 
● 
Pregnancy test for females of childbearing potential 
● 
Serum chemistry panel 
● 
CBC with differential 
● 
PT/PTT/INR 
● 
Spot urine for UPC calculation 
○ 
24-hour urine collection if UPC >2 (within 5 days after UPC assessment) 
● 
Blood samples for PK, ATA, and biomarker assessments (see Table 3) 
● 
For patients discontinuing treatment due to disease progression: if a tumor biopsy was 
performed at the time of disease progression as part of standard of care, submit 
sample of tumor specimen, if available (see Section 7.4.4) 


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The following response assessments are required (unless progressive disease [PD] was 
documented within the previous 6 weeks by diagnostic CT/PET scan): 
● 
CT of diagnostic quality of neck, chest, abdomen, and pelvis (see Section 7.2) 
● 
PET scan (Note: a combined CT/PET may be obtained to satisfy the requirements for 
CT and PET scanning, as long as the CT is of diagnostic quality) 
● 
If patient is scheduled to undergo stem cell collection and bone marrow biopsy is 
performed as part of standard of care, record the bone marrow biopsy result for 
lymphoma involvement in the CRF. 
6.7 Long-Term Follow-Up Visits 
Patients who discontinue from study treatment will remain on the study for follow-up until 
discontinuation from the study by withdrawal of consent, loss to follow-up, death, or study 
closure, whichever occurs first (see Section 4.3.2). 
For patients who discontinue study treatment for any reason other than disease progression or 
initiation of a non-protocol therapy (with the exception of ASCT) for treatment of 
lymphoma, long-term follow-up visits for PFS assessment will occur at 3, 6, 12, 18, 
24 months (±1 month), and then annually after ASCT or EOT (for patients who don’t receive 
ASCT). 
The following assessments will be performed at long-term follow-up visits: 
● 
Clinical assessment of disease status by history and physical examination 
● 
CT scan of diagnostic quality of the neck, chest, abdomen, and pelvis (see 
Section 7.2) until disease progression or initiation of a new anticancer treatment (with 
the exception of a stem cell transplant); perform at follow-up visits and at any time 
disease progression is suspected 
● 
PET scan, unless disease is PET negative; required until disease is PET negative 
(Note: a combined CT/PET may be obtained to satisfy the requirements for CT and 
PET scanning, as long as the CT is of diagnostic quality) 
● 
Record subsequent anticancer therapies received 
● 
For patients who receive ASCT, collect PBSC mobilization outcomes, and time to 
neutrophil and platelet engraftment 
At any time during the follow-up period, if a bone marrow biopsy is performed as part of 
standard of care, the results from the bone marrow biopsy for lymphoma involvement will be 
recorded in the CRF. 
For patients who proceed to ASCT, an ophthalmology exam and ocular health survey will be 
performed approximately 30-days post ASCT. 


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In addition, for patients who develop ocular toxicity during study treatment, ophthalmologic 
exams should be conducted monthly during the follow-up period (unless discussed with the 
medical monitor) until resolution or return to baseline. 
All patients who receive at least one dose of denintuzumab mafodotin in the experimental 
arm or RICE in the control arm will be followed for survival at 6-month intervals after ASCT 
or EOT for the first 24 months and then yearly thereafter until death or study closure, 
whichever occurs first. At the time of study closure, patients will be contacted for a final 
survival assessment. 
6.8 End of Study/End of Follow-Up 
The date the patient met criteria for study discontinuation and the reason for study 
discontinuation will be recorded (see Section 4.3.2). 
7 
STUDY ASSESSMENTS 
7.1 Screening/Baseline Assessments 
Only patients who meet all inclusion and exclusion criteria specified in Section 4 will be 
enrolled in this study. 
Histologically-confirmed DLBCL must be determined by local pathology assessment. 
Submission of the tumor block or approximately 15 unstained slides from a biopsy of 
relapsed disease (or diagnostic specimen if refractory) is required for subsequent central 
pathology disease confirmation and further evaluation of pharmacodynamic biomarkers (see 
Section 7.4). The biopsy specimen must be from a malignant lymph node or extranodal tissue 
obtained by core or excisional/incisional biopsy. Cutaneous samples alone are unacceptable. 
Fine needle aspiration and cytology samples are also unacceptable. Details and shipping 
instructions are provided in the research specimen laboratory manual. 
If representative tissue from the most recent tumor biopsy after the last therapy is 
unavailable, a fresh biopsy must be obtained. 
If available, archived tumor tissue from the initial biopsy is also required to be submitted 
during the trial. 
A blood sample for hepatitis serology and biomarker assessments is required (Table 3). 
Patient medical history includes a thorough review of: 
● 
The patient’s current and previous conditions 
● 
Disease status after each previous systemic therapy received prior to entering this 
study 
● 
Concomitant medications and prior therapies for malignancy 
 


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Included with the medical history is a review of any inflammatory conditions; patients with 
certain inflammatory conditions of interest at Screening/Baseline will have an additional 
review at the EOT visit. 
Patient second-line, age-adjusted International Prognostic Index (saaIPI) scores should be 
calculated based on the method initially published by Shipp et al, Moskowitz et al, and 
updated by Hamlin et al (see Appendix D) to be used for randomization of patients ≤60 years 
of age. The saaIPI is calculated by scoring 3 prognostic factors: stage of disease, lactate 
dehydrogenase (LDH) level, and ECOG score. The standard IPI should be used for 
randomization of patients >60 years of age. The standard IPI incorporates additional scores 
for age and extranodal involvement. Refer to the study manual for details and scoring sheet. 
Patient disease stage will be calculated to determine eligibility, per the Cotswolds 
Modification of Ann Arbor Staging System (Lister 1989). 
Cardiac assessment will be performed with an ECG. 
7.2 Response/Efficacy Assessments 
The determination of antitumor activity will be based on response assessments made 
according to the Lugano Classification Revised Staging System for malignant lymphoma 
(see Appendix F) (Cheson 2014). Treatment decisions by the investigator will be based on 
these assessments. PET and CT scans are required per protocol as directed in Section 6 and 
Appendix A. Staging will be performed by PET/CT of diagnostic quality, with disease 
involvement determined by focal FDG uptake in nodal and extranodal (including spleen, 
liver, bone marrow, and thyroid) sites that is consistent with lymphoma, according to the 
pattern of uptake and/or CT characteristics. CT scans will be of diagnostic quality (i.e., 
contrast-enhanced with IV and oral contrast, unless contrast is medically contraindicated). 
Up to 6 of the largest nodes, nodal masses, or other involved lesions that are measurable in 
2 diameters should be identified as target lesions; if possible, they should be from disparate 
regions of the body, and they should include mediastinal and retroperitoneal areas of disease 
whenever these sites are involved. 
A metabolic response of progressive disease (PD), stable disease (SD), partial remission 
(PR), or complete remission (CR) will be determined per the Lugano classification criteria. If 
clinical progression is determined by the investigator, radiographic staging should also be 
performed to determine response assessment per the Lugano classification criteria. The PET 
scan metabolic uptake will be graded in the 5-point Deauville scale with a score of ≤3 
considered to represent a complete metabolic response (CMR). For all follow-up response 
assessments, both PET and CT scanning will be required until disease is PET negative; 
responses will then be followed by CT scan of diagnostic quality and evaluated by CT-based 
response criteria per the Lugano classification criteria. 
At any time on study, if bone marrow biopsies are performed as part of standard of care, 
results from the biopsy reports will be recorded in the CRF. The results will be used to 
confirm the presence or absence of lymphoma in the marrow. At the screening visit, a result 


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from a biopsy performed within 60 days of the first dose of denintuzumab mafodotin in the 
19A+RICE Arm or RICE in the control arm, as part of clinical care, is preferred, if available. 
At EOT, if a patient is scheduled to undergo stem cell collection and a bone marrow biopsy is 
performed as part of standard of care, the result will be recorded. All available bone marrow 
biopsy results will also be recorded in the CRF. 
B symptom assessment will also be performed. B symptoms are defined as: unexplained 
fevers greater than 38°C, drenching night sweats, or weight loss greater than 10% of body 
weight. 
Patients’ clinical data must be available for CRF source verification. Copies of all tumor 
imaging studies must be submitted for IRF review as described in the study manual. 
7.3 Pharmacokinetic and Antitherapeutic Antibody Assessments 
Sensitive, qualified assays will be used to measure concentrations of denintuzumab 
mafodotin ADC and released cys-mcMMAF in plasma. PK samples will be collected and 
archived for possible analysis of other denintuzumab mafodotin-related species and 
rituximab concentrations. Samples for rituximab PK will only be collected and archived for 
the first 20 patients treated in the RICE Arm and the first 50 patients treated in the 
19A+RICE Arm. The assays will include enzyme-linked immunosorbent assays (ELISA) and 
liquid chromatography/tandem mass spectrometry (LC-MS/MS) assays, as well as other 
assays if further characterization is required. A qualified electrochemiluminescence assay 
will be used to determine the levels of antitherapeutic antibodies (ATA). 
The PK parameters to be estimated include, but are not limited to, maximum plasma 
concentration (Cmax), area under the plasma concentration-time curve (AUC), plasma 
concentrations at trough (Ctrough), terminal half-life (T1/2), plasma clearance (CL), steady-state 
volume of distribution (Vss), and accumulation ratio (AR). Related analytes of denintuzumab 
mafodotin may also be measured using appropriate assays. 
Blood samples for PK and antitherapeutic antibodies (ATA) testing will be collected at 
timepoints throughout the study as described in Table 3. Refer to the Central Laboratory 
Manual for information on collection, processing, storage, and shipment of samples. 
 


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Table 3: 
Pharmacokinetic, antitherapeutic antibody, and biomarker sampling timepoints 
 
 
 
 
 
 
 
 
Biomarker Samples 
Study 
Day 
Time 
Window 
Relative Timec 
SGN-CD19A 
PKa 
Rituximab 
PKb 
ATA 
Tumor 
Tissue 
Whole 
Blood Serum Plasma 
Cell 
Pellet 
Screening/ 
Baseline 
Day 
–28 to 1 
N/A 
N/A 
N/A 
 
 
 
Xd 
X 
 
 
 
Cycle 1 
Day 1 
Pre-dose 
Within 24 hrs prior 
to start of infusion 
Start of infusion 
X 
X 
X 
 
X 
X 
X 
X 
End of SGN-CD19A 
infusion 
Within 5 min post 
end of infusion 
End of infusion 
X 
 
 
 
 
 
 
 
End of rituximab 
infusion 
Within 5 min post 
end of infusion 
End of infusion 
 
X 
 
 
 
 
 
 
4 h 
±15 min 
End of infusion 
X 
 
 
 
 
 
 
 
8 h 
±30 min 
End of infusion 
X 
 
 
 
 
 
 
 
Day 2 
24 hr 
±4 hr 
Start of infusion 
X 
X 
 
 
X 
X 
X 
 
Day 4 
72 hr 
±4 hr 
Start of infusion 
X 
X 
 
 
 
X 
X 
 
Day 8 
168 hr 
±24 hr 
Start of infusion 
X 
X 
 
 
X 
X 
X 
 
Day 15 
336 hr 
±24 hr 
Start of infusion 
X 
X 
 
 
X 
X 
X 
 
Day 22f 
504 hr 
±72 hr 
Start of infusion 
X 
X 
 
 
 
 
 
 
Cycles 
2 and 3 
Day 1 
Pre-dose 
Within 8 hr 
Start of infusion 
X 
X 
X 
 
X 
X 
X 
 
End of SGN-CD19A 
infusion 
Within 5 min post 
end of infusion 
End of infusion 
X 
 
 
 
 
 
 
 
End of rituximab 
infusion 
Within 5 min post 
end of infusion 
End of infusion 
 
X 
 
 
 
 
 
 
Day 22f 
504 hr 
±72 hr 
Start of infusion 
X 
X 
 
 
 
 
 
 
EOT 
 
X 
X 
X 
Xe 
X 
X 
X 
 
a 
19A+RICE Arm only. 
b 
Collected for the first 20 patients treated in the RICE Arm and the first 50 patients treated in the 19A+RICE Arm. 
c 
Relative time is based on the denintuzumab mafodotin infusion in the 19A+RICE Arm and based on the rituximab infusion in the RICE Arm. 
d 
Representative tissue from the most recent biopsy after the last therapy or fresh tumor specimen for study entry (see Section 7.1) and biomarker analysis (see Section 7.4.4). If available, archived 
tumor tissue from the initial biopsy is also required. 
e 
If a tumor biopsy is obtained at time of disease progression as part of institutional standard of care, submit a sample of the tumor tissue, if available (see Section 7.4.4). 
f 
For Cycle 1 and Cycle 2 only. Sample obtained only for patients not continuing on treatment or not starting the next cycle on Day 22. 


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7.4 Biomarker Analysis 
Samples from patients in both treatment arms will be analyzed and compared for target and 
pathway component expression that may affect the efficacy of denintuzumab mafodotin or 
change in response to treatment with denintuzumab mafodotin. Analysis of tumor tissue and 
blood may also include markers associated with prognosis, response, or resistance. Depletion 
of B-cell subsets in peripheral blood will be measured as potential pharmacodynamic 
markers of denintuzumab mafodotin activity and compared to that in the RICE control 
treatment cohort. Circulating proteins such as soluble CD19 (sCD19) may be assessed at 
baseline and post treatment to understand their potential prognostic and predictive value to 
denintuzumab mafodotin treatment. Blood sampling timepoints for biomarker analyses are 
listed in Table 3. 
7.4.1 B-Cell Subsets Analysis 
Whole blood samples will be collected for evaluation of markers of circulating B cells by 
flow cytometry. Reduction in circulating B cell subsets may be a pharmacodynamic marker 
of denintuzumab mafodotin activity. Flow cytometry measurements will include but not be 
limited to: CD3, CD14, CD19, CD20, CD27, CD38, CD56, CD269, and IgD. 
7.4.2 Protein Markers in Blood 
Serum and plasma will be obtained and evaluated for soluble mediator quantification. 
Soluble CD19 is elevated in autoimmune disorders. The level of sCD19 in DLBCL patients 
at baseline may be predictive of denintuzumab mafodotin treatment response. sCD19 may be 
measured pre- and post-treatment with denintuzumab mafodotin to understand its value as a 
potential predictive marker as well as a pharmacodynamic marker. Circulating proteins 
related to tumor burden or other potentially prognostic characteristics of the disease will also 
be monitored. In addition, Minimal Residual Disease (MRD) evaluation may also be carried 
out to understand the depth of response to therapy and correlate with PFS and other patient 
outcomes. Molecular MRD status may be analyzed using the Adaptive ClonoSEQ assay. 
7.4.3 Fc-γ Receptor (FcγR) Variants 
Peripheral blood cell pellets will be collected for assessment of FC gamma receptor (FcγR) 
polymorphisms. Carriage of alleles that encode high-affinity variants of FCGR2A and 
FCGR3A may predict better responses to IgG1 antibody-based therapies, possibly due to 
increased activation of anti-tumor effector cells or prolonged duration of therapeutic drug 
levels in patients with these alleles. Denintuzumab mafodotin maintains effector functions 
such as antibody-dependent cellular cytotoxicity (ADCC); therefore, enhanced ADCC in 
patients with high-affinity FcγR variants may contribute to better anti-tumor activity. 
Germline single nucleotide polymorphisms (SNPs) that may inform efficacy and toxicity 
may also be explored from patients who give optional pharmacogenomics (PGx) consent. 
The genes of interest may include, but are not limited to, CEP27, an inherited genetic variant 
found associated with vincristine-related peripheral neuropathy in patients with acute 
lymphoblastic leukemia (ALL). No additional blood draw is necessary. 


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7.4.4 Characterization of Tumor Tissue 
Fresh or archived tumor tissue blocks after last relapse will be collected at screening to 
evaluate biomarkers potentially predictive of response to denintuzumab mafodotin treatment. 
If available, initial diagnostic biopsies will also be collected to understand changes in 
response and resistant biomarkers. If a biopsy on residual tumor is performed at the end of 
treatment or at progression as part of standard of care, a sample will be collected (if 
available) to evaluate response at the cellular level and potential resistant biomarkers (see 
Section 6.6). Tumor biopsies may be evaluated for CD19, CD20, CD21, and other immune-
cell marker expression by immunohistochemistry (IHC). Although all B-cell lymphomas are 
expected to express CD19, response to therapy may vary depending on the intensity and 
pattern of CD19 expression. DLBCL cell of origin and additional gene expression analysis 
may also be evaluated. Further molecular characterization of the tumor, such as mechanism-
based resistance and somatic mutations prognostic to treatment outcome such as Myc/BCL2 
translocation and BCL6 expression, as well as the presence of infiltrating lymphocytes and 
macrophages may also be carried out if sufficient samples are available. 
7.5 Biospecimen Repository 
In the US only, for patients who provide additional consent, remaining de-identified unused 
blood and/or tissue will be retained by Seattle Genetics and used for future research, 
including but not limited to the evaluation of targets for novel therapeutic agents, the biology 
of antibody-drug conjugate (ADC) sensitivity and resistance mechanisms, and to identify 
biomarkers of ADCs. Blood and tissue samples donated for future research will be retained 
for a period of up to 25 years. If additional consent is not provided, any remaining biological 
samples will be destroyed following study completion. 
7.6 Patient-Reported Outcomes 
7.6.1 Ocular Health Survey 
The Visual Function Questionnaire (VFQ-25) is a validated 25-item patient-reported vision-
targeted health survey designed to quantify the patients’ perception of overall eye health, 
ocular symptoms, and the effect these symptoms have on the patients’ regular activities 
(Mangione 2001). Surveys will be administered as specified in Section 6 and should be 
completed at or around the time of each ophthalmology exam (±2 days). 
7.7 Safety Assessments 
Safety assessments will include the surveillance and recording of adverse events (AEs), 
clinical laboratory tests, and physical examination findings during the course of this study. 
Ophthalmologic examinations and ocular health survey will be conducted. PBSC collection 
will also be assessed as a measure of safety. Additionally, transplant-related data following 
ASCT will be collected and will include, but not be limited to, the time to neutrophil and 
platelet engraftment in each treatment arm. 
Safety will be monitored over the course of the study by an SMC as described in Section 
3.1.2. 


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7.7.1 Adverse Events 
7.7.1.1 Definitions 
Adverse Event 
According to the International Council on Harmonization (ICH) E2A guideline Definitions 
and Standards for Expedited Reporting, and 21 CFR 312.32, Investigational New Drug 
(IND) Safety Reporting, an AE is any untoward medical occurrence in a patient or clinical 
investigational subject administered a medicinal product and which does not necessarily have 
a causal relationship with this treatment. 
The following information should be considered when determining whether or not to record a 
test result, medical condition, or other incident on the Adverse Events and Pre-Existing 
Conditions case report form (CRF): 
● 
From the time of informed consent through the day prior to study Day 1, only study 
protocol-related AEs should be recorded. A protocol-related AE is defined as an 
untoward medical event occurring as a result of a protocol mandated procedure. 
● 
All medical conditions present or ongoing predose on study Day 1 should be 
recorded. 
● 
All AEs (regardless of relationship to study drug) should be recorded from study Day 
1 (during and post-dose) through the end of the safety reporting period (see 
Section 7.7.1.3). Complications that occur in association with any procedure (e.g., 
biopsy) should be recorded as AEs whether or not the procedure was protocol 
mandated. 
● 
Changes in medical conditions and AEs, including changes in severity, frequency, or 
character, during the safety reporting period should be recorded. 
● 
In general, an abnormal laboratory value should not be recorded as an AE unless it is 
associated with clinical signs or symptoms, requires an intervention, results in a 
serious adverse event (SAE), or results in study termination or 
interruption/discontinuation of study treatment. When recording an AE resulting from 
a laboratory abnormality, the resulting medical condition rather than the abnormality 
itself should be recorded (e.g., record “anemia” rather than “low hemoglobin”). 


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Serious Adverse Events 
An AE should be classified as an SAE if it meets one of the following criteria: 
Fatal: 
AE resulted in death 
Life threatening: 
The AEs placed the 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 
SAEs by this criterion. Admission to a palliative unit or hospice care facility is not 
considered to be a hospitalization. Hospitalizations or prolonged hospitalizations 
for scheduled therapy of the underlying cancer or study target disease need not be 
captured as SAEs. 
Disabling/ 
incapacitating: 
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 National Cancer Institute’s Common Terminology 
Criteria for Adverse Events (NCI CTCAE), version 4.03, with the exception of ocular 
adverse events which will be graded according to a modified CTCAE version 4.03 scheme 
(Appendix E). The NCI CTCAE, version 4.03 criteria are provided in the study manual or 
may be accessed at http://ctep.cancer.gov/reporting/ctc.html. 
AE severity and seriousness are assessed independently. ‘Severity’ characterizes the intensity 
of an AE. ‘Serious’ is a regulatory definition and serves as a guide to the sponsor for defining 
regulatory reporting obligations (see definition for Serious Adverse Events). 
Relationship of the Adverse Event to Study Treatment 
The relationship of each AE to each study treatment (denintuzumab mafodotin or RICE) 
should be evaluated by the investigator using the following criteria: 
Related: 
There is evidence to suggest a causal relationship between the drug and the AE, such as: 
● an event that is uncommon and known to be strongly associated with drug exposure 
(e.g., angioedema, hepatic injury, Stevens-Johnson Syndrome) 
● an event that is not commonly associated with drug exposure, but is otherwise 
uncommon in the population exposed to the drug (e.g., tendon rupture) 
Unrelated: 
Another cause of the AE is more plausible (e.g., due to underlying disease or occurs 
commonly in the study population), or a temporal sequence cannot be established with 
the onset of the AE and administration of the study treatment, or a causal relationship is 
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7.7.1.2 Procedures for Eliciting and Recording Adverse Events 
Investigator and study personnel will report all AEs and SAEs whether elicited during patient 
questioning, discovered during physical examination, laboratory testing and/or other means 
by recording them on the CRF and/or SAE form, as appropriate. 
Eliciting Adverse Events 
An open-ended or non-directed method of questioning should be used at each study visit to 
elicit the reporting of AEs. 
Recording Adverse Events 
The following information should be recorded on the Adverse Events and Pre-Existing 
Conditions CRF: 
● 
Description including onset and resolution dates 
● 
Whether it met serious criteria 
● 
Severity 
● 
Relationship to study treatment or other causality 
● 
Outcome 
Diagnosis vs. Signs or Symptoms 
In general, the use of a unifying diagnosis is preferred to the listing out of individual 
symptoms. Grouping of symptoms into a diagnosis should only be done if each component 
sign and/or symptom is a medically confirmed component of a diagnosis as evidenced by 
standard medical textbooks. If any aspect of a sign or symptom does not fit into a classic 
pattern of the diagnosis, report the individual symptom as a separate AE. 
Important exceptions for this study are adverse reactions associated with the infusion of 
study drug. For infusion-related reactions, do not use the NCI CTCAE terms of ‘cytokine 
release syndrome,’ ‘acute infusion reaction,’ or ‘allergic or hypersensitivity reaction.’ 
Instead, record each sign or symptom as an individual AE. If multiple signs or symptoms 
occur with a given infusion-related event, each sign or symptom should be recorded 
separately with its level of severity. 
Recording Events Related to Corneal Abnormalities 
Corneal abnormalities observed with denintuzumab mafodotin are not well defined by the 
available CTCAE v4.03 toxicity categories for ocular toxicities; therefore, grading should be 
according to a modified CTCAE grading scheme as provided in Appendix E. 
Recording Serious Adverse Events 
For SAEs, record the event(s) on both the CRF and an SAE form. 


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The following should be considered when recording SAEs: 
● 
Death is an outcome of an event. The event that resulted in the death should be 
recorded and reported on both an SAE form and CRF. 
● 
For hospitalizations, surgical, or diagnostic procedures, the illness leading to the 
surgical or diagnostic procedure should be recorded as the SAE, not the procedure 
itself. The procedure should be captured in the narrative as part of the action taken in 
response to the illness. 
Progression of the Underlying Cancer 
Do not use the term ‘disease progression’ alone when reporting AEs, including SAEs, 
because it is too nonspecific. Symptoms of disease progression that meet the criteria for an 
SAE must be reported. When possible, report the specific disease (clinical) manifestation of 
the progression (e.g., ‘malignant pleural effusion’, ‘spinal bone metastases’, 
‘lymphadenopathy’, ‘brain metastases’). Otherwise, it is acceptable to report the specific 
disease (e.g., non-Hodgkin lymphoma) as an SAE. 
Pregnancy 
Notification to Drug Safety: Complete a Pregnancy Report Form for all pregnancies that 
occur from the time of first study drug dose until 12 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. Email or fax to the sponsor’s Drug Safety 
Department within 48 hours of becoming aware of a pregnancy. All pregnancies will be 
monitored for the full duration; all perinatal and neonatal outcomes should be reported. 
Infants should be followed for a minimum of 8 weeks. 
Collection of data on the CRF: All pregnancies (as described above) that occur within 
30 days of the last dose of study drug(s) will also be recorded on the Adverse Events and Pre-
Existing Conditions CRF. 
Abortion, whether accidental, therapeutic, or spontaneous, should be reported as an SAE. 
Congenital anomalies or birth defects, as defined by the ‘serious’ criterion above (see 
definitions Section 7.7.1.1) should be reported as SAEs. 
7.7.1.3 Reporting Periods for Adverse Events and Serious Adverse Events 
The safety reporting period for all AEs and SAEs is from study Day 1 (predose) through the 
EOT visit or 30 days after last study treatment (denintuzumab mafodotin or any component 
of RICE), whichever is later. However, all study protocol-related AEs are to be recorded 
from the time of informed consent. All SAEs that occur after the safety reporting period and 
are considered study treatment-related in the opinion of the investigator should also be 
reported to the sponsor. 


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SAEs will be followed until significant changes return to baseline, the event stabilizes 
(recovering/resolving) or is no longer considered clinically significant by the investigator, or 
the patient dies or withdraws consent. All non-serious AEs will be followed through the 
safety reporting period. Certain non-serious AEs of interest may be followed until resolution, 
return to baseline, or study closure. 
7.7.1.4 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 emailed or faxed to the 
sponsor’s Drug Safety Department (see email address or fax number included on the SAE 
report form) within 24 hours. 
Relevant follow-up information is to be submitted to the sponsor as soon as it becomes 
available. 
7.7.1.5 Sponsor Safety Reporting to Regulatory Authorities 
Investigators are required to report all SAEs, including anticipated SAEs, to the sponsor (see 
Section 7.7.1.4). 
The sponsor will report all SAEs to regulatory authorities as required per local regulatory 
reporting requirements. In the United States, endpoints that assess disease-related mortality 
or major morbidity as well 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 Food and Drug Administration (FDA) as individual 
Investigational New Drug (IND) safety reports per the final rule amending the IND safety 
reporting requirements under 21 CFR 312.32 and the FDA’s guidance Safety Reporting 
Requirements for INDs and Bioavailability (BA) and Bioequivalence (BE) Studies 
(December 2012). 
In this study, the SAEs that do not require individual IND safety reports to the FDA are 
progression of the underlying cancer. These anticipated SAEs will be reviewed periodically 
by the Seattle Genetics Drug Safety Department. If, upon review, an SAE is occurring at a 
higher rate than that which would be expected for the investigational arm (19A+RICE), then 
an IND safety report for the SAE will be submitted to the FDA. 


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7.7.2 Vital Signs 
Vital signs measures are to include heart rate, blood pressure, and temperature. Vital signs 
should be collected per institutional standard for RICE infusion. For patients in the 
19A+RICE Arm, vitals will be measured and recorded prior to the start of the denintuzumab 
mafodotin infusion and upon the completion of the infusion. All vitals should be measured 
after the patient has been sitting/resting for at least 5 minutes. 
7.7.3 Clinical Laboratory Tests 
Samples will be drawn for local labs. Local laboratory testing will include institutional 
standard tests for evaluating safety and making clinical decisions. The following laboratory 
assessments will be performed by the local lab to evaluate safety at scheduled timepoints (see 
Appendix A) during the course of the study: 
● 
The chemistry panel includes, but is not limited to, the following tests: albumin, 
alkaline phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase 
(AST), blood urea nitrogen, calcium, creatinine, chloride, glucose (fasting at 
baseline), lactate dehydrogenase (LDH), phosphorus, potassium, sodium, total 
bilirubin, and uric acid. 
● 
Hgb A1c 
● 
The CBC with differential is to include the following tests: white blood cell count 
with five-part differential (neutrophils, lymphocytes, monocytes, eosinophils, and 
basophils), platelet count, hemoglobin, and hematocrit. Manual differential should be 
completed when clinically indicated. 
● 
PT/PTT/INR 
● 
Hepatitis B surface antigen and anti-hepatitis B core antibody testing. If either is 
positive, PCR for hepatitis B viremia must also be performed. 
● 
A serum or urine β-hCG pregnancy test for females of childbearing potential 
(FOCBP) 
● 
Spot Urine. A spot urine will be performed to test urine samples for urine protein and 
creatinine values, and results will be used to calculate a UPC ratio. 
● 
A 24-hour urine collection to test for total protein value will be required at visits 
where the UPC >2. If UPC >2 during a treatment cycle, only one 24-hour urine 
collection is required prior to the next cycle dosing. 
7.7.4 Physical Examination 
Physical examinations should include assessments of the following body parts/systems: 
abdomen, extremities, head, heart, lungs, neck, and neurological. Measurements of weight 
will be obtained. Measurements of height obtained within the prior 12 months may be 
utilized. 


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7.7.5 Ocular Monitoring Plan 
In order to assess the effects of denintuzumab mafodotin on the eye, patients in both study 
arms will have complete ophthalmology assessments at protocol-defined timepoints (see 
Section 6 and Appendix A). Ophthalmology assessments are to include, but are not limited 
to, visual acuity and slit lamp examination. A baseline dilated fundus examination is 
required; subsequent dilated fundus examinations are to be conducted as clinically indicated. 
In particular, corneal epithelium changes must be assessed at each timepoint. Assessments 
must also include evaluation of steroid eye drop-induced changes including, but not limited 
to, intraocular pressure measurements and subcapsular cataracts. In addition, ophthalmologic 
evaluations will be obtained in the event of subjective visual or ocular disturbances while on 
study. 
The results of the ophthalmological exam should be reviewed prior to the next dosing of 
denintuzumab mafodotin, and dose modifications of denintuzumab mafodotin should be 
made based on ocular toxicity grading of symptoms or corneal changes (see Section 5.8.1 
and Appendix E) following discussion with the medical monitor. 
Ophthalmology exams and ocular health surveys are required at baseline, the end of Cycles 2 
and 3 (Days 15–21), EOT, and approximately 30-days post ASCT (for those patients who 
proceed to ASCT). In the event of ocular toxicity, ophthalmology exams should be 
conducted at least monthly during the follow-up period (unless discussed with the medical 
monitor) until resolution or return to baseline. 
7.7.6 Monitoring for Tumor Lysis Syndrome 
Patients who are in the opinion of the investigator to be at high risk for tumor lysis syndrome 
(TLS) should be monitored for TLS after the Cycle 1, Day 1 dose according to the 
institutional standard. 
7.7.7 ECOG Performance Status 
ECOG performance status will be evaluated at protocol-specified timepoints. See Appendix 
B for the ECOG scale and the Karnofsky performance status equivalents. 
7.8 Appropriateness of Measurements 
Response will be assessed according to the Lugano classification criteria (Cheson 2014), 
internationally accepted criteria for the evaluation of lymphoma. The criteria will be 
employed to assess tumor lesion size and extent of disease in the determination of response 
rate and PFS in this study. The schedule for tumor imaging is consistent with general 
oncological practice and appropriately balances measurement of tumor control with the 
expense and patient inconvenience associated with CT and PET scanning. 
The safety measures that will be used in this trial are considered standard procedures for 
evaluating the potential adverse effects of study medications. AEs and, when applicable, 
clinical laboratory data will be graded using NCI CTCAE v4.03. To detect any alteration in 
renal function, UPC ratios and serum creatinine levels will be obtained at specified 


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timepoints and 24-hour urine collections for protein quantification will be conducted when 
the UPC is >2. To evaluate ocular toxicities, and to understand the ocular toxicity associated 
with denintuzumab mafodotin, complete ophthalmology exams and ocular health surveys 
will be conducted in both study arms at specified timepoints. 
ATA is commonly assessed for biologics; therefore, standard tests will be performed to 
detect the possible presence of specific antibodies to denintuzumab mafodotin. 
Pharmacokinetic assessments are required to characterize drug effect, as are biomarker 
assessments, and are included in this trial. 
8 
DATA QUALITY CONTROL AND QUALITY ASSURANCE 
8.1 Site Training and Monitoring Procedures 
A study manual with instructions for study compliance and CRF completion will be 
provided. Prior to the enrollment of patients at the site, Seattle Genetics or its designated 
clinical and medical personnel will review the following items with the investigator and 
clinic staff: 
● 
The protocol, study objectives, eligibility requirements, study procedures, registration 
and withdrawal processes 
● 
Current Investigator’s Brochure/ package insert 
● 
Recording and reporting AE and SAE 
● 
Enrollment goals and study timelines 
● 
The CRF completion process and source documentation requirements 
● 
Monitoring requirements 
● 
Institutional Review Board/Independent Ethics Committee (IRB/IEC) review and 
approval process 
● 
Informed consent process 
● 
Good Clinical Practice guidelines and related regulatory documentation requirements 
● 
Key study team roles and responsibilities 
● 
Investigational product storage, accountability, labeling, dispensing and record 
keeping 
● 
Patient coding and randomization 
● 
Study samples/specimen collection, handling and shipping 
● 
Protocol compliance 
● 
Clinical study record keeping, document retention, and administrative requirements 


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Monitoring visits will occur periodically, with frequency dependent on the rate of enrollment 
and workload at each site. During monitoring visits, the Seattle Genetics representative will 
review regulatory documentation, CRFs, source documentation, and investigational product 
storage, preparation, and accountability. The CRFs will be reviewed for completeness, 
adherence to the provided guidelines, and accuracy compared to the source documents. The 
investigators must ensure that the monitor is allowed to inspect all source documents 
pertinent to study patients, and must cooperate with the monitor to ensure that any problems 
noted in the course of the trial are resolved. The investigator must maintain a comprehensive 
and centralized filing system of all study-related documentation that is suitable for inspection 
by Seattle Genetics or its designated monitors and by quality assurance auditors, or 
representatives of regulatory authorities. 
8.2 Data Management Procedures 
Seattle Genetics will provide CRF Completion Guidelines for electronic CRF (eCRF) data 
entry. Study specific data management procedures will be maintained in the data 
management plan. Queries resulting from edit checks and/or data verification procedures will 
be posted electronically in the eCRF. 
8.3 Access to Source Data 
The investigator will permit the sponsor’s representatives to monitor the study as frequently 
as the sponsor deems necessary to determine that protocol adherence and data recording are 
satisfactory. Appropriate measures to protect patient confidentiality are to be employed 
during monitoring. The CRFs and related source documents will be reviewed in detail by the 
monitor at each site visit. Original source documents or certified copies are needed for 
review. This review includes inspection of data acquired as a requirement for participation in 
this study and other medical records as required to confirm that the information contained in 
the CRFs, such as disease assessments, AEs, and concomitant medications, is complete and 
correct. Other study records, such as correspondence with the sponsor and the IRB/IEC and 
screening and drug accountability logs will also be inspected. All source data and study 
records must also be available for inspection by representatives of regulatory authorities. 
8.4 Accuracy and Reliability of Data 
Steps to be taken to assure the accuracy and reliability of data include: 
● 
The selection of qualified investigators and appropriate study centers. 
● 
Review of protocol procedures with the investigators and associated personnel prior 
to the study. 
● 
Periodic monitoring visits by the designated monitor(s). 
● 
CRFs will be reviewed for accuracy and completeness by the designated monitor(s) 
during monitoring visits to the study centers. Any discrepancies will be resolved with 
the investigator or designees as appropriate. 


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8.5 Quality Assurance Procedures 
The Clinical Quality Assurance group or its designee may conduct audits at the clinical site 
or other study-related facilities and organizations. Audit reports will be retained by the 
Clinical Quality Assurance group of Seattle Genetics as part of the written record. 
8.6 Data Handling and Record Keeping 
8.6.1 Data Handling 
It is the investigator’s responsibility to ensure the accuracy, completeness, legibility, and 
timeliness of the data reported to the sponsor in the CRFs and in all required reports. Data 
reported on the CRF that is derived from source documents should be consistent with the 
source documents or the discrepancies should be explained. 
Any change or correction to a CRF will be maintained in an audit trail within the electronic 
data capture system. Data changes may only be made by those individuals so authorized. The 
investigator should retain records of the changes and corrections, written and/or electronic. 
8.6.2 Investigator Record Retention 
The investigator shall retain study drug disposition records and all source documentation 
(such as original ECG tracings, laboratory reports, inpatient or office patient records) for the 
maximum period required by the country and Institution in which the study will be 
conducted, or for the period specified by Seattle Genetics, whichever is longer. The 
investigator must contact Seattle Genetics prior to destroying any records associated with the 
study. If the investigator withdraws from the study (due to relocation, retirement, etc.), the 
records shall be transferred to a mutually agreed upon designee, such as another investigator 
or IRB/IEC. Notice of such transfer will be provided in writing to Seattle Genetics. 
9 
DATA ANALYSIS METHODS 
9.1 Determination of Sample Size 
With approximately 100 patients randomized in a 1:1 ratio to each treatment arm (~50 
patients per arm),the study is designed to have approximately 80% power to detect an 
increase in the CR rate of 25%. It is assumed that the CR rates for the 19A+RICE Arm and 
the RICE Arm are 60% and 35%, respectively. This calculation is based on a two-sided χ2 
test with significance level of α= 0.1 using EAST (version 5.4). 
If the dose of denintuzumab mafodotin in the investigational 19A+RICE arm is modified, up 
to 50 additional patients may be randomized (25 in each arm) so that a total of 100 patients 
will be randomized in a 1:1 ratio to either the 19A (modified dose) + RICE arm or the RICE 
only arm. Up to approximately 150 patients may be randomized in this study. If a subset of 
patients appears to potentially derive benefit from 19A+RICE versus RICE at a pre-planned 
evaluation, the Sponsor may continue enrolling those patients beyond the planned sample 
size (approximately 100 patients), but will not exceed the planned maximum number of 
patients to be randomized in this study (up to approximately 150 patients). 


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9.2 Study Endpoint Definitions 
9.2.1 Primary Efficacy Endpoint: CR Rate per IRF 
CR rate per IRF is defined as the proportion of patients with complete metabolic response by 
PET/CT or complete radiologic response by CT only per IRF at the end of treatment 
according to the Lugano Classification Revised Staging System for malignant lymphoma 
(Cheson 2014). Patients whose disease response cannot be assessed will be scored as non-
responders for calculating the CR rate. 
CR rate by investigator assessment will also be evaluated. 
9.2.2 Secondary Efficacy Endpoints 
9.2.2.1 Progression-Free Survival (PFS) 
PFS is defined as the time from randomization to first documentation of disease progression 
per investigator (including progressive metabolic disease by PET/CT or progressive disease 
by CT as assessed by the Lugano classification criteria (Cheson 2014), or investigator claim 
of clinical progression), death due to any cause, or receipt of subsequent anticancer therapy, 
whichever comes first. Note that patients receiving post-treatment consolidative 
radiotherapy, post-treatment chemotherapy for the purpose of mobilizing PBSC, or ASCT 
will not be considered as having started new anticancer therapy. 
PFS by IRF may also be evaluated. 
9.2.2.2 Overall Survival 
Overall survival (OS) is defined as the time from date of randomization to date of death due 
to any cause. In the absence of confirmation of death, survival time will be censored at the 
last date the patient is known to be alive. If the last recorded date where a patient is known to 
be alive is the date of randomization, survival time will be censored on the date of 
randomization (i.e., OS duration of 1 day). 
9.2.2.3 Duration of Complete Remission 
Duration of CR is defined as the time from the start of the first radiographic documentation 
of CR per investigator to the first documentation of PD (including progressive metabolic 
disease by PET/CT or progressive disease by CT as assessed by the Lugano classification 
criteria (Cheson 2014), or investigator claim of clinical progression), death due to any cause, 
or receipt of subsequent anticancer therapy, whichever comes first. Note that patients 
receiving post-treatment consolidative radiotherapy, post-treatment chemotherapy for the 
purpose of mobilizing PBSC, or ASCT will not be considered as having started new 
anticancer therapy. 
Duration of CR by IRF may also be evaluated. 


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9.2.2.4 Proportion of Patients Achieving PBSC Mobilization 
The proportion of patients achieving PBSC mobilization is defined as the number of patients 
who are able to adequately mobilize PBSC (defined as 2 x 106 CD34 cells/kg) on or after 
completion of study treatment, prior to subsequent anticancer therapy (excluding post-
treatment consolidative radiotherapy, post-treatment chemotherapy for the purpose of 
mobilizing PBSCs, and consolidative autologous or allogeneic SCT), divided by the total 
number of patients. 
9.2.2.5 Proportion of Patients Receiving ASCT 
The proportion of patients receiving ASCT is defined as the number of patients receiving 
ASCT after completion of study treatment, prior to subsequent anticancer therapy (excluding 
post-treatment consolidative radiotherapy, post-treatment chemotherapy for the purpose of 
mobilizing PBSCs, and consolidative autologous or allogeneic SCT), divided by the total 
number of patients. 
9.2.2.6 Objective Response Rate 
ORR is defined as the proportion of patients with CR or partial remission (PR) per IRF at the 
end of treatment according to the Lugano classification criteria (Cheson 2014). CR includes 
complete metabolic response by PET/CT or complete radiologic response by CT. PR 
includes partial metabolic response by PET/CT or partial remission by CT. Patients whose 
disease response cannot be assessed will be scored as non-responders for calculating the 
ORR. 
ORR by investigator assessment will also be evaluated. 
9.2.2.7 Duration of Objective Response 
Duration of OR is defined as the time from the start of the first radiographic documentation 
of objective response (CR or PR) per investigator to the first documentation of PD (as 
assessed by the Lugano classification criteria (Cheson 2014), or investigator claim of clinical 
progression), death due to any cause, or receipt of subsequent anticancer therapy, whichever 
comes first. Note that patients receiving post-treatment consolidative radiotherapy, post-
treatment chemotherapy for the purpose of mobilizing PBSC, or ASCT will not be 
considered as having started new anticancer therapy. 
Duration of OR by IRF may also be evaluated. 
9.3 Statistical and Analytical Plans 
The statistical and analytical plans presented below summarize the more complete plans to be 
detailed in the statistical analysis plan (SAP). A change to the data analysis methods 
described in the protocol will require a protocol amendment only if it alters site conduct (e.g., 
adding baseline assessments to define a subgroup). The SAP will be finalized prior to 
database lock. Any changes to the methods described in the final SAP will be described and 
justified in the clinical study report. 


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9.3.1 General Considerations 
This is a phase 2, randomized, open-label study with a formal statistical hypothesis for the 
primary efficacy endpoint. There are no formal pre-specified statistical hypotheses for the 
primary safety objective. 
Descriptive statistics (mean, median, standard deviation, minimum, maximum) will be used 
to summarize continuous variables. Frequencies and percentages will be used to summarize 
categorical variables. 
9.3.1.1 Randomization and Blinding 
This is a randomized, open-label study that may enroll up to approximately 150 patients. 
Approximately 100 patients will be randomized in a 1:1 ratio to receive either 19A+RICE or 
RICE. In the 19A+RICE Arm, the planned dose for denintuzumab mafodotin is 3 mg/kg; 
however, in the case that the SMC recommends modification of the dose of denintuzumab 
mafodotin (e.g., to 2 mg/kg), up to 50 additional patients may be enrolled and randomized 
(25 in each arm) so that a total of 100 patients will be randomized in a 1:1 ratio to receive 
either 19A (modified dose) + RICE or RICE only. 
Patients will be stratified based on the following variables to ensure that patient specific risk 
factors are appropriately balanced between treatment arms. Randomization will be stratified 
by: 
● 
Disease status 
○ 
CR to frontline systemic therapy and relapsed more than 12 months after initial 
diagnosis (i.e., initiation of frontline therapy) 
○ 
PR or SD to frontline systemic therapy, or CR to frontline and relapsed less than 
or equal to 12 months after initial diagnosis (i.e., initiation of frontline therapy) 
● 
Second-line age-adjusted IPI (saaIPI) score or standard IPI score at randomization 
○ 
Low-risk disease: saaIPI of 0 or 1, or standard IPI of 0, 1, or 2 
○ 
High-risk disease: saaIPI of 2 or 3, or standard IPI of 3, 4, or 5 
● 
Disease type 
○ 
De novo DLBCL and Grade 3b follicular lymphoma 
○ 
Transformed DLBCL 
 
After stratification, patients will be randomized into 1 of 2 treatment arms, for a total of 
approximately 50 patients per arm. 
Stratified randomization with a fixed block size will be performed centrally using a system 
that will assign both the treatment and a unique patient randomization number. 
9.3.1.2 Adjustments for Covariates 
Stratified analyses will include adjustment for the stratification factor as recorded at 
randomization (described in Section 9.3.1.1). Covariates may be considered for adjustment in 
exploratory regression analyses. 


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9.3.1.3 Handling of Dropouts and Missing Data 
Missing data will not be imputed, with the exception of AE dates while calculating duration 
of events and treatment emergent status. Patients with missing values of a variable other than 
response endpoints (CR and OR) and time-to-event endpoints (PFS, duration of response, 
and OS) will be excluded from the analysis of that endpoint. Patients whose disease response 
cannot be assessed will be scored as non-responders for calculating the response rate (CR 
rate and ORR). Censoring rules will be applied to the estimation of the distribution of the 
time-to-event endpoints, details will be provided in the SAP. 
9.3.1.4 Multicenter Studies 
There are multiple centers in this study, however it is not anticipated that any center will 
accrue enough patients to warrant an analysis by center. 
9.3.1.5 Multiple Comparisons and Multiplicity 
The overall two-sided alpha level for the primary endpoint is 0.1. 
Formal statistical tests will be performed for the CR per IRF, and the key secondary 
endpoints of PFS and duration of CR. If the test for the primary analysis of CR rate is 
statistically significant in favor of the investigational arm at a two-sided alpha level of 0.1, 
formal statistical tests will be performed for the key secondary endpoints at an overall two-
sided alpha level of 0.1. A fixed sequence testing procedure, where testing is carried out 
sequentially at an unadjusted alpha level as long as all preceding null hypotheses are rejected, 
will be used to ensure type I error control for key secondary endpoints. The testing order will 
be: 1) PFS, and 2) duration of CR. If the test for CR rate per IRF is not statistically 
significant, the p-value of the tests for the key secondary endpoints will still be calculated, 
but will be considered descriptive. 
9.3.1.6 Data Transformations and Derivations 
For efficacy assessments per investigator, the date of response will be the latest of all 
radiologic scan dates for the given restage assessment. The date of progression will be the 
earliest of all radiologic scan dates for the given disease assessment, or the date of 
investigator claim of clinical progression, whichever comes first. No other data 
transformations are planned for the primary or secondary endpoints. 
9.3.1.7 Analysis Sets 
Intent-to-Treat (ITT) Analysis Set: The ITT analysis set will include all randomized 
patients. Patients will be included in the treatment arm assigned at randomization regardless 
of the actual treatment received. 
Modified Intent-to-Treat (mITT) Analysis Set: The mITT analysis set will include all 
patients who are randomized to the recommended dose level of 19A+RICE or RICE, and 
receive at least 1 cycle of study treatment. If the dose of denintuzumab mafodotin is modified 
from 3 mg/kg (e.g., to 2 mg/kg), the mITT Analysis Set includes all patients randomized 


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after the dose modification decision is made. Patients will be included in the treatment arm 
assigned at randomization regardless of the actual treatment received. 
Safety Analysis Set: The safety analysis set will include all patients who receive any amount 
of denintuzumab mafodotin or any component of RICE. Treatment group will be determined 
using the actual treatment arm received, regardless of the randomization treatment 
assignment. 
Per-Protocol (PP) Analysis Set: The per-protocol analysis set includes patients who receive 
at least 1 cycle of RICE (all components) or recommended dose of 19A+RICE (with all 
components of RICE) combination therapy and who had both a baseline and at least one 
post-baseline evaluable disease assessment (per the Lugano classification criteria or 
determination of clinical disease progression per the investigator), and no other major 
protocol deviations that could potentially affect tumor response. The per-protocol analysis set 
is a subset of the mITT analysis, and patients will be grouped in the same manner as mITT 
analysis set. 
9.3.1.8 Examination of Subgroups 
All analyses will be presented by treatment arm. 
As exploratory analyses, subgroup analyses may be conducted for selected endpoints. The 
subgroups that may be examined include, but are not limited to, the following: 
● 
Disease status 
● 
Low-risk versus high-risk disease (saaIPI or standard IPI score, as appropriate to 
patient age) 
● 
Disease type 
● 
Cell of origin (germinal center B cell [GCB] or non-GCB/activated B cell [ABC]) 
 
Detailed methodology will be provided in the SAP. 
9.3.1.9 Timing of Analyses 
Three interim evaluations for safety are planned as specified in Section 3.1.2. 
There are no formal interim efficacy analyses planned for this study, however, two 
administrative looks at overall safety and efficacy may be performed when approximately 40 
and 75 patients have completed EOT as specified in Section 9.3.1.9. 
The analysis of the primary endpoint of CR per IRF will occur after all patients in the mITT 
analysis set have completed EOT. Comparison of the CR rates between the 2 treatment arms 
will be conducted. The database cutoff date for this analysis will be determined once all 
study patients have completed treatment. 
The primary analysis of PFS and OS endpoints will occur approximately 2 years after the last 
patient’s enrollment. If 70% of patients have experienced a PFS and/or OS event prior to 
2 years after the last patient’s enrollment, the primary analysis of PFS and/or OS may be 


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performed earlier than scheduled. Subsequent cutoff dates may be defined and corresponding 
database locks may occur to allow for more precise estimates of the time-to-event endpoints 
prior to study closure. 
9.3.2 Patient Disposition 
An accounting of study patients by disposition will be tabulated and the number of patients in 
each analysis set will be summarized. Patients who discontinue study treatment and patients 
who withdraw from the study will be summarized with reason for discontinuation or 
withdrawal and listed. 
9.3.3 Patient Characteristics 
Demographics and other baseline characteristics will be summarized. Details will be 
provided in the SAP. 
9.3.4 Treatment Compliance 
The dose administered at each cycle for each treatment agent will be summarized. Details 
will be provided in the SAP. 
9.3.5 Efficacy Analyses 
Hypothesis test for primary and key secondary endpoints will be performed based on mITT 
analysis set. If the dose of denintuzumab mafodotin is modified (e.g., to 2 mg/kg), patients 
randomized after modification of the dose of denintuzumab mafodotin will be included in the 
testing for the primary and key secondary endpoints. Summary of all efficacy endpoints may 
be performed on ITT, mITT, and PP analysis sets. Response as assessed by investigator will 
also be summarized for associated efficacy endpoints. Concordance with response per IRF 
will be explored. 
9.3.5.1 Primary Efficacy Analysis 
Complete remission (CR) rate is defined as the proportion of patients achieving CR by IRF at 
the end of treatment in the mITT analysis set using the Lugano classification criteria 
(Cheson 2014). Patients whose disease response cannot be evaluated per the Lugano 
classification criteria or investigator claim of clinical progression will be scored as Not 
Evaluable. The primary efficacy hypotheses will be tested at a two-sided 0.1 alpha level 
using a Cochran-Mantel-Haenszel (CMH) test stratified by the randomization strata. In 
situations where a stratum cannot be included in a stratified analysis of an endpoint, it may 
be necessary to pool strata prior to the analysis. The details of pooling strategy will be 
specified in the SAP. 
The primary efficacy hypotheses can be expressed as follows: 
H0: The odds ratio of CR is 1 between the 19A+RICE and RICE arms, adjusting for 
stratification factors. 
Ha: The odds ratio of CR is different from 1 between the 19A+RICE and RICE arms, 
adjusting for stratification factors. 


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CR rate and exact two-sided 90% confidence interval (CI) using the Clopper-Pearson method 
(Clopper 1934) will be calculated. 
9.3.5.2 Secondary Efficacy Analyses 
PFS, OS, duration of CR, and duration of OR will be estimated using Kaplan-Meier 
methodology and Kaplan-Meier plots will be provided. The median survival time and its 
two-sided 90% CI using the log-log transformation method (Collett 1994) will be calculated. 
The stratified log-rank test will be used to compare PFS between the two treatment arms at a 
two-sided 0.1 alpha level. If the dose of denintuzumab mafodotin is modified (e.g., to 
2 mg/kg), the definition of treatment arm will follow Section 9.3.5.1. 
ORR, the proportion of patients achieving PBSC mobilization, and the proportion of patients 
receiving ASCT will be summarized. An exact two-sided 90% CI using the Clopper-Pearson 
method (Clopper 1934) will be calculated. 
9.3.6 Pharmacokinetic and Antitherapeutic Antibody Analyses 
The individual plasma concentrations of denintuzumab mafodotin ADC and unconjugated 
drug (cys-mcMMAF) will be summarized with descriptive statistics at each PK sampling 
timepoint using the Safety Analysis Set. Any additional PK and PK/PD analyses may be 
described in a separate analysis plan and presented in a separate report. 
The ATA incidence rate is defined as the proportion of patients that develop ATA at any time 
during the study. ATA incidence will be summarized using the Safety Analysis Set. 
9.3.7 Biomarker Analyses 
Absolute and relative biomarker measurements and changes from baseline will be listed and 
summarized. Summary statistics may be tabulated. Relationships of absolute and relative 
biomarker changes from baseline to efficacy, safety and pharmacokinetic parameters will be 
explored. Similarly, the relationship of baseline biomarker measurements to efficacy will be 
explored. Details will be described in a separate analysis plan Bioinformatics Analysis Plan 
(BAP), SAP, or PK Analysis Plan. 
9.3.8 Patient-Reported Health Outcome Analyses 
VFQ-25 composite score and select sub-scale scores may be summarized with descriptive 
statistics by treatment arm. In addition, change from baseline may be tabulated or presented 
graphically by treatment arm, as appropriate. 
9.3.9 Safety Analyses 
9.3.9.1 Extent of Exposure 
Duration of treatment, number of cycles, total dose will be summarized by treatment arm 
using the Safety Analysis Set. Dose modifications will also be summarized and listed. 
Details will be provided in the SAP. 


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9.3.9.2 Adverse Events 
Adverse events will be defined as treatment emergent if they are newly occurring or worsen 
following study treatment. The incidence of all AEs, treatment-emergent AEs, and treatment-
related AEs will be tabulated using the Safety Analysis Set. AEs will be classified by system 
organ class and preferred term using the Medical Dictionary for Regulatory Activities 
(MedDRA). 
AEs will be listed and summarized by MedDRA preferred term, severity, and relationship to 
study drug. In the event of multiple occurrences of the same AE with the same preferred term 
in one patient, the AE will be counted once as the occurrence. AEs leading to premature 
discontinuation of study drug will be summarized and listed in the same manner. 
9.3.9.3 Deaths and Serious Adverse Events 
Serious adverse events will be listed and summarized in the same manner as all AEs. Events 
with a fatal outcome will be listed. 
9.3.9.4 Clinical Laboratory Results 
Summary statistics for actual values and for change from baseline may be tabulated or 
presented graphically as appropriate for laboratory results by treatment arm and scheduled 
visit. Laboratory values outside of the normal reference range at any postbaseline assessment 
will be listed by treatment arm with grade per NCI CTCAE and out of the normal range 
flags. 
9.3.9.5 Other Safety Analyses 
Vital Signs 
Vital signs will be presented graphically for each vital sign by scheduled visit. Summary 
statistics and change from baseline and/or predose to postdose may be tabulated where 
appropriate. 
ECOG Status 
ECOG status may be summarized for each visit. Shifts from baseline to the best and worst 
postbaseline score may be tabulated. 
ECG 
ECG status (normal, abnormal clinically significant, or abnormal not clinically significant) 
may be summarized for each scheduled ECG, and shifts from baseline may be tabulated. 
Ocular Toxicities 
Patient incidence of ocular toxicities (as defined by the MedDRA system organ class [SOC] 
of eye disorders or custom queries) will be presented by treatment arm. Additional analyses 
may be done, including incidence of ocular toxicities by maximum severity, ocular toxicities 
that lead to treatment discontinuation, etc. 


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Transplant-Related Information Following ASCT 
Time to neutrophil and platelet engraftment may be summarized and tabulated where 
appropriate. 
9.3.10 Interim Analyses 
The SMC will periodically monitor the trial for safety during the treatment period. Three 
formal safety interim evaluations are planned as specified in Section 3.1.2. Enrollment will 
only be paused during the first safety review, unless required by the SMC. The SMC will 
review data for both treatment arms to include, but not be limited to, the following: 
● 
Incidence of DDT 
● 
Adverse events 
● 
Clinical laboratory tests 
● 
Response assessments, if requested 
● 
PBSC mobilization, if available 
 
After reviewing the aggregate data, the SMC will make a recommendation to the sponsor 
regarding further conduct of the trial, as specified in Section 3.1.2. 
An ongoing real-time review of serious AEs (SAEs) in both treatment arms will be 
conducted by the Seattle Genetics Program Safety Monitoring Team. 
In addition, two interim administrative evaluations of overall safety are planned when 
approximately 40 and 75 patients have completed EOT. The hypothesis test that compares 
the CR rate of the 2 arms will not be performed. The study will not be discontinued unless 
there is a safety concern. If a subset of patients appears to potentially derive benefit from 
19A+RICE versus RICE at a pre-planned evaluation, the Sponsor may continue enrolling 
those patients beyond the planned sample size (approximately 100 patients), but will not 
exceed the planned maximum number of patients to be randomized in this study (up to 
approximately 150 patients). 
A summary of activity may be used for risk/benefit assessment. Additionally, interim data 
from the study may be presented at scientific meetings such as the annual meetings of the 
American Society of Clinical Oncology and the American Society of Hematology. 
10 INFORMED CONSENT, ETHICAL REVIEW, AND REGULATORY 
CONSIDERATIONS 
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 (Brazil 2013), and all applicable regulatory requirements. 
10.1 Informed Consent 
The investigator is responsible for presenting the risks and benefits of study participation to 
the subject in simple terms using the IRB/IEC approved informed consent document and for 


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ensuring patients are re-consented when the informed consent document is updated during 
the study, if required. The investigator will ensure that written informed consent is obtained 
from each patient, or legally authorized representative, if applicable to this study, by 
obtaining the signature and date on the informed consent document prior to the performance 
of protocol evaluations or procedures. 
If informed consent is obtained from a legally authorized representative for a patient who is 
unable to provide informed consent at study entry (if applicable), but the patient is later able 
to provide informed consent, the investigator must obtain written informed consent from the 
patient. 
10.2 Ethical Review 
The investigator will provide the sponsor or its designee with documentation of the IRB/IEC 
approval of the protocol and the informed consent document before the study may begin at 
the investigative site(s). The name and address of the reviewing ethics committee are 
provided in the investigator file. 
The investigator will supply the following to the investigative site’s IRB/IEC: 
● 
Protocol and amendments 
● 
Informed consent document and updates 
● 
Clinical Investigator’s Brochure and updates 
● 
Relevant curricula vitae, if required 
● 
Required safety and SAE reports 
● 
Any additional submissions required by the site’s IRB/IEC 
 
The investigator must provide the following documentation to the sponsor or its designee: 
● 
The IRB/IEC periodic (e.g., quarterly, annual) re-approval of the protocol. 
● 
The IRB/IEC approvals of any amendments to the protocol or revisions to the 
informed consent document. 
● 
The IRB/IEC receipt of safety and SAE reports, as appropriate. 
10.3 Regulatory Considerations 
This study will be conducted in accordance with the protocol and ethical principles stated in 
the applicable guidelines on good clinical practice, and all applicable local and/or regional 
laws, rules, and regulations. 
10.3.1 Investigator Information 
The contact information and qualifications of the principal investigator and subinvestigators 
and name and address of the research facilities are included in the investigator file. 


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10.3.2 Protocol Amendments and Study Termination 
Any investigator-initiated changes to the protocol (with the exception of changes to eliminate 
an immediate hazard to a study patient) must be approved by the sponsor prior to seeking 
approval from the IRB/IEC, and prior to implementing. The investigator is responsible for 
enrolling patients who have met protocol eligibility criteria. Protocol deviations must be 
reported to the sponsor and the local IRB/IEC in accordance with IRB/IEC policies. 
The sponsor may terminate the study at any time. The IRB/IEC must be advised in writing of 
study completion or early termination. 
10.4 Study Documentation, Privacy and Records Retention 
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 applicable IRB/IEC with direct access to original source documents 
or certified copies. 
Records containing patient medical information must be handled in accordance with local 
and national laws, rules, and regulations and consistent with the terms of the patient 
authorization contained in the informed consent document for the study (the Authorization). 
Care should be taken to ensure that such records are not shared with any person or for any 
purpose not contemplated by the Authorization. Furthermore, CRFs and other documents to 
be transferred to the sponsor should be completed in strict accordance with the instructions 
provided by the sponsor, including the instructions regarding the coding of patient identities. 
In compliance with local and/or regional regulations, this trial may be registered and trial 
results may be posted on public registries, such as ClinicalTrials.gov. 
10.5 Clinical Trial Agreement 
Payments by the sponsor to investigators and institutions conducting the trial, requirements 
for investigators’ insurance, the publication policy for clinical trial data, and other 
requirements are specified in the clinical trial agreement. 


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Lymphomas. http://www.nccn.org/ Accessed: 1/9/2015. 
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chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin's lymphoma. N Engl J Med 333(23): 1540-5. 
Shipp MA, Harrington DP, Anderson JR, Armitage JO, Bonadonna G, Brittinger G, Cabanillas F, Canellos GP, 
Coiffier B, Connors JM, Cowan RA, Crowther D, Dahlberg S, Engelhard M, Fisher RI, Gisselbrecht C, Horning 
SJ, Lepage E, Lister TA, Meerwaldt JH, Montserrat E, Nissen NI, Oken MM, Peterson BA, Tondini C, 
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Terasawa T, Dahabreh IJ, Nihashi T (2010). Fluorine-18-fluorodeoxyglucose positron emission tomography in 
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van Imhoff GW, McMillan A, Matasar MJ, Radford J, Ardeshna KM, Kuliczkowski K, Kim W, Hong X, 
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Vose JM, Carter S, Burns LJ, Ayala E, Press OW, Moskowitz CH, Stadtmauer EA, Mineshi S, Ambinder R, 
Fenske T, Horowitz M, Fisher R, Tomblyn M (2013). Phase III randomized study of rituximab/carmustine, 
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trial. J Clin Oncol 31(13): 1662-8. 
 
 


 
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APPENDIX A: SCHEDULE OF EVENTS 
 
Screening 
Baseline 
Enrollment/ 
Randomization 
Every cycleA 
EOTB 
Time of 
Transplant 
Long-term F/U 
Months after ASCT or EOT 
Visit Window 
D –28 to 1 D –7 to 1 
 
D1 
(±1d) 
D2V 
D4V 
D8 
(±1d) 
D15 
(±1d) 
D22W 
(±3d) 
14–30 days post 
start of last cycle 
 
3 
6 
12 
18 
24 
>24 
±1 month 
Annually 
±1 mo 
Screening/ 
Baseline  
Assessments 
Informed consent 
X 
 
Eligibility documentation submitted to Sponsor  
prior to randomization 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inflammatory conditions review 
X 
 
 
 
 
 
 
 
XC 
 
 
 
 
 
 
 
Tumor specimen 
XD 
 
 
 
 
 
 
 
XE 
 
 
 
 
 
 
 
saaIPI score or standard IPI scoreX 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serology (hepatitis B)F 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Electrocardiogram 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Pregnancy test for FOCBP 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Treatment 
Study treatment administration 
 
 
XG,Y 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood-based 
PK/Biomarker/ 
ATA 
PK 
 
 
Refer to Sections 7.3 and 7.4, and Table 3 
 
 
 
 
 
 
 
ATA 
 
 
 
 
 
 
 
 
 
Biomarker samples 
X 
 
 
 
 
 
 
 
 
Response  
Assessments 
CT (chest, neck, abdomen, pelvis)H 
X 
 
 
 
 
 
 
 
XI 
 
X 
X 
X 
X 
X 
X 
PETH 
X 
 
 
 
 
 
 
 
XI 
 
XJ 
XJ 
XJ 
XJ 
XJ 
XJ 
BM biopsy resultsK 
XK 
 
 
 
 
 
 
 
XK 
 
 
 
 
 
 
 
B symptoms 
 
X 
XL 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Survival status 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
Safety 
Assessments 
Physical exam with weight 
 
X 
XL 
 
 
 
 
 
XZ 
 
XZ 
XZ 
XZ 
XZ 
XZ 
XZ 
Vital signs (Section 7.7 2) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG (Appendix B) 
 
X 
XL 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Serum chemistry (Section 7.7.3) 
 
XAA 
XM 
 
 
X 
X 
 
X 
 
 
 
 
 
 
 
Hgb A1c 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with differential 
 
X 
XM 
 
 
X 
X 
 
X 
 
 
 
 
 
 
 
PT/PTT/INR 
 
X 
XM 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Spot urine for UPC ratio (Section 7.7.3) 
 
X 
XM 
 
 
X 
X 
 
X 
 
 
 
 
 
 
 
24-hr urine collection if UPC>2 
 
 
XM, N 
 
 
XN 
XN 
 
XO 
 
 
 
 
 
 
 
Ophthalmology exam (Section 7.7.5) 
X 
 
 
 
 
 
XL,P 
 
XQ,R 
XS 
XR 
XR  
XR 
XR 
XR 
XR 
Ocular health surveyT (Section 7.6.1) 
X 
 
 
 
 
 
XL 
 
XQ,R 
XS 
XR 
XR 
XR 
XR 
XR 
XR 
Con meds & AEs 
Collect any related to study procedures 
Collect from Day 1 (predose) thru 30 days post last dose 
XU 
 
 
 
 
 
 
Collect PBSC mobilization info 
(Section 6.5) 
 
 
 
At time of PBSC collection 
 
Collection of PBSC mobilization outcome. 
Refer to Section 6.7. 
 
A  
Cycles 2 and 3 should not begin until adequate recovery of peripheral blood counts (i e , platelets ≥75,000/µL and ANC 
≥1000/µL)  A delay of >7 days is discouraged  
B  
Perform EOT evaluations before initiation of non-protocol therapy  If EOT visit is <30 days after completion of study 
treatment, conduct a phone screen 30–37 days after completion of study treatment to ensure no change in AE profile 
has occurred  
C  
Required for patients with inflammatory conditions of interest at Screening (Section 7 1)  
D  
For screening (Section 7 1) and biomarker analysis (Section 7 4 4)  Representative tissue from the most recent biopsy 
after the last therapy must be available; if such tissue is not available, a fresh biopsy must be obtained  
E  
For patients discontinuing treatment due to PD: if a tumor biopsy was performed at the time of disease progression as 
part of standard of care, submit sample of tumor specimen, if available  
F  
If positive, PCR for hepatitis B viremia must also be performed (Section 5 5 1)  
J  
Required until disease is PET negative  
K  
Results collected at screening and/or EOT visit and at any time on study, if performed as part of standard of care 
(Section 7 2)  
L  
Not required at Cycle 1  
M  
If baseline activities occur within 1 day prior to Cycle 1 Day 1, assessment does not need to be repeated  
N  
Prior to next cycle dosing, or prior to EOT visit if discontinuing study treatment  
O  
Within 5 days after UPC assessment  
P  
Window Day 14 to 21  
Q  
Not required if an exam was performed within 4 weeks prior to the EOT visit, and following the last dose of study 
treatment 
R  
In the event of ocular toxicity, continue at least monthly in follow-up until resolution or return to baseline  
S  
Ophthalmology exam and ocular health survey approximately 30-days post ASCT  
T  
±2 days from the ophthalmology exam  


 
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G  
For 19A+RICE Arm: Steroid eye drop prophylaxis should begin 1 day prior to denintuzumab mafodotin dose  See 
Section 5 4 1 and Table 1 for additional prophylactic interventions including artificial tears, vasoconstrictor eye drops, 
and cooling eye mask to be given at the time of infusion  
H  
A combined CT/PET may be obtained to satisfy the requirements for CT and PET scanning, as long as the CT is of 
diagnostic quality (i e , contrast-enhanced with IV and oral contrast, unless contrast is medically contraindicated)  
Images should be submitted for central review  
I  
Unless PD is documented within the previous 6 weeks by diagnostic CT scan  
U  
In each treatment arm, additional transplant-related data will be collected following ASCT until time of engraftment 
and will include, but not be limited to, the time to neutrophil and platelet engraftment   
V  
Cycle 1 only  Blood samples for PK and biomarker testing (Table 3)  
W  
Cycle 1 and Cycle 2 only  Only for patients not continuing on treatment or not starting the next cycle on Day 22  Blood 
sample for PK testing (Table 3)  
X  
saaIPI for patients aged ≤60 years, and standard IPI for patients aged >60 years (Appendix D)  
Y  
For both treatment arms, RICE administration to occur on Days 1–3 (±1 day)  
Z  
Weight not required  
AA  Fasting blood glucose at baseline  
 


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


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


 
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APPENDIX D: SECOND-LINE AGE-ADJUSTED INTERNATIONAL PROGNOSTIC 
INDEX (IPI) SCORE AND STANDARD IPI SCORE FOR NHL 
saaIPI Score for Patients Aged ≤60 Years 
 
Score 
Risk Factor 
0 point 
1 point 
Serum LDH 
≤1 x ULN 
>1 x ULN 
ECOG Performance Status 
0 or 1 
2, 3, or 4 
Stage 
I or II 
III or IV 
LDH = lactate dehydrogenase 
ECOG = Eastern Cooperative Oncology Group 
ULN = upper limit of normal 
 
Risk Category 
Low 
0 
Low-intermediate 
1 
High-intermediate 
2 
High 
3 
Based on (Hamlin 2003; Moskowitz 1999; Shipp 1993). 
 
Standard IPI Score for Patients Aged >60 Years 
 
Score 
Risk Factor 
0 point 
1 point 
Age 
≤60 years 
>60 years 
Serum LDH 
≤1 x ULN 
>1 x ULN 
ECOG Performance Status 
0 or 1 
2, 3, or 4 
Stage 
I or II 
III or IV 
Extranodal involvement 
≤1 site 
>1 site 
LDH = lactate dehydrogenase 
ECOG = Eastern Cooperative Oncology Group 
ULN = upper limit of normal 
 
Risk Category 
Low 
0, 1 
Low-intermediate 
2 
High-intermediate 
3 
High 
4, 5 
 


 
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APPENDIX E: MODIFIED* CTCAE V4.03 GRADING SCHEME FOR OCULAR 
TOXICITY 
Adverse Event 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Ocular Symptoms 
Symptomatic 
(with or without 
clinical findings) 
Symptomatic 
Possible change in 
vision 
Symptomatic 
Change in vision 
-- 
Does not affect 
ADL 
Affects instrumental 
ADL (i.e., preparing 
meals, shopping for 
groceries or clothes, 
using the telephone 
or computer, 
managing money, 
driving, etc.) 
Affects self-care 
ADL (i.e., bathing, 
dressing and 
undressing, feeding 
self, using the toilet, 
taking medications, 
and not bedridden) 
Corneal Findings 
(as determined by 
ocular 
examination) 
Corneal findings, 
but no change in 
visual acuity from 
baseline 
Corneal findings 
with change in 
visual acuity from 
baseline; see table 
below for visual 
acuity criteria 
Corneal findings 
with change in 
visual acuity from 
baseline; see table 
below for visual 
acuity criteria 
Corneal findings 
with change in 
visual acuity from 
baseline; see table 
below for visual 
acuity criteria 
ADL=activities of daily living 
*  Modified portion of CTCAE refers to when patient does not have 20/20 vision at baseline 
 
Visual acuity for grading 
Baseline Vision 
(cc or sc) 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
20/20 
No change 
20/25 – 20/40 or better 
20/50 – better than 
20/200 
20/200 or worse 
20/25 
No change 
20/30 – 20/50 
20/60 – better than 
20/200 
20/200 or worse 
20/30 
No change 
20/40 – 20/60 
20/70 – better than 
20/200 
20/200 or worse 
20/40 
No change 
20/50 – 20/70 
20/80 – better than 
20/200 
20/200 or worse 
20/50 
No change 
20/60 – 20/80 
20/100 – 20/200 
Worse than 20/400 
20/60 
No change 
20/70 – 20/100 
20/125 – 20/400 
Worse than 20/400 
20/70 
No change 
20/80 – 20/125 
20/200 – 20/400 
Worse than 20/400 
20/80 
No change 
20/100 – 20/200 
20/400 
Worse than 20/400 
20/100 
No change 
20/125 – 20/400 
Worse than 20/400 
-- 
 
 


 
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APPENDIX F: 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 3a with or without a residual mass on 5PSb 
It is recognized that in Waldeyer’s ring or extranodal sites with high 
physiologic uptake or with activation within spleen or marrow (e.g., 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 5b with reduced uptake compared with baseline and residual 
mass(es) of any size 
At interim, these findings suggest responding disease 
At end of treatment, these findings indicate residual disease 
≥50% decrease in SPD of up to 6 target  measurable nodes and 
extranodal sites 
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 


 
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Response and Site 
PET-CT–Based Response 
CT-Based Response 
Complete Response 
Complete metabolic response 
Complete radiologic response (all of the following) 
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 (e.g., 
a 15-cm spleen must increase to >16 cm). If no prior 
splenomegaly, must increase by at least 2 cm from baseline 
New or recurrent splenomegaly 
Nonmeasured lesion 
None 
New or clear progression of preexisting nonmeasured lesions 
New lesions 
New FDG-avid foci consistent with lymphoma rather than another 
etiology (e.g., 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  
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 
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 (e.g., 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 (e.g., 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 (e.g., with marrow activation as a result of chemotherapy or myeloid growth factors). 
b 
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 (Barrington 2014). 
From: (Cheson 2014) 
 


 
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APPENDIX G: INVESTIGATOR SIGNATURE PAGE 
 
Investigator Statement and Signature 
 
I have read the attached protocol entitled, “A randomized, open-label phase 2 study of 
denintuzumab mafodotin (SGN-CD19A) plus rituximab, ifosfamide, carboplatin, and etoposide 
(19A+RICE) chemotherapy vs. RICE in the treatment of patients with relapsed or refractory 
diffuse large B-cell lymphoma (DLBCL) who are candidates for autologous stem cell 
transplant”. 
I understand and agree to the provisions of the protocol, and I accept the responsibilities listed 
above in my role as principal investigator for the study. 
 
 
 
Investigator Signature 
 
Date 
 
 
 
 
 
 
 
 
 
Investigator Name, Printed 
 
 
 


 
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APPENDIX H: DOCUMENT HISTORY 
Version 
Date 
Original 
16-Jun-2015 
Amendment 1 
23-Sep-2016 
Amendment 2 
28-Oct-2017 
 
 


 
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Summary of Changes in Amendment 2  
Section(s) 
Change 
Rationale 
Section 1.1 
Added recently published results on patients with DLBCL who experience 
primary treatment failure. 
To provide additional background on a subset of 
DLBCL patients who experience primary 
treatment failure. 
Section 3.1, 9.1, and 
9.3.10 
Added that if a subset of patients appears to potentially derive benefit from 
19A+RICE versus RICE at a pre-planned evaluation, the Sponsor may continue 
enrolling those patients beyond the planned sample size (approximately 100 
patients), but will not exceed the planned maximum number of patients to be 
randomized in this study (up to approximately 150 patients). 
To allow continued enrollment of patients who 
have been observed to potentially benefit from 
19A+RICE versus RICE at a pre-planned 
evaluation. 
Section 4.1 
Removed the requirement for patients to have CD20-positivity for eligibility 
(Eligibility criterion 1). 
To enroll patients who have experienced early 
relapse regardless of CD20 status. 
Section 4.1 
Added the following eligibility criterion: 
4a. Relapsed less than or equal to 6 months from the completion of frontline 
therapy at the time of initial dosing in this clinical trial (applicable only to 
patients enrolled under Amendment 2). 
To enroll patients who have experienced early 
relapse. 
Section 5.5.1 
Examples for tumor lysis prophylaxis, including treatment with allopurinol or 
rasburicase, as well as adequate hydration (Cairo 2010) were added. 
Clarification. 
Section 6.2 and 7.1 
Added a blood sample for biomarker assessments  
To allow analysis of biomarkers at screening. 
Section 7.1 
Clarified that a blood sample for hepatitis serology will be taken at screening 
To align with other previously written sections of 
the protocol. 
Section 7.4 and 7.4.2 
Clarified that soluble CD19 may be assess rather than will be assessed. 
Clarification. 
 


 
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Summary of Changes in Amendment 1 
Section(s) 
Change 
Rationale 
2.4.2, 9.2.2.1, 9.2.2.3, 
9.2.2.7  
Secondary endpoints of duration of response (OR and CR) and PFS will be 
assessed using investigator-assessed response. Response by IRF may also be 
used to evaluate these endpoints. 
For time-to-event endpoints, investigator-assessed 
response is more clinically relevant for the 
purposes of this Phase 2 study and will be used as 
the primary method of analysis for these secondary 
endpoints. 
3.1, 3.2.2, 5.3.3, 
Synopsis 
Specified units for carboplatin dosage to be area under the curve 5 mg/mL x 
min; maximum dose, 800 mg. 
Clarification 
3.1, 6.2, 6.6, 6.7, 7.2, 
Appendix A 
CT scans will be of diagnostic quality (i.e., contrast-enhanced with IV and oral 
contrast, unless contrast is medically contraindicated). 
Clarification 
3.1, 6.2, 6.6, 6.7, 7.2, 
Appendix A 
At any time on study, if a bone marrow biopsy is performed as part of standard 
of care, the results from the biopsy report for the presence of lymphoma will be 
recorded in the CRF. 
Clarification. Bone marrow biopsy is not a 
required procedure for this study. However, if a 
bone marrow biopsy is performed as part of 
standard of care outside of the study, the result 
will be recorded in the CRF. 
3.2.1, 6.2, 7.1, 
9.3.1.1, 9.3.1.8, 
Appendix A, 
Appendix D, 
Synopsis 
Added standard IPI for patients aged >60 years; saaIPI will be used for patients 
aged ≤60 years. 
Measure the IPI as appropriate to the patient’s age. 
3.2.2 
Corrected as indicated: 
Cys-mcMMAF is metabolically stable in human microsomal preparations and, 
at concentrations up to 1 μM (roughly 100500-fold higher than circulating 
levels after a 3 mg/kg dose of denintuzumab mafodotin), was not a direct, time- 
or metabolism-dependent inhibitor or inducer of CYP 3A or 2B6 in vitro 
(denintuzumab mafodotin IB). 
Correction 
4.1, Synopsis 
Inclusion criterion #1: Added that eligible patients must have histologically 
confirmed CD20-positive disease. 
Clarification 


 
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Section(s) 
Change 
Rationale 
4.2, 6.2, 7.7.3, 
Synopsis 
Hepatitis B positivity is demonstrated by testing positive for either hepatitis B 
surface antigen or anti-hepatitis B core antibody. 
Correction. 
Note that this correction appears as no change in 
this amendment. Prior to this Protocol Amendment 
1, Administrative Letter 2 (12-Oct-2015) stated 
that hepatitis B testing should be performed by 
testing for hepatitis B surface antigen only. 
This Protocol Amendment 1 (23-Sep-2016) reverts 
back to the original protocol language where 
positivity by either surface antigen or core 
antibody testing demonstrates hepatitis B 
positivity. 
5.3.3 
Rituximab administration should be initiated approximately 30 to 60 minutes 
after the completion of denintuzumab mafodotin study drug infusion. 
Administrative correction to align with Section 
5.2.2 
5.4 
Premedication for the rituximab infusion may be given during the 30 to 
60 minute period between the completion of the denintuzumab mafodotin 
infusion and the start of the rituximab infusion 
Clarification 
5.4.1, 5.8.1, Table 1, 
Table 2 
For patients in the 19A+RICE Arm, prophylactic preservative-free artificial 
tears should be administered beginning on Cycle 1 Day 1 until EOT. 
Artificial tears should be used prophylactically 
with denintuzumab mafodotin, and may be used 
more frequently in the event of ocular symptoms, 
as needed. 
5.4.1, Table 1, 6.4.1, 
6.4.7, Appendix A 
For patients in the 19A+RICE Arm, the use of cooling eye masks and 
vasoconstrictor eye drops is recommended as described. 
Evaluate the use of cold eye masks and 
vasoconstrictor eye drops during and after 
denintuzumab mafodotin infusion to vasoconstrict 
the vessels of the eye, and potentially reduce 
exposure of the eye tissue to denintuzumab 
mafodotin. 
5.5.1 
Require concomitant antiviral prophylaxis for patients with negative PCR assay 
who also tested positive for hepatitis B surface antigen. 
Patients in this situation should be administered 
standard of care therapy as per the institutional 
standard. 
5.5.1 
Require concomitant prophylaxis for patients assessed to be at risk for tumor 
lysis. 
Patients in this situation should be administered 
standard of care therapy as per the institutional 
standard. 


 
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Section(s) 
Change 
Rationale 
5.5.2 
Allow prophylactic intrathecal chemotherapy as a concomitant therapy if the 
investigator deems it necessary. 
In order to decrease the risk of relapse within the 
CNS, intrathecal methotrexate or Ara-C is given to 
patients with an increased risk of CNS 
involvement. Although known CNS involvement 
is an exclusion criterion for trial participation, 
patients with testicular, bone marrow, and 
paraspinous disease are at increased risk for 
relapse in the CNS (a sanctuary site). At the 
investigator’s discretion, CNS prophylaxis may be 
added (to RICE) as part of standard treatment. 
6.3, 6.4.1 
For patients randomized to the 19A+RICE Arm, steroid eye drop prophylaxis is 
recommended to begin 1 day prior to denintuzumab mafodotin dose. However, 
for the first cycle of treatment, if beginning eye drop prophylaxis 1 day prior is 
not possible, starting on Day 1 is acceptable for the first cycle of treatment. 
Clarification 
6.4.6, 6.4.11, Table 3, 
Appendix A 
For Cycles 1 and 2, added Day 22 PK testing for patients who are not 
continuing treatment or not starting the next cycle on Day 22. 
To measure comparable Day 22 trough PK for 
denintuzumab mafodotin and/or rituximab (as 
applicable) if a patient does not continue treatment 
or start the next cycle of treatment on Day 22. 
6.5 
Allow the use of chemotherapy for the mobilization of stem cells. 
Clarification to distinguish the use of 
chemotherapy for the mobilization of stem cells 
(an allowed concomitant medication) from its post 
study-treatment use to treat residual disease (a 
prohibited concomitant medication).  
6.7 
Added clinical assessments of disease status by history and physical 
examinations at long-term follow-up visits 
To document investigator assessment of clinical 
progression during the long-term follow-up period. 
7.1 
If representative tissue from the most recent tumor biopsy after the last therapy 
is unavailable, a fresh biopsy must be obtained. 
Clarification 
7.7.3, Appendix A 
Patients should be fasting for baseline blood glucose testing. 
To determine whether a patient has a baseline 
predisposition to hyperglycemia. 
7.7.3 
Specified that a spot urine urinalysis must be performed.  
Clarification. The spot urine must be performed in 
order to provide the urine protein and creatinine 
values needed to collect the UPC ratios required. 


 
Study SGN19A-003  
 Clinical Protocol  
 Amendment 2; 28-Oct-2017 
Denintuzumab mafodotin  
 Seattle Genetics, Inc. - Confidential  
 Page 82 of 83 
Section(s) 
Change 
Rationale 
7.7.3 
The 24-hour urine collected will be used to test for total protein value. 
Clarification 
9.1, Synopsis 
The following correction: 
Up to approximately 150 patients may be treatedrandomized in this study. 
Correction 
9.2.1 
CR rate using investigator-assessed response will also be evaluated. 
Clarification 
9.2.2.6 
Objective response rate using investigator-assessed response will also be 
evaluated. 
Clarification 
9.3 
The SAP will be finalized prior to database lock. 
Clarification 
9.3.1.1 
Disease status is determined from the time of initial diagnosis (i.e., initiation of 
frontline therapy). 
Also, clarified the stratification group assignment for patients that were CR to 
frontline therapy and relapsed exactly 12 months after initial diagnosis. 
Clarifications  
9.3.1.5 
Deleted the following paragraph: 
Two interim administrative evaluations of the overall safety and activity may be 
performed when approximately 40 and 75 patients have completed EOT. The 
hypothesis test that compares the CR rate of the 2 arms will not be performed. 
The study will not be discontinued unless there is a safety concern. No alpha 
adjustment is planned. 
Administrative correction. This deleted paragraph 
is duplicated in Section 9.3.10 (Interim Analyses). 
9.3.1.7, 9.3.5 
Adjusted the mITT analysis set as follows: 
The mITT analysis set will include all patients who are randomized to the 
recommended dose level of 19A+RICE or RICE, and receive at least 1 cycle of 
study treatment. 
Treated patients represent the most clinically 
meaningful primary analysis set to investigate the 
treatment activity 
9.3.1.7 
Adjusted the PP analysis set as follows: 
The pre-protocol analysis set includes patients who receive at least 1 cycle of 
RICE (all components) or recommended dose any amount of 19A+RICE (with 
all components of RICE) combination therapy and who had both a baseline and 
at least one post-baseline evaluable disease assessment (per the Lugano 
classification criteria or determination of clinical disease progression per the 
investigator), and no other major protocol deviations that could potentially 
affect rumor response. 
Completing the 1st cycle of treatment is regarded 
as the minimal exposure to the treatment regimen, 
and most closely reflects the scientific model 
underlying the protocol. 


 
Study SGN19A-003  
 Clinical Protocol  
 Amendment 2; 28-Oct-2017 
Denintuzumab mafodotin  
 Seattle Genetics, Inc. - Confidential  
 Page 83 of 83 
Section(s) 
Change 
Rationale 
9.3.5.1, 9.3.5.2 
90% confidence intervals will be calculated rather than 95% confidence 
intervals. 
Correction. The study is powered at a 0.1 alpha 
level. 
9.3.10 
The 2 interim administrative evaluations will evaluate overall safety, but not 
activity. However, a summary of activity may be used for risk/benefit 
assessment. 
Clarification 
Appendix A 
Footnote A. Definition of platelet recovery corrected to ≥75,000/µL. 
Correction 
Appendix F 
Corrections and clarifications were made to response criteria, the Lugano 
classification criteria. 
Administrative corrections to align the Lugano 
classification criteria to match the reference article 
(Cheson 2014) 
Throughout protocol 
Administrative changes and corrections. 
To improve clarity and to achieve consistency 
throughout protocol. 
 

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Study SGN19A-003 
Statistical Analysis Plan Version 1  
21-Oct-2016 
Denintuzumab mafodotin 
Seattle Genetics, Inc. - Confidential 
Page 2 of 36 
 
APPROVAL SIGNATURES 
Product: 
Denintuzumab mafodotin (SGN-CD19A) 
Protocol Number/Amendment: 
SGN19A-003 
SAP Version: 
1 
Version Date: 
21-Oct-2016 
 
The individuals signing below have reviewed and approve this statistical analysis plan. 
 
(as signed in the original) 
 
 
 
Biostatistician 
 
Date 
 
 
 
(as signed in the original) 
 
 
 
Head of Biostatistics 
 
Date 
 
 
 
(as signed in the original) 
 
 
 
Medical Monitor 
 
Date 
 
 
 
 


Study SGN19A-003 
Statistical Analysis Plan Version 1  
21-Oct-2016 
Denintuzumab mafodotin 
Seattle Genetics, Inc. - Confidential 
Page 3 of 36 
 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ................................................................................................................................ 5 
1 
INTRODUCTION ........................................................................................................................................... 6 
2 
STUDY OBJECTIVES ................................................................................................................................... 6 
2.1 
Primary Objectives ................................................................................................................................ 6 
2.2 
Secondary Objectives ............................................................................................................................ 6 
2.3 
Additional Objectives ............................................................................................................................ 6 
3 
STUDY ENDPOINTS .................................................................................................................................... 7 
3.1 
Primary Endpoint .................................................................................................................................. 7 
3.2 
Secondary Endpoints ............................................................................................................................. 7 
3.3 
Additional Endpoints ............................................................................................................................. 7 
4 
STUDY DESIGN ............................................................................................................................................ 7 
5 
ANALYSIS SETS ........................................................................................................................................... 8 
5.1 
Intent-to-Treat (ITT) Analysis Set ......................................................................................................... 8 
5.2 
Modified Intent-to-Treat (mITT) Analysis Set ...................................................................................... 8 
5.3 
Safety Analysis Set ................................................................................................................................ 8 
5.4 
Per Protocol Analysis Set ...................................................................................................................... 8 
6 
STATISTICAL CONSIDERATIONS ............................................................................................................ 9 
6.1 
General Principles ................................................................................................................................. 9 
6.2 
Determination of Sample Size ............................................................................................................... 9 
6.3 
Randomization and Blinding ............................................................................................................... 10 
6.4 
Data Transformations and Derivations ................................................................................................ 10 
6.5 
Handling of Dropouts and Missing Data ............................................................................................. 11 
6.6 
Pooling Strategy for Strata .................................................................................................................. 11 
6.7 
Multicenter Studies ............................................................................................................................. 12 
6.8 
Multiple Comparison/Multiplicity ....................................................................................................... 12 
6.9 
Examination of Subgroups .................................................................................................................. 12 
6.10  Covariates ............................................................................................................................................ 12 
6.11  Timing of Analyses ............................................................................................................................. 12 
7 
PLANNED ANALYSES .............................................................................................................................. 13 
7.1 
Disposition .......................................................................................................................................... 13 
7.2 
Demographic and Baseline Characteristics ......................................................................................... 14 
7.3 
Protocol Deviations ............................................................................................................................. 14 
7.4 
Treatment Administration ................................................................................................................... 14 
7.5 
Efficacy Analyses ................................................................................................................................ 16 
7.5.1 
Primary Endpoint ................................................................................................................... 16 
7.5.2 
Secondary Endpoints .............................................................................................................. 17 
7.5.3 
Pharmacokinetics and Immunogenicity Endpoints ................................................................. 22 
7.6 
Safety Analyses ................................................................................................................................... 22 
7.6.1 
Adverse Events ....................................................................................................................... 23 
7.6.2 
Clinical Laboratory Parameters .............................................................................................. 24 
7.6.3 
ECOG Performance Status ..................................................................................................... 25 
7.6.4 
Vital Signs .............................................................................................................................. 25 
7.6.5 
Concomitant Medications ....................................................................................................... 25 
7.6.6 
Additional Safety Analyses .................................................................................................... 25 
7.6.7 
Deaths ..................................................................................................................................... 25 
8 
INTERIM ANALYSIS.................................................................................................................................. 26 
9 
CHANGES FROM PLANNED ANALYSES .............................................................................................. 26 
9.1 
Changes from the Original Protocol .................................................................................................... 26 
9.2 
Changes from the Original SAP .......................................................................................................... 26 
10  REFERENCES .............................................................................................................................................. 27 


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APPENDIX A 
IMPUTATION OF PARTIALLY UNKNOWN ADVERSE EVENT DATES ..................... 28 
APPENDIX B 
DEFINITION OF THE TERM “TREATMENT-EMERGENT” WITH RESPECT TO AE 
CLASSIFICATION ...................................................................................................................................... 31 
APPENDIX C: 
CALCULATION OF VFQ-25 COMPOSITE AND SUBSCALE SCORES ......................... 33 
 
LIST OF IN-TEXT TABLES 
Table 1: PFS Event Rules for Primary PFS Analysis (Investigator Assessment) ................................................. 18 
Table 2: PFS Event Rules for Secondary PFS Analysis (IRF Assessment) ......................................................... 19 
 


Study SGN19A-003 
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Seattle Genetics, Inc. - Confidential 
Page 5 of 36 
 
LIST OF ABBREVIATIONS 
19A 
SGN-CD19A (denintuzumab mafodotin) 
ADC 
antibody-drug conjugate 
ADI 
absolute dose intensity 
AE 
adverse event 
ASCT 
autologous stem cell transplant 
ATA 
antitherapeutic antibodies 
BAP 
bioinformatics analysis plan 
CMH 
Cochran-Mantel-Haenszel 
CR 
complete remission 
cys-mcMMAF 
cysteine maleimidocaproyl monomethyl auristatin F 
DDT 
dose-delaying toxicity 
DLBCL 
diffuse large B-cell lymphoma 
EOS 
end of study 
EOT 
end of treatment 
GEP 
Gene expression profiling 
IDI 
intended dose intensity 
IPI 
international prognostic index 
IRF 
independent review facility 
ITT 
Intent to treat 
MedDRA 
medical dictionary for regulatory activities 
mITT 
modified intent to treat 
MRD 
minimal residual disease 
ORR 
objective response rate 
PBSC 
peripheral blood stem cells 
PD 
pharmacodynamic 
PK 
pharmacokinetics 
PR 
partial remission 
RICE 
rituximab, ifosfamide, carboplatin, and etoposide chemotherapy 
RDI 
relative dose intensity 
saaIPI 
second-line age-adjusted internal diagnostic index 
SAE 
serious adverse event 
SMC 
safety monitoring committee 
SSQ 
sponsor-specified query 
TEAE 
treatment-emergent adverse event 
 


Study SGN19A-003 
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Seattle Genetics, Inc. - Confidential 
Page 6 of 36 
 
1 
INTRODUCTION 
This document outlines the statistical methods to be implemented within the scope of 
Protocol SGN19A-003, entitled “A randomized, open-label phase 2 study of denintuzumab 
mafodotin (SGN-CD19A) plus rituximab, ifosfamide, carboplatin, and etoposide 
(19A+RICE) chemotherapy vs. RICE in the treatment of patients with relapsed or refractory 
diffuse large B-cell lymphoma (DLBCL) who are candidates for autologous stem cell 
transplant”.  Results of the proposed analyses will become the basis of the clinical study 
report for this protocol. 
The purpose of this plan is to provide specific guidelines from which the analysis will 
proceed.  All planned analyses specified in this document will be performed.  Any changes to 
this plan, in the form of “post hoc” or “data driven” analyses will be identified as such in the 
final clinical study report.  Any changes will either be reflected in amendments to this plan 
before the database lock or specifically documented in the clinical study report. 
2 
STUDY OBJECTIVES 
2.1 Primary Objectives 
● 
To compare the complete remission (CR) rates in patients with relapsed/refractory 
DLBCL who are candidates for autologous stem cell transplant (ASCT) treated with 
denintuzumab mafodotin plus RICE (19A+RICE) versus RICE 
2.2 Secondary Objectives 
● 
To evaluate the safety of denintuzumab mafodotin given in combination with RICE  
● 
To compare progression-free survival (PFS) between study arms 
● 
To compare overall survival (OS) between study arms 
● 
To compare the proportion of patients who are able to adequately mobilize peripheral 
blood stem cells (PBSC) between study arms 
● 
To compare the proportion of patients receiving ASCT following study treatment 
between study arms 
● 
To compare other measures of antitumor activity between study arms 
2.3 Additional Objectives 
● 
To evaluate the pharmacokinetics (PK) of denintuzumab mafodotin (antibody-drug 
conjugate [ADC] and cys-mcMMAF) when denintuzumab mafodotin is given in 
combination with RICE chemotherapy 
● 
To evaluate the incidence of antitherapeutic antibodies (ATA) against denintuzumab 
mafodotin 
● 
To assess denintuzumab mafodotin-mediated pharmacodynamic (PD) effects and 
potential biomarkers to stratify response 


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3 
STUDY ENDPOINTS 
3.1 Primary Endpoint 
● 
Complete remission (CR) rate as determined by an independent review facility (IRF) 
following the completion of study treatment 
3.2 Secondary Endpoints 
● 
Type, incidence, severity, seriousness, and relatedness of adverse events (AEs) and 
laboratory abnormalities 
● 
Objective response rate (ORR) per IRF following the completion of study treatment 
● 
Duration of response (objective response [OR] and CR) 
● 
Progression-free survival (PFS) 
● 
Overall survival (OS) 
● 
Proportion of patients achieving PBSC mobilization 
● 
Proportion of patients receiving ASCT 
3.3 Additional Endpoints 
● 
Estimates of selected PK parameters of denintuzumab mafodotin and released 
cys-mcMMAF 
● 
Incidence of antitherapeutic antibodies (ATA) 
● 
Exploratory biomarkers of denintuzumab mafodotin-mediated PD effects 
4 
STUDY DESIGN 
This is a randomized, open-label phase 2 study designed to compare the CR rates in patients 
with relapsed or refractory DLBCL who are candidates for ASCT. Approximately 100 
patients will be randomized in a 1:1 ratio to 1 of 2 study arms: 
● 
Control, RICE Arm:  3 cycles (3 weeks per cycle) of rituximab 375 mg/m2 
administered as the first component of RICE on Day 1 of every cycle; and followed 
by etoposide (100 mg/m2 per day), ifosfamide (5,000 mg/m2) infused continuously 
with mesna, and carboplatin (area under the curve 5 mg/mL x min; maximum dose, 
800 mg) administered during each cycle in an order as per institutional standard of 
care 
● 
Investigational, 19A+RICE Arm:  3 cycles (3 weeks per cycle) of denintuzumab 
mafodotin 3 mg/kg on Day 1 of every cycle in conjunction with 3 cycles (3 weeks per 
cycle) of RICE; denintuzumab mafodotin is administered prior to the rituximab 
component of RICE therapy given on Day 1 of each cycle 


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A safety monitoring committee (SMC) comprising the study investigators, medical monitor, 
and study biostatistician will periodically monitor the safety of patients at predefined interim 
safety evaluations and during the treatment period. Upon its evaluation of the data, the SMC 
may recommend modification of the dose of denintuzumab mafodotin in the 19A+RICE Arm 
(e.g., to 2 mg/kg) in subsequently enrolled patients.  If dose modification is necessary, up to 
50 additional patients may be randomized (25 in each arm) so that a total of 100 patients will 
be randomized in a 1:1 ratio to receive either 19A (modified dose) + RICE or RICE alone. 
5 
ANALYSIS SETS 
This section defines each of the analysis sets that will be utilized.  The use of each analysis 
set will be discussed in Section 7. 
5.1 Intent-to-Treat (ITT) Analysis Set 
The ITT analysis set will include all randomized patients.  Patients will be included in the 
treatment arm assigned at randomization regardless of the actual treatment received. 
5.2 Modified Intent-to-Treat (mITT) Analysis Set  
The mITT analysis set will include all patients who are randomized to the recommended dose 
level of 19A+RICE or RICE, and receive at least 1 cycle of study treatment.  If the dose of 
denintuzumab mafodotin is modified from 3 mg/kg (e.g., to 2 mg/kg), the mITT analysis set 
includes all patients randomized after the dose modification decision is made.  Patients will 
be included in the treatment arm assigned at randomization regardless of the actual treatment 
received.   
5.3 Safety Analysis Set  
The safety analysis set will include all patients who receive any amount of denintuzumab 
mafodotin or any component of RICE.  Treatment group will be determined using the actual 
treatment arm received, regardless of the randomization treatment assignment.  
5.4 Per Protocol Analysis Set 
The per-protocol (PP) analysis set includes patients who receive at least 1 cycle of RICE (all 
components) or recommended dose of 19A+RICE (with all components of RICE) 
combination therapy and who had both a baseline and at least one post-baseline evaluable 
disease assessment (per the Lugano classification criteria or determination of clinical disease 
progression per the investigator), and no other major protocol deviations that could 
potentially affect tumor response.  The major protocol deviations include: 
● 
Patients who were randomized but at least one of the eligibility criteria was not met, 
regardless of whether an exception is granted. 
● 
Patients who received protocol prohibited medications during the treatment period of 
the study. 
● 
Patient who received treatment to which they were not randomized  


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The per-protocol analysis set is a subset of the mITT analysis, and patients will be grouped in 
the same manner as mITT analysis set.  
6 
STATISTICAL CONSIDERATIONS 
6.1 General Principles 
Descriptive statistics (mean, median, standard deviation, minimum and maximum) will be 
used to summarize continuous variables.  Frequencies and percentages will be used to 
summarize categorical variables.  The median survival time will be estimated using the 
Kaplan-Meier method; the associated confidence interval (CI) will be calculated based on the 
complementary log-log transformation (Collett 1994). All summaries will be presented by 
treatment arm and total unless otherwise specified. If the dose of denintuzumab mafodotin is 
decreased from 3mg/kg to 2 mg/kg, summaries for each level of denintuzumab mafodotin 
and subtotal will be presented. 
Unless otherwise specified, all statistical tests will be performed using a two-sided alpha of 
0.1.  Confidence intervals will be calculated at a two-sided 90% level.  Multiplicity 
adjustment for alpha level is discussed in Section 6.8. 
Any analysis not described in this plan will be considered exploratory, and will be 
documented in the clinical study report (CSR) as a post hoc analysis or a change to the 
planned analysis. 
To comply with regulatory electronic submission guidelines, listings of all clinical data will 
be submitted as electronic data sets.  To facilitate data review for the study report, only 
pertinent data listings will be created and attached to the appendix of the CSR.   
All statistical output will be produced using SAS®, version 9.3 or more recent.  Other 
statistical software, if used, will be described in the CSR. 
6.2 Determination of Sample Size 
A total of approximately 100 patients (approximately 50 patients per treatment arm) will be 
enrolled and randomized to a treatment arm in this study. 
With approximately 100 patients randomized  in a 1:1 ratio to each treatment arm (~50 
patients per arm), the study is designed to have approximately 80% power to detect an 
increase in the CR rate of 25%.  It is assumed that the CR rates for the 19A+RICE Arm and 
the RICE Arm are 60% and 35%, respectively.  This calculation is based on a two-sided 2 
test with significance level of α= 0.1 using EAST (version 5.4). 
If the dose of denintuzumab mafodotin in the investigational 19A+RICE arm is modified, up 
to 50 additional patients may be randomized (25 in each arm) so that a total of 100 patients 
will be randomized in a 1:1 ratio to either the 19A (modified dose) + RICE arm or the RICE 
only arm.  Up to approximately 150 patients may be randomized in this study. 


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6.3 Randomization and Blinding 
This is a randomized, open-label study that may enroll up to approximately 150 patients in a 
1:1 manner.  Randomization will be stratified by: 
● 
Disease status 
○ 
CR to frontline systemic therapy and relapsed more than 12 months after initial 
diagnosis (i.e., initiation of frontline therapy) 
○ 
PR or SD to frontline systemic therapy, or CR to frontline and relapsed less than 
or equal to 12 months after initial diagnosis (i.e., initiation of frontline therapy) 
● 
Second-line age-adjusted IPI score (saaIPI) for patients ≤60 years of age or standard 
IPI score for patients >60 years of age, as assessed at randomization 
○ 
Low-risk disease: saaIPI of 0 or 1, or standard IPI of 0, 1, or 2 
○ 
High-risk disease: saaIPI of 2 or 3, or standard IPI of 3, 4, or 5 
● 
Disease type 
○ 
De novo DLBCL and Grade 3b follicular lymphoma  
○ 
Transformed DLBCL 
Stratified randomization with a fixed block size will be performed centrally using a system 
that will assign a patient to one of the two treatment arms.  
6.4 Data Transformations and Derivations 
Reported age in years will be used; if not available, age in years will be calculated with the 
SAS INTCK function (with method specified as “continuous”) using date of randomization 
and birth date. 
Study Day will be calculated as Date–First Dose Date+1 for dates on or after the first dose 
date unless otherwise specified.  For dates prior to the first dose date, Study Day will be 
calculated as Date–First Dose Date.  For all calculations of Study Day, the First Dose Date 
will be the earliest date of treatment administration for denintuzumab mafodotin or RICE. 
Other time variables based on two dates, e.g., Start Date and End Date, will be calculated as 
(End Date–Start Date+1) (in days) unless otherwise specified in the planned analysis section. 
The following unit conversion will be implemented unless otherwise specified: 
Months=Days/30.4375 
Years=Days/365.25 
Unless otherwise specified, baseline values used in all analyses will be the most recent non-
missing measurement prior to the first dose of study treatment. 
The end-of-treatment (EOT) date will be the date the EOT visit is performed; if an EOT visit 
is not performed then the EOT date will be either the EOS date or 30 days after the last dose 
of any study treatment, whichever is earlier. 


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For efficacy assessments by investigator, the date of response assessment (CR, PR or SD) 
will be the latest of all radiologic scan dates for the given restage assessment.  The date of 
progression will be the earliest of all radiologic scan dates for the given restage assessment, 
or the date of investigator claim of clinical progression.  Patients who have a response of 
Stable Disease or better per Lugano criteria at the same visit as investigator claim of clinical 
progression will be counted as clinical progression.  At EOT, an adequate tumor assessment 
must include a radiologic scan that is evaluable for response per Lugano classification 
criteria.  However, an investigator claim of clinical progression is adequate for an assessment 
of disease progression.  During long-term follow-up, for those patients who achieved a 
response, a physical exam is adequate for determining a patient has not progressed by 
investigator assessment. 
For efficacy assessments by IRF, the date of progression and response will be specified in the 
IRF charter. 
6.5 Handling of Dropouts and Missing Data 
With the exception of the scenarios covered in this section, missing data will not be imputed. 
AE dates will be imputed for the purpose of calculating duration of events and treatment-
emergent status (see Appendix A for imputation details and Appendix B for treatment-
emergent definition).  Censoring will be described in Section 7 with each planned analysis, as 
applicable. 
Unless otherwise specified, lab values which are recorded or provided as being less than x.x 
will be included in figures and summaries as x.x/2.  For the purpose of grading, lab values 
reported as less than x.x will be imputed as x.x. 
6.6 Pooling Strategy for Strata 
The randomization of this study is stratified by 3 factors with a total of 8 strata. In situations 
where a stratum cannot be included in a stratified analysis of an endpoint, it may be 
necessary to pool strata prior to the analysis. For example, strata will be pooled if no patients 
are randomized under a stratum. Should pooling be necessary, it will be performed in the 
following order: 
1. Do not include the stratification factor of Disease Type, i.e. De novo DLBCL and Grade 
3b follicular lymphoma (G3bFL) will be pooled with Transformed DLBCL for each 
combination of other two stratification factors 
2. Only include the stratification factor based on the saaIPI or standard IPI score: Low-risk 
disease (saaIPI of 0 or 1, or standard IPI of 0, 1, or 2) vs.  High-risk disease (saaIPI of 2 
or 3, or standard IPI of 3, 4, or 5)  
3. If further pooling is necessary, no stratified analysis will be performed.  


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6.7 Multicenter Studies 
There are multiple centers in this study, however it is not anticipated that any center will 
accrue enough patients to warrant an analysis by center. 
6.8 Multiple Comparison/Multiplicity 
A fixed sequence testing procedure (Westfall 2001), where testing is carried out sequentially 
at an unadjusted alpha level as long as all preceding null hypotheses are rejected, will be used 
to ensure type I error control for key secondary endpoints.  The testing order will be: 1) CR 
rate per IRF; 2) PFS per investigator assessment; and 3) duration of CR per investigator 
assessment.  If the test for CR rate is not statistically significant, the p-value of the tests for 
the subsequent endpoints will still be calculated, but will be considered descriptive. 
6.9 Examination of Subgroups 
As exploratory analyses, subgroup analyses may be conducted for selected endpoints.  
Subgroups may include but are not limited to the following: 
● 
Disease status ([CR to frontline systemic therapy and relapsed >12 months after 
initial diagnosis] versus [PR or SD to frontline systemic therapy, or CR to frontline 
and relapsed ≤12 months after initial diagnosis]) 
● 
Disease risk as determined by standard IPI or saaIPI 
● 
Disease type (De novo DLBCL/G3bFL versus Transformed DLBCL) 
● 
Cell of origin by gene expression profiling (GEP)  
● 
Double- and triple- hit lymphoma 
● 
Double expresser lymphoma  
● 
CD19 expression 
● 
CD20 expression 
● 
Minimum Residual Disease (MRD) status 
● 
Age  (18- 64 vs. ≥ 65years; and/or < 60 vs >60 years) 
● 
Gender 
● 
Baseline ECOG 
● 
Disease stage 
● 
Patients with and without post-baseline consolidative ASCT 
6.10 Covariates 
Stratified analyses specified in Section 7 will include adjustment for the stratification factors 
as recorded at randomization.  Selected baseline values may be used as covariates in the 
exploratory analysis of efficacy endpoints. 
6.11 Timing of Analyses 
The SMC will periodically monitor the trial for safety during the treatment period.  Three 
formal safety interim evaluations are planned:  


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 when approximately 12 patients (6 patients in 19A+RICE ARM) have been 
randomized and evaluated for DDTs delaying the Cycle 2 dose 
 when the first 12 patients in the 19A+RICE Arm have been randomized and 
evaluated for DDTs delaying the Cycle 2 dose 
 when the first 12 patients in the 19A+RICE Arm have completed cycle 3 or EOT 
In addition, two interim administrative evaluations of the overall safety will be performed 
when approximately 40 and 75 patients have completed EOT. The hypothesis test that 
compares the CR rate of the 2 arms will not be performed.  The study will not be 
discontinued unless there is a safety concern.  A summary of activity may be used for 
risk/benefit assessment.     
When conditions for these analyses are met, a cut-off date for the database will be 
determined and the analysis can take place. Data collected before this cut-off date will be 
analyzed.  Every effort will be attempted to make the database as current and accurate as 
possible to the cut-off date. 
The analysis of the primary endpoint of CR per IRF will occur after all patients have 
completed EOT response assessment.  Comparison of the CR rates between the 2 treatment 
arms will be conducted.  The database cutoff date for this analysis will be determined once 
all study patients have completed EOT. 
The analysis of PFS and OS endpoints will occur approximately 2 years after the last 
patient’s enrollment.  If 70% of patients have experienced a PFS and/or OS event prior to 2 
years after the last patient’s enrollment, the analysis of PFS and/or OS may be performed 
earlier than scheduled.  Subsequent cutoff dates may be defined and corresponding database 
locks may occur to allow for more precise estimates of the time-to-event endpoints prior to 
study closure. 
7 
PLANNED ANALYSES 
7.1 Disposition 
An accounting of study patients by disposition will be tabulated using the ITT and mITT 
analysis sets. The table will include the number and percentage of patients who were 
randomized, received study treatment, received treatment per randomization assignment, and 
participated in follow-up visits.  The number and percentage of patients who discontinued 
treatment and study will be summarized. Number of patients who signed informed consent, 
the number of screen failures, and number of patients in each analysis set will be summarized 
for all randomized patients.  Screen failures will also be described, if applicable. 
The number and percentage of patients enrolled in each country and at each site will be 
summarized for all enrolled patients. Follow up time will be summarized. 
Disposition data will be listed by patient using the ITT analysis set. 


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7.2 Demographic and Baseline Characteristics 
Demographics and baseline characteristics, including age, gender, ethnicity, race, baseline 
height, weight, body mass index, and ECOG score will be listed and summarized using the 
ITT and mITT analysis set.  Disease specific characteristics, including time from diagnosis 
and previous cancer-related treatments will be listed and summarized using the ITT and 
mITT analysis sets. Stratification factors at randomization will be summarized for ITT and 
mITT analysis set. Concordance of stratification factors used for randomization and recorded 
on baseline disease diagnosis CRF page will be presented. 
7.3 Protocol Deviations 
Important protocol deviations (defined as protocol violations by Seattle Genetics) are those 
that represent a divergence from the protocol that could have a significant effect on the 
integrity of the study data, or on the subject’s rights, safety, or welfare.  Important protocol 
deviations also include exemptions to the study inclusion/exclusion criteria and will be 
summarized by category.  A list of patients with important protocol deviations will be 
presented. 
7.4 Treatment Administration 
Treatment administration will be summarized for each treatment component (denintuzumab 
mafodotin and each component of RICE) using the safety analysis set.  Summary statistics 
for duration of therapy (in weeks) and the number of cycles per patient will be presented, as 
well as the number and percentage of patients who were treated at each cycle and completed 
each cycle.  Cumulative dose, absolute dose intensity (ADI) and relative dose intensity (RDI) 
will be described.  The number and percentage of patients whose dose was ever modified will 
be summarized by modification type, cycle and overall (i.e., over all drug administrations for 
a patient) for each treatment component. Listings may be presented as well.  Dose 
modifications by dose may also be presented. 
Duration of treatment (except when calculating exposure) is defined as the time from first 
dose date to the earliest of either: 
1. last dose date + length of one dosing cycle, or 
2. date of death 
Intended Dose Intensity (IDI) is defined as the intended dose of drug (e.g., 3 mg/kg) per unit 
of time. The IDI for denintuzumab mafodotin and each component of RICE is presented in 
the following table. 
Regimen Component 
Intended Dose Regimen 
Unit of 
time 
(weeks) 
IDI 
denintuzumab mafodotin 
3 mg/kg 
3 
1 
rituximab 
375 mg/m2 
3 
125.00 
ifosfamide 
5,000 mg/m2 
3 
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carboplatin 
AUC 5 mg/mL x min 
3 
1.67 
etoposide 
300 mg/m2 
3 
100.00 
 
Absolute Dose Intensity (ADI) is defined as the actual dose (e.g., mg/kg, mg/m2 or AUC) per 
unit of time that the patient received over the entire treatment period. The treatment period 
will be the time from first dose date to (last dose date + length of one dosing cycle). 
Relative Dose Intensity (RDI) is defined as the absolute dose intensity over the intended dose 
intensity where RDI = ADI/IDI × 100%. 
Example 1 
For denintuzumab mafodotin, consider a patient with an intended dose of 3 mg/kg, and is 
treated for three cycles (i.e., 9 weeks).  For the last treatment the infusion was not completed 
and the patient received less than the full dose, as represented in the following table: 
Visit 
Intended Dose Regimen 
(mg/kg) 
Weight 
(kg) 
Intended Dose 
(mg) 
Actual Dose 
(mg) 
Duration 
(week) 
C1D1 
3 
50 
150 
150 
3 
C2D1 
3 
52 
156 
156 
3 
C3D1 
3 
49 
147 
70 
3 
 
IDI 
= (3mg/kg) / (3 weeks) = 1 mg/kg/week 
ADI 
= (150mg/50kg + 156mg/52kg + 70mg/49kg) / (9 weeks) 
= (3mg/kg + 3mg/kg + 1.43mg/kg) / (9 weeks) 
=0.82 mg/kg/week 
RDI 
= ADI/IDI × 100% = 0.826 /1 × 100%  
 
= 82.6% 
Example 2 
For denintuzumab mafodotin, consider a patient with an intended dose of 3 mg/kg, and is 
treated for two cycles. Patient had one week delay before cycle 2, and died one week after 
the second dose. 
Visit 
Intended Dose Regimen 
(mg/kg) 
Weight 
(kg) 
Intended Dose 
(mg) 
Actual Dose 
(mg) 
Duration 
(week) 
C1D1 
3 
50 
150 
150 
3+1 
C2D1 
3 
40 
120 
120 
3* 
*Although patient died one week after cycle 2 dosing, the duration is still 3 weeks for the purpose of calculating dose intensity. 
 
IDI 
= (3mg/kg) / (3 weeks) = 1 mg/kg/week 
ADI 
= (150mg/50kg + 120mg/40kg) / (4 + 3 weeks) 


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= (3mg/kg + 3mg/kg) / (7 weeks) 
=0.857 mg/kg/week 
RDI 
= ADI/IDI × 100% = 0.857 /1 × 100 % 
 
= 85.7% 
7.5 Efficacy Analyses 
The primary analysis CR rate will be based on the mITT analysis set. Secondary efficacy 
endpoint of response rate will also be summarized using the mITT analysis set. Secondary 
efficacy analysis of time to event endpoints will be summarized using the mITT analysis set. 
Additional analyses of efficacy endpoints using the ITT, safety, and per-protocol analysis 
sets will also be presented as appropriate. Analyses may also be performed using the 
subgroups listed in Section 6.8. For efficacy analyses, study day will be counted from date of 
randomization, i.e. Study Day = Date – Randomization Date + 1. 
7.5.1 Primary Endpoint 
7.5.1.1 Complete Remission (CR) Rate  
The primary analysis for CR rate will be performed for mITT Analysis Set based on IRF 
assessment. CR rate is defined as the proportion of patients achieving CR (CMR by PET or 
CR by PET) at the EOT assessment using the Lugano classification criteria (Cheson 2014).  
The hypotheses will be tested at a two-sided 0.1 alpha level using a Cochran-Mantel-
Haenszel (CMH) test stratified by the randomization strata (see Section 6.3).  In situations 
where a stratum cannot be included in a stratified analysis of an endpoint, it may be 
necessary to pool strata prior to the analysis (Section 6.6).  
The null and alternative hypotheses can be written respectively as:  
H0:  The two treatments have equal CR rates with respect to the common odds ratio (OR=1). 
HA: The two treatments have different CR rates with respect to the common odds ratio 
(OR≠1). 
 
The CR rate and exact two-sided 90% CI using the Clopper-Pearson method (Clopper 1934) 
will be presented by stratification factor and overall.  
The Mantel-Haenszel estimate of the common CR rate difference adjusted for the 
randomization strata and 90% stratified Newcombe confidence interval (Yan and Su 2010) 
may be presented. 
Secondary Analyses 
The secondary analyses will be performed the same way as the CR rate per IRF. The 
secondary analysis of CR rate will be performed for CR rate per investigator based on the 
mITT Analysis Set.   


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Sensitivity Analyses 
Sensitivity analyses of CR rate will be performed if appropriate.  Sensitivity analyses may 
include, but will not be limited to, the following 
1. Analyses for CR rate at EOT for ITT, Safety and PP analysis sets  
2. CMH test stratified by stratification factors recorded on baseline disease diagnosis 
CRF page for CR rate   
3. An unstratified test for CR rate 
 
The concordance in response assessment between IRF and investigator assessment will be 
summarized. The Kappa statistic may be calculated to evaluate the agreement between IRF 
and investigator assessment. 
The determination of antitumor activity will be based on response assessments made 
according to the Lugano Classification criteria (Cheson 2014).  Staging will be performed by 
PET/CT of diagnostic quality, with disease involvement determined by focal FDG uptake in 
nodal and extranodal (including spleen, liver, bone marrow, and thyroid) sites that is 
consistent with lymphoma, according to the pattern of uptake and/or CT characteristics.  
Lugano 5 Point Score by IRF and by investigator assessment will be summarized by response 
as appropriate.  The concordance of the Lugano 5 Point Score between the IRF and the 
investigator assessment will be summarized as appropriate. 
SPD for target lesions is defined as the sum of the products of diameters of the target lesions. 
The SPD change from baseline will be derived for each patient. The maximum SPD percent 
reduction (or minimum percent increase if there is no reduction) for each patient will be 
graphically displayed (e.g., using a waterfall plot).  
The Minimal Residual Disease (MRD) status will be explored. The CR achieved after EOT 
assessment may also be explored. 
7.5.2 Secondary Endpoints 
7.5.2.1 Progression Free Survival (PFS) 
Progression-free survival (PFS) is defined as the time from randomization to the first 
documentation of disease progression, death due to any cause, or receipt of subsequent 
anticancer therapy, whichever occurs first. Receipt of post treatment consolidative 
radiotherapy, or post treatment chemotherapy for the purpose of mobilizing PBSCs, or ASCT 
will not be considered to have started new anticancer therapy. Specifically, 
PFS=Date of first documented progression, receipt of subsequent anticancer therapy 
or death–Date of randomization+1. 
For patients who have not experienced a PFS event, the censoring date is defined as the last 
date on which progression status was adequately assessed.  The primary PFS analysis will be 


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performed for mITT set based on the investigator assessment. The primary PFS will be 
censored based on FDA guidance and is described in Table 1.   
Table 1: PFS Event Rules for Primary PFS Analysis (Investigator Assessment) 
Situation 
Date of Progression or Censoring  
Outcome  
No baseline and/or post-baseline assessment 
Date of randomization  
Censored 
Documented progression  
Date of documented progressiona 
Event  
New anticancer therapy initiated prior to documented 
progression with the exception of post treatment 
consolidative radiotherapy, or post treatment 
chemotherapy for the purpose of mobilizing PBSCs, or 
ASCT  
Start date of new anticancer therapy 
Event 
Investigator claim of clinical progression without 
documented progression 
Date of investigator claimed clinical 
progression 
Event  
Death before first documented progression and new 
anticancer therapy 
Date of death  
Event  
No progression, new anticancer therapy or death  
Date of last adequate assessmenta,b 
Censored  
a 
as defined in Section 6.4 
b 
Date of randomization in the absence of post-baseline response assessment 
Additional details of censoring rules are as follows: 
● 
Patients who do not have tumor progression or a new anticancer therapy and are still 
on study at the time of an analysis will be censored at the date of the last disease 
assessment documenting absence of progressive disease (including physical exam 
during long-term follow-up) 
● 
Patients who have started post treatment consolidative radiotherapy, palliative 
radiotherapy, post treatment regimen for the purpose of mobilizing PBSCs, or SCT 
other than the study treatment prior to tumor progression or new anticancer therapy 
will be censored at the date of the last disease assessment documenting absence of 
progressive disease (including physical exam during long-term follow-up) 
● 
Patients who are removed from study prior to documentation of tumor progression or 
initiation of new anticancer therapy will be censored at the date of the last disease 
assessment documenting absence of progressive disease (including physical exam 
during long-term follow-up) 
Specifically, censored PFS will be calculated as: 
Censored PFS=max (1, last disease assessment date–date of randomization+1), 
Where the last disease assessment date is the date of the last disease assessment obtained 
during study, or before the initiation of subsequent anticancer therapy (if applicable).  
The statistical hypothesis for PFS can be expressed in terms of the hazard ratio  
λ19A+RICE /λRICE where λ19A+RICE represents the hazard of progression on the 19A+RICE arm 
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that the risk of disease progression or death is reduced for patients on the 19A+RICE arm 
compared with patients on the RICE arm. 
The null and alternative hypotheses can be written respectively as: 
H0: λ19A+RICE / λRICE = 1 
HA: λ19A+RICE / λRICE ≠ 1 
Kaplan-Meier methods will be used to estimate the PFS.  The hypothesis test will be 
performed only if the null hypothesis for the primary endpoint of CR by IRF is rejected. The 
stratified log-rank test without adjustments for covariates will be used to assess the difference 
in PFS between 19A+RICE and RICE. The test will be performed using a two-sided, α=0.1 
level test in the mITT analysis set.  All events entered in the database at the time of analysis 
that have been source data verified will be included in the analysis of PFS. If the test for CR 
rate per IRF is not statistically significant, the p-value of the tests for PFS will still be 
calculated, but will be considered descriptive. 
Kaplan-Meier Curves depicting PFS in the two arms will be generated.  Additionally, median 
PFS and probability of PFS will be reported at 6 month intervals.  The two-sided 90% 
confidence intervals (CI) for the median will be calculated using the complementary log-log 
transformation method (Collett 1994). 
The primary analysis of PFS will be performed based on investigator assessment. PFS may 
be performed for each of the subgroups specified in Section 6.8. 
Cox regression of PFS will be used to estimate the hazard ratio of 19A+RICE to RICE.  The 
baseline covariates specified in Section 6.9 may be included in the model.  The treatment 
group variable will always be included in the model.  Interaction effects may be considered 
whenever possible. 
Secondary Analysis for PFS 
The censoring rule for PFS based on IRF assessment is presented in Table 2 as follows: 
Table 2: PFS Event Rules for Secondary PFS Analysis (IRF Assessment) 
Situation 
Date of Progression or Censoring  Outcome  
No baseline and/or post-baseline assessment 
Date of randomization  
Censored 
Documented progression documented between scheduled 
visits  
Date of documented progressiona 
Event  
New anticancer therapy initiated prior to documented 
progression or without documented progression or death, 
with the exception of post treatment consolidative 
radiotherapy, or post treatment chemotherapy for the 
purpose of mobilizing PBSCs, or ASCT  
Start date of new anticancer 
therapy 
Event 
Death before first documented progression and new 
anticancer therapy 
Date of death  
Event  
No progression, new anticancer therapy or death 
Date of last adequate assessmenta,b 
Censored  
a 
Determined by IRF based on IRF charter 


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b 
Date of randomization in the absence of post-baseline response assessment 
In this analysis, investigator claim of clinical progression that is not confirmed by IRF 
assessment at the same visit will not be regarded as having a progression event.   
Sensitivity Analyses 
Sensitivity analyses of PFS will be performed.  Sensitivity analyses may include, but will not 
be limited to, the following 
1. For patients with new anticancer therapy initiated prior to documented progression, PFS 
will be censored at the date of last adequate assessment prior to the new therapy.    
2. An unstratified log-rank test will be used to compare the PFS by investigator between the 
treatment groups.  PFS will be censored according to Table 1. Additionally, an 
unstratified Cox regression model will be used to estimate the hazard ratio and the 
corresponding 90% CI for the treatment effect.   
3. Stratified log-rank test by stratification factors recorded on the baseline disease diagnosis 
CRF will be used to compare the PFS by investigator between the treatment groups.  PFS 
will be censored according to Table 1.  
4. Allogeneic SCT will not be regarded as an event. 
7.5.2.2 Duration of Complete Remission 
Duration of complete remission (CR) is defined as the time from start of the first 
documentation of CR to the first documentation of disease progression, new anticancer 
therapy or to death due to any cause, whichever comes first.  Note that receipt of post 
treatment consolidative radiotherapy, post treatment chemotherapy for the purpose of 
mobilizing PBSCs, or consolidative autologous SCT will not be considered to have started 
new anticancer therapy. 
The analysis for the duration of CR will be performed for patients in mITT set who achieved 
CR at EOT based on investigator assessment. The censoring of the duration of CR will 
follow the censoring rule for PFS based on the investigator assessment in Table 1. The 
secondary analysis for duration of CR will be based on IRF assessment as specified in Table 
2. If a patient received subsequent allogeneic SCT, a sensitivity analysis may be performed 
and allogeneic SCT will not be regarded as an event.  
Kaplan-Meier methodology will be used to analyze duration of CR. The median time and its 
two-sided 90% CI using the log-log transformation method (Collett 1994) will be calculated 
when appropriate. Kaplan-Meier plots for the two treatment groups will be provided.   
A stratified log-rank test without adjustment for covariates will be used in the evaluation of 
differences between the treatment arms in the mITT analysis set when appropriate. If the p-
values for the analyses of CR and PFS are not statistically significant, the p-value for 
duration of CR will be descriptive.   


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7.5.2.3 Overall Survival 
Overall survival (OS) is defined as the time from randomization to death due to any cause.  
Specifically, 
 
OS = Date of death – Date of randomization + 1. 
In the absence of confirmation of death, OS will be censored at the last date the patient is 
known to be alive. If the last recorded date where a patient is known to be alive is the date of 
randomization, survival time will be censored on the date of randomization (i.e., OS duration 
of 1 day). 
OS will be analyzed using Kaplan-Meier methodology. The median survival time and its 
two-sided 90% CI using the log-log transformation method (Collett 1994) will be calculated 
and presented when appropriate. Kaplan-Meier plots for the two treatment groups will be 
provided.  Additionally, probability of OS will be reported at various time intervals (e.g. 
every 6 months).  The associated two-sided 90% CIs will be calculated. 
7.5.2.4 Objective Response Rate (ORR) 
ORR is defined as the proportion of patients with CR or PR at the EOT visit according to the 
Lugano classification criteria (Cheson 2014). Patients whose disease response cannot be 
assessed per Lugano classification criteria will be scored as Not Evaluable for calculating the 
ORR.  
ORR by IRF and by investigator assessment will be summarized and the corresponding exact 
two-sided 90% confidence interval using the Clopper-Pearson method (Clopper 1934) will be 
presented. 
7.5.2.5 Duration of Objective Response 
Duration of objective response (DOR) is defined as the time from start of the first 
documentation of OR to the first documentation of PD, new anticancer therapy or to death 
due to any cause, whichever comes first.  Note that receipt of post treatment consolidative 
radiotherapy, post treatment chemotherapy for the purpose of mobilizing PBSCs, or ASCT 
will not be considered to have started new anticancer therapy. 
DOR will be analyzed in the same methodology as duration of CR as described in Section 
7.5.2.2. 
7.5.2.6 The Proportion of Patients Achieving Peripheral Blood Stem Cell 
(PBSC) Mobilization 
The proportion of patients achieved PBSC mobilization will be summarized by treatment arm 
and total using the mITT Analysis Set. The total number of CD34-positive cells mobilized 
will be summarized. The corresponding exact two-sided 90% confidence interval using the 
Clopper-Pearson method (Clopper 1934) will be presented. PBSC mobilization collection 
will be listed for each patient by visit. 


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7.5.2.7 The Proportion of Patients Receiving Autologous Stem Cell Transplant 
(ASCT) 
The proportion of patients intent to receive and received ASCT will be summarized by 
treatment arm and total using the mITT Analysis set. The reason for not receiving subsequent 
stem cell transplant after EOT will be summarized for patients who intended to receive 
ASCT.  
7.5.3 Pharmacokinetics and Immunogenicity Endpoints 
7.5.3.1 Pharmacokinetics 
The individual plasma concentrations of denintuzumab mafodotin and rituximab will be 
summarized with descriptive statistics (including geometric mean and coefficient of 
variation) at each PK sampling timepoint using the Safety Analysis Set. The PK parameters 
may include, but are not limited to, maximum plasma concentration (Cmax), area under the 
plasma concentration-time curve (AUC), and plasma concentrations at trough (Ctrough). PK 
data from this study will be analyzed by non-compartmental analysis (NCA) methods.  If 
performed, exploratory PK/pharmacodynamic (PD), PK/safety, or PK/efficacy analyses will 
be described in a separate analysis plan and the results reported separately from the CSR.  
Geometric mean ratio estimates and 90% CIs of pharmacokinetic parameters against Cycle 1 
will be computed from a log-transformed model for Cycles 2 and beyond.  These data may 
also be combined with data from other studies for population PK (POPPK) and exposure-
response analyses through a separate analysis plan and through separate reporting. 
7.5.3.2 Antitherapeutic Antibody (ATA) Incidence Rate 
The ATA incidence rate is defined as the proportion of patients that develop ATA at any time 
during the study. ATA incidence will be summarized by visit and overall using the Safety 
Analysis Set.  
7.5.3.3 Pharmacodynamic (PD) and Mechanism of Action Biomarkers 
The analyses for pharmacodynamic biomarkers and for biomarkers related to drug 
mechanism(s) of action will be defined in a separate Biomarker Analysis Plan and may be 
included in a separate report.  
7.6 Safety Analyses 
The Safety analysis set will be used to summarize all safety endpoints. 
Adverse events will be coded using Medical Dictionary for Regulatory Activities (MedDRA, 
Version 18.0 or higher). 
Laboratory values will be graded according to the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE version 4.03 or higher). 
Concomitant medications will be coded using WHO Drug (version: June 2015 or more 
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7.6.1 Adverse Events 
Adverse events will be summarized by MedDRA preferred term in descending frequency of 
occurrence unless otherwise specified.  For incidence reporting, if a patient reports more than 
one AE that was coded to the same system organ class or preferred term, the patient will be 
counted only once for that specific system organ class or preferred term. 
A treatment-emergent AE is defined as a newly occurring or worsening AE after the first 
dose of study treatment.  See Appendix B for details regarding treatment-emergent 
classification.  An overall summary of AEs will be provided.  Summaries of AEs will also be 
provided for the following: 
● 
All treatment-emergent AEs 
● 
Serious Adverse Events (SAEs) 
● 
AEs related to study treatment  
● 
SAEs related to study treatment 
● 
AEs leading to dose modification (delay, elimination, reduction, and unplanned 
adjustments)  
● 
AEs regarded as infusion reactions  
● 
AEs regarded as hypersensitivity reactions  
● 
AEs regarded as protocol-defined “dose delay toxicity” (by cycle and overall) 
● 
AEs leading to treatment discontinuation 
● 
Grade 3 - 5 treatment-emergent AEs 
● 
Treatment-emergent AEs by system organ class, preferred term and maximum 
severity.  At each system organ class or preferred term, multiple occurrences of 
events within a patient are counted only once at the highest severity 
● 
Treatment-emergent AEs by system organ class and preferred term 
All adverse events, serious adverse events, adverse events leading to treatment 
discontinuation, and adverse events leading to death will be listed. 
7.6.1.1 Adverse Events of Special Importance 
Adverse events of ocular AEs will be considered AEs of special importance. 
7.6.1.1.1 Ocular AEs 
Incidence, onset and improvement/resolution of ocular AEs of interest will be summarized 
based on the safety analysis set. The ocular AEs of interest will be defined by Standardised 
MedDRA Queries (SMQs) or Sponsor Specified Queries (SSQs) as appropriate. The 


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definition of the SSQs will be maintained in a separate document and will be finalized prior 
to database lock. 
Patient incidence of treatment-emergent ocular AEs of interest will be presented by system 
organ class, preferred term and maximum severity. Ocular AEs leading to treatment 
discontinuation will be summarized. 
Time to onset and duration to improvement or resolution will be summarized at the patient 
level for ocular AEs.  
Date of onset is defined as the date of earliest occurrence of events of interest. Time to onset 
for will be summarized by descriptive statistics. 
Improvement and resolution of ocular AEs will be derived per patient level. The date of 
resolution is defined as the earliest time that the patient does not have any ongoing ocular 
events (i.e. all events with outcome of resolved/recovered or resolved/recovered with 
sequelae, or all events with severity decreasing to baseline condition or better).   
Improvement of ocular AEs is defined based on the worst grade for each patient. If a patient 
has worst grade 3 or 4 events, date of improvement or resolution is defined as the earliest 
date that the patient does not have any ongoing grade 3 or 4 events (i.e. the worst grade the 
patient is experiencing is 2 or below). If a patient has worst grade 2 ocular events of interest, 
the date of improvement or resolution is defined as the earliest date that the patient does not 
have any ongoing grade 2 events(i.e. the worst grade the patient is experiencing is 1 or 
below).  
Time to improvement and resolution from first onset and from last treatment of 19A will be 
summarized for the patients who experienced ocular AEs of interest. Duration of ocular AEs 
may be summarized by Kaplan-Meier methodology. If a patient does not experience an 
improvement or resolution, the patient will be censored at last contact date for ocular 
symptoms, and censored at the date of last ophthalmology exam for corneal findings. 
The relationship between ocular AEs and ocular interventions may be explored. 
7.6.2 Clinical Laboratory Parameters 
Blood 
Clinical laboratory data (CBC with differential, serum chemistry) may be presented 
graphically for selected lab tests by scheduled visit.  Summary statistics may be tabulated 
where appropriate.  The worst post baseline NCI CTCAE v4.03 grade will be presented for 
each lab test. 
Laboratory results and NCI CTCAE grades for hematology, and serum chemistry will be 
presented in data listings.  All laboratory data will be presented in conventional units. 


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Urine 
UPC ratio will be presented graphically by scheduled visit.  All other urine parameters will 
be listed. 
7.6.3 ECOG Performance Status 
Shifts from baseline to the best and worst post-baseline score will be tabulated. 
7.6.4 Vital Signs 
Vital sign measurements (systolic and diastolic blood pressure, heart rate, and body 
temperature) will be listed by patient for each time point and presented graphically for each 
vital sign by scheduled visit. 
7.6.5 Concomitant Medications 
Concomitant medications with WHO Drug substance name will be listed by patient. 
Transfusion, G-CSF administration, systemic steroids, and ocular interventions will be 
summarized and listed as appropriate.  
7.6.6 Additional Safety Analyses 
7.6.6.1 Ocular Examination Results 
Ocular examination results will be presented in data listings.   The improvement/resolution of 
corneal AEs may also be explored through visual acuity exam results. 
7.6.6.2 Patient-Reported Health Outcome (VFQ-25) 
VFQ-25 composite score and select sub-scale scores may be summarized with descriptive 
statistics. The derivation of the composite score and sub-scale scores are specified in 
Appendix C. Scores and the change from baseline may be listed or tabulated. The 
relationship between ocular AEs and VFQ-25 scores may be explored.  
7.6.6.3 Electrocardiogram (ECG) 
ECG status (normal, abnormal clinically significant, or abnormal not clinically significant) at 
EOT and shift from baseline will be summarized. 
7.6.6.4 Transplant-Related Information Following ASCT 
The incidence of post-transplant viral reactivation and infections will be listed and 
summarized for patients who received ASCT. The duration from stem cell infusion to 
neutrophil and platelet engraftment will also be listed and summarized.  
7.6.7 Deaths 
The number of total deaths, deaths that occur within 30 days of last study treatment, and 
deaths that occur more than 30 days after last study treatment as well as the relationship to 
disease will be summarized.  In addition, cause of death will be summarized by descending 


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MedDRA preferred term (unless otherwise specified).  Death information will be listed by 
patient. 
8 
INTERIM ANALYSIS 
A Safety Monitoring Committee (SMC) comprising the study investigators, medical monitor, 
and study biostatistician will monitor the trial for safety and dose delay toxicities (DDTs).  
For the planned safety reviews, enrollment will only be paused during the first safety review, 
unless required by the SMC.  The SMC will review data for both treatment arms to include, 
but not be limited to, the following: 
● 
Incidence of DDT 
● 
Adverse events 
● 
Clinical laboratory tests 
● 
Response assessments, if available 
● 
PBSC mobilization, if available 
The SMC will review data for both treatment arms, and may make a recommendation  
● 
Continue the trial as planned 
● 
Modify the dose of denintuzumab mafodotin (e.g., to 2 mg/kg) in patients 
subsequently enrolled to the 19A+RICE Arm 
● 
Temporarily halt enrollment 
Two interim administrative evaluations of the overall safety and activity may be performed 
when approximately 40 and 75 patients have completed EOT.  The hypothesis test that 
compares the CR rate of the 2 arms will not be performed.  The activity data will be used for 
risk/benefit discussion. The study will not be discontinued unless there is a safety concern. 
9 
CHANGES FROM PLANNED ANALYSES 
9.1 Changes from the Original Protocol 
Not Applicable. 
9.2 Changes from the Original SAP 
Not Applicable. 


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10 REFERENCES 
Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, Lister TA, Alliance AL, Lymphoma 
G, Eastern Cooperative Oncology G, European Mantle Cell Lymphoma C, Italian Lymphoma F, European 
Organisation for R, Treatment of Cancer/Dutch Hemato-Oncology G, Grupo Espanol de Medula O, German 
High-Grade Lymphoma Study G, German Hodgkin's Study G, Japanese Lymphorra Study G, Lymphoma Study 
A, Group NCT, Nordic Lymphoma Study G, Southwest Oncology G and United Kingdom National Cancer 
Research I (2014). Recommendations for initial evaluation, staging, and response assessment of Hodgkin and 
non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol 32: 3059-68. 
Clopper CJ and Pearson ES (1934).  The use of confidence or fiducial limits illustrated in the case of the 
binomial.  Biometrika 26: 404-413. 
Collett D (1991). Statistical inference for binary data. Modelling Binary Data. London, Chapman and Hall: 23-
26. 
Collett D (1994). Interval-censored survival data. Modelling survival data in medical research. Boca Raton, 
Fla., Chapman & Hall/CRC: 237-251. 
Mangione CM, Lee PP, Gutierrez PR, et al.  Development of the 25-item National Eye Institute Visual Function 
Questionnaire (VFQ-25). Archives of Ophthalmology, 119, 1050-1058.2001 
US Food and Drug Administration. (2007). FDA guidance for industry: clinical trial endpoints for the approval 
of cancer drugs and biologics. 
Westfall PH and Krishen A (2001). Optimally weighted, fixed sequence and gatekeeper multiple testing 
procedures. Journal of Statistical Planning and Inference 99: 25-40. 
Yan, X. and Su, X. G. (2010), “Stratified Wilson and Newcombe Confidence Intervals for Multiple Binomial 
Proportions,” Statistics in Biopharmaceutical Research, 2, 329–335 


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


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○ 
AE start date will be imputed as the minimum of (AE condition end date*, last 
day of the month) 
● 
If the month/year is after the month/year of first dose of investigational agent: 
○ 
AE start date will be imputed as the minimum of (AE condition end date*, last day 
of the month) 
* Only use condition end date if known and complete end date is available. 
 
The following algorithm should be used to impute AE condition end dates.  The AE records 
for a condition/event should be sorted by the imputed start dates then record position (order 
of entry into the eCRF).  After sorting, if any condition end date month/year is greater than 
any subsequent record end date month/year, then change the imputed start day only to end of 
month.  Repeat as necessary.  
After sorting the AE records, apply the following rules to partial or missing AE condition end 
dates: 
For all records excluding the last chronological record for a condition/event 
● 
AE condition end date will be imputed as the start date of the subsequent record 
For the last chronological record for a condition/event 
● 
If outcome is “recovered/resolved”, ”recovered/resolved with sequelae”, or “fatal” 
apply the following:  
○ 
If only year is provided for the end date and year is equal to the year of the last 
dose date: 
■ 
AE condition end date will be imputed as the minimum of (last dose date+30, 
death date, data extraction date, December 31st of the end date year) 
○ 
If only year is provided for the end date and year is not equal to the year of the 
last dose date: 
■ 
AE condition end date will be imputed as the minimum of (death date, data 
extraction date, December 31st of the end date year) 
○ 
If month and year are provided for the end date: 
■ 
AE condition end date will be imputed as the minimum of (death date, data 
extraction date, last day of the end date month/year) 
● 
If outcome is “recovering/resolving”, “not recovered/resolved”,“unknown”, or blank: 
○ 
AE condition end date will not be imputed. 


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


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Appendix B 
Definition of the Term “Treatment-Emergent” with Respect to 
AE Classification 
The algorithm below should be used to determine whether an adverse event (AE) is classified 
as a treatment-emergent adverse event (TEAE).  A TEAE is defined as any AE which is 
newly occurring or worsening in severity, where newly occurring means that the AE was not 
present at baseline.  For ease of reading, both pre-existing conditions and AEs will be 
referred to as AEs for the remainder of this document.  AE dates should be imputed in 
accordance with the algorithm detailed in Appendix A prior to determination of TEAE 
classification.  Details of the TEAE classification are as follows: 
1. Determine the first/earliest dose date of any study treatment (for combination studies this 
includes any component of the regimen) 
2. Baseline AEs: classify an AE as a baseline AE if it satisfies both of criteria a and b 
below: 
a The onset period field is: “started before the signing of informed consent”; or “started 
after consent but before the first dose of any study treatment”; or, the onset period 
field is missing and the AE start date is prior to the first dose date of any study drug 
(step 1, above). 
b The stop date satisfies either of i or ii below: 
i. The stop date is the same as or a later date than the first dose date of any study 
treatment 
ii. The stop date is missing with outcome equal to  
● 
recovering/resolving (this outcome may or may not be associated with a date), 
or 
● 
not recovered/not resolved, or  
● 
unknown. 
● 
Note: if the AE has no outcome or stop date provided, the CRF data should be 
queried 
c Note: If the event ended on Day 1 (the date of first dose of any study drug) it will be 
considered a baseline event. 
3. Post-baseline AEs: classify an AE as post-baseline if it meets either of criteria a or b 
below: 
a The onset period of the AE is “started after the first dose of any study treatment” 
b The onset period of the AE is missing and the AE start date is the same as or a later 
date than the first dose date of any study treatment 
4. Compare post-baseline AEs to baseline AEs using the lower level term (LLT) and 
determine classification.  Note that classification may not be possible and the TEAE 
variable will be missing: 
a Classify all baseline AEs as not treatment emergent (not TEAEs). 


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b If a baseline and post-baseline AE have the same LLT but the post-baseline AE has a 
greater CTC grade then classify the post-baseline AE as a TEAE.  If the post-baseline 
grade is less than or equal to the baseline grade then the post-baseline AE is not a 
TEAE. 
c If there are no baseline AEs with a matching LLT for the post-baseline AE then 
classify the post-baseline AE as a TEAE. 
d If the post-baseline AE is uncoded then classify the post-baseline AE as a TEAE. 
NOTE: 
1. For summaries which include only treatment emergent AEs include all AEs which 
are classified as TEAEs as well as those AEs for which TEAE status could not be 
determined (e.g., the value of the TEAE variable may be missing if the event cannot 
be identified as baseline or post-baseline - missing information on the AE CRF 
should be queried).  Only exclude those AEs which were determined to not be 
treatment emergent. 
2. Events that have an end date prior to the first dose date (e.g. protocol procedure 
related events) should be classified as not treatment emergent (not TEAEs). 
 






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General Vision 
1 
2 
Ocular Pain 
2 
4, 19 
Near Activities 
3 
5, 6, 7 
Distance Activities 
3 
8, 9, 14 
Vision Specific: 
 
 
Social Functioning 
2 
11, 13 
Mental Health 
4 
3, 21, 22, 25 
Role Difficulties 
2 
17, 18 
Dependency 
3 
20, 23, 24 
Driving 
3 
15c, 16, 16a 
Color Vision 
1 
12 
Peripheral Vision 
1 
10 
 
Example of scoring subscale “Near Activities” 
Items 5, 6, and 7 are used to generate the near activities subscale score (Table 3). Each of the 
items has 6 response choices. Response choice 6 indicates that the respondent does not 
perform the activity because of reasons that are unrelated to vision. If a respondent selects 
this choice, the answer is treated as missing and an average of the remaining items is 
calculated. Response choice 5 indicates that an activity is so difficult that the participant no 
longer performs the activity.  This extremely poor near vision response choice is recoded to 
“0” points before taking an average of all three items. To score all items in the same 
direction, Table 2 shows that responses 1 through 5 for items 5, 6, and 7 should be recoded to 
values of 100, 75, 50, 25, and 0 respectively. If the respondent is missing one of the items, 
the person's score will be equal to the average of the two non-missing items. The number 
with parenthesis below is the item’s response. 
Figure 1. Example of VFQ-25 Scoring Algorithm for Near Activities Sub-Scale 
 
5.  How much difficulty do you have reading ordinary print in newspapers?  Would you 
say you have: 
 
No difficulty at all............................................................... 1 
A little difficulty ................................................................. 2 
Moderate difficulty ............................................................. 3 
Extreme difficulty ............................................................. 4 
Stopped doing this because of your eyesight ........................ 5 
Stopped doing this for other reasons or not 
interested in doing this.................................................... 6 
  
 
6.  How much difficulty do you have doing work or hobbies that require you to see well 
up close, such as cooking, sewing, fixing . . . ?  Would you say you have: 
 
No difficulty at all............................................................. 1 
A little difficulty ................................................................. 2 


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Moderate difficulty ............................................................. 3 
Extreme difficulty ............................................................... 4 
Stopped doing this because of your eyesight ........................ 5 
Stopped doing this for other reasons or not 
interested in doing this.................................................... 6 
  
7.  Because of your eyesight, how much difficulty do you have finding something on a 
crowded shelf?  Would you say you have: 
 
No difficulty at all............................................................... 1 
A little difficulty ................................................................. 2 
Moderate difficulty ............................................................. 3 
Extreme difficulty ............................................................. 4 
Stopped doing this because of your eyesight ........................ 5 
Stopped doing this for other reasons or not 
interested in doing this.................................................... 6 
Formula: 
 
Subscale Score =    (Sum of score for each item with a non-missing answer) 
 
                       Total number of items with non-missing answers 
 
Example for Near Activities sub-scale: 
 
With responses converted:  =    (25 + 100 + 25) = 50 
                                                              3 
 
Note:   100 = Best, 0 = Worst possible score.