Conditions: Diffuse, Large B-Cell, Lymphoma Follicular Lymphoma, Grade 3b Transformed Lymphoma / DLBCL
Keywords: Antibodies, Monoclonal SGN-19A Denintuzumab Mafodotin DLBCL Antibody-Drug Conjugate Antigens, CD19 Hematologic Diseases Immune System Diseases Immunoproliferative Disorders Immunotherapy Lymphatic Diseases Lymphoma Lymphoma, B-Cell Lymphoma, Large B-Cell, Diffuse Lymphoma, Non-Hodgkin Monomethyl auristatin F Neoplasms Neoplasms by Histologic Type Transformed Lymphoma / DLBCL Cyclophosphamide Doxorubicin Liposomal doxorubicin Prednisone Rituximab Vincristine Alkylating Agents Anti-Inflammatory Agents Antibiotic, Antineoplastic Antimitotic Agents Antineoplastic Agents, Alkylating Antineoplastic Agents Phytogenic Antirheumatic Agents Glucocorticoids Drug Therapy Follicular Lymphoma Grade 3b immunosuppressive agents
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 24
Healthy volunteers: no

Brief summary:
This is a Phase 2 study to evaluate the combination of denintuzumab mafodotin in combination with RCHOP or RCHP compared with RCHOP alone as front-line therapy in patients with diffuse large B-cell lymphoma or follicular lymphoma Grade 3b.

Detailed description:
In Part A of the study, patients will be randomized 1:1 to receive denintuzumab mafodotin plus RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) or denintuzumab mafodotin plus RCHP (rituximab, cyclophosphamide, doxorubicin, and prednisone) to assess the safety of these 2 combination regimens. Part B of the study is designed to evaluate the antitumor activity and safety of denintuzumab mafodotin in combination with either RCHOP or RCHP (Experimental Arm) compared with RCHOP alone (Comparator Arm).

Arms:
arm 1: Part A: denintuzumab mafodotin (SGN-CD19A) + RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) arm 2: Part A: denintuzumab mafodotin (SGN-CD19A) + RCHP (rituximab, cyclophosphamide, doxorubicin, and prednisone) arm 3: Part B: denintuzumab mafodotin (SGN-CD19A) + RCHOP or RCHP arm 4: Part B: RCHOP alone: (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone)

Interventions: intervention 1: denintuzumab mafodotin intervention 2: rituximab intervention 3: cyclophosphamide intervention 4: doxorubicin intervention 5: vincristine intervention 6: prednisone
Intervention descriptions: intervention 1: SGN-CD19A at 3 mg/kg will be administered every 6 weeks via intravenous (IV) infusion, up to a maximum of three (3) doses, on Day 1 of Cycles 1, 3, and 5 of 21-day cycles intervention 2: 375 mg/m2 every 3 weeks by IV infusion for up to 6 cycles intervention 3: 750 mg/m2 every 3 weeks by IV infusion for up to 6 cycles intervention 4: 50 mg/m2 every 3 weeks by IV infusion for up to 6 cycles intervention 5: 1.4 mg/m2 every 3 weeks by IV infusion for up to 6 cycles (dose capped at 2 mg total) intervention 6: 100 mg on Days 1 to 5 of each 3-week cycle, orally for up to 6 cycles

Protocol document:
Prot_000.pdf: 




Study SGN19A-004
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Investigator
I have read and agree to the protocol SGN19A-004, entitled ‘An open-label phase 2 study of 
denintuzumab mafodotin (SGN-CD19A) in combination with RCHOP (rituximab, 
cyclophosphamide, doxorubicin, vincristine, and prednisone) or RCHP (rituximab, 
cyclophosphamide, doxorubicin, and prednisone) compared with RCHOP alone as frontline
therapy in patients with diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma 
(FL) Grade 3b’. I am aware of my responsibilities as an Investigator under the guidelines of 
GCP, local regulations (as applicable) and the study protocol. I agree to conduct the study 
according to these responsibilities and to appropriately direct and assist the staff under my 
control, who will be involved in the study.
Site Principal Investigator:
Print Name
Title
Signature
Date


Study SGN19A-004
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2.
SYNOPSIS
NAME OF SPONSOR: Seattle Genetics, Inc.
PROTOCOL No.: SGN19A-004
NAME OF STUDY TREATMENT: Denintuzumab mafodotin
TITLE OF STUDY: An open-label phase 2 study of denintuzumab mafodotin (SGN-CD19A) in 
combination with RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) or 
RCHP (rituximab, cyclophosphamide, doxorubicin, and prednisone) compared with RCHOP alone as 
frontline therapy in patients with diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL) 
Grade 3b
PHASE OF DEVELOPMENT: Phase 2
OBJECTIVES: 
Primary Objectives:
•
To compare the complete response (CR) rate at the end of treatment (EOT) in treatment-naive 
patients with high-intermediate or high-risk systemic DLBCL or FL Grade 3b treated with 
denintuzumab mafodotin plus RCHOP or RCHP versus RCHOP alone (Part B)
•
To assess the safety profile of denintuzumab mafodotin administered in combination with RCHOP 
or RCHP in treatment-naive patients with high-intermediate or high-risk systemic DLBCL or FL 
Grade 3b (Part A and Part B)
Secondary Objectives:
•
To compare event-free survival (EFS) between study arms (Part B)
•
To compare progression-free survival (PFS) between study arms (Part B)
•
To compare overall survival (OS) between study arms (Part B)
•
To compare the objective response rate (ORR) at EOT between study arms (Part B)
•
To compare the duration of objective response and of CR between study arms (Part B)
Additional Objectives: 
•
To evaluate the pharmacokinetics (PK) of denintuzumab mafodotin administered in combination 
with RCHOP or RCHP (Parts A and B)
•
To evaluate the incidence of antitherapeutic antibodies (ATAs) against denintuzumab mafodotin
(Parts A and B)
•
To assess denintuzumab mafodotin-mediated pharmacodynamic effects and potential biomarkers 
of response to denintuzumab mafodotin in combination with RCHOP or RCHP (Parts A and B)
STUDY DESIGN AND METHODOLOGY: This open-label study has 2 parts (Part A and Part B).  
Part A of the study is a safety evaluation of denintuzumab mafodotin in combination with either RCHOP or 
RCHP in patients with newly diagnosed, treatment-naive DLBCL or FL Grade 3b.  Up to approximately 
24 patients will be randomized 1:1 to receive denintuzumab mafodotin plus RCHOP or denintuzumab 
mafodotin plus RCHP to assess the safety, including peripheral neuropathy, of these 2 combination 
regimens. Patient randomization will be stratified by high-intermediate or high-risk disease. Study 
treatment is up to six 21-day cycles of either RCHOP or RCHP combined with up to 3 doses of 
denintuzumab mafodotin administered on Day 1 of Cycles 1, 3, and 5.  
The safety of the combinations will be assessed at predefined interim safety evaluations as well as over the 
course of the treatment period by a Safety Monitoring Committee (SMC) comprised of the study 
investigators, medical monitor, biostatistician, and sponsor medical expert.  In Part A, at each interim 
safety evaluation, the SMC will review the cumulative safety data of denintuzumab mafodotin in 
combination with RCHOP or RCHP. At the last formal safety evaluation in Part A, a comprehensive 
evaluation of the safety and antitumor activity data will be performed to determine the regimen (RCHOP or 
RCHP) to be tested in combination with denintuzumab mafodotin in the Experimental Arm in Part B of the 
study.  


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Part B of the study is a phase 2, randomized, open-label, multicenter study designed to evaluate the 
antitumor activity and safety of denintuzumab mafodotin in combination with either RCHOP or RCHP 
(Experimental Arm) compared with RCHOP alone (Comparator Arm).  Approximately 136 patients will be 
randomized 1:1 to either the Experimental or Comparator Arm.  Randomization will be stratified by 
high-intermediate or high-risk disease and cell of origin (COO).  Up to six 21-day cycles of either RCHOP 
or RCHP (as determined using the safety data from Part A) will be administered with up to 3 doses of 
denintuzumab mafodotin administered on Day 1 of Cycles 1, 3, and 5 in the Experimental Arm versus up to 
six 21-day cycles of RCHOP in the Comparator Arm.  The SMC will continue to monitor the safety of the 
combination of denintuzumab mafodotin and either RCHOP or RCHP at predefined interim safety 
evaluations and throughout the study period.     
In Part A and Part B, lymphoma response and progression will be assessed using the Lugano Classification 
Revised Staging System (Cheson, 2014) for malignant lymphoma.  Diagnostic quality computed 
tomography (CT) scans (neck, chest, abdomen, and pelvis with IV and oral contrast) and positron emission 
tomography (PET) scans will be performed at baseline and at 5 weeks after the last dose of study treatment; 
all other EOT evaluations will be assessed 30 to 37 days after the last dose.  Follow-up assessments will be 
performed every 4 months from the last scan until 24 months, then every 6 months until 48 months, and 
then annually until study closure.  For all follow-up assessments, both PET and CT scans are required until 
disease is PET negative; responses will then be followed by CT scan only.  A CT scan will also be 
performed at the time of suspected clinical progression.  Follow-up assessments will continue until disease 
progression, initiation of a new anti-cancer treatment, or study closure, whichever comes first.  Survival 
status follow-up will continue until patient death or study closure, whichever comes first.  
STUDY POPULATION AND MAIN CRITERIA FOR INCLUSION/EXCLUSION: 
Patients cannot be enrolled or randomized before all inclusion and exclusion criteria (including test results) 
are confirmed.
Inclusion Criteria: Eligible patients must meet the following criteria:
1.
treatment-naive patients with histologically confirmed systemic de novo or transformed DLBCL
(from follicular or marginal zone lymphoma), or FL Grade 3b; patients must have 
high-intermediate or high-risk disease based on standard International Prognostic Index (IPI)
(score ≥3 for patients >60 years of age) or age-adjusted IPI (aaIPI) (score 2 or 3 for patients 
≤60 years of age), and stage IAX (bulk defined as single lymph node mass >10 cm in diameter)–
IV disease
2.
tumor tissue available from most recent biopsy to determine COO by immunohistochemistry using 
Hans algorithm, as assessed by site pathologist.  In addition, tumor tissue must be submitted for 
central pathological review during the trial; if such tissue is not available, a fresh biopsy must be 
obtained.  
3.
fluorodeoxyglucose (FDG)-avid disease by PET and measurable disease of at least 1 nodal lesion 
greater than 1.5 cm in the longest diameter or a non-nodal tumor lesion greater than 1.0 cm in the 
longest diameter by CT, as assessed by the site radiologist
4.
an Eastern Cooperative Oncology Group (ECOG) performance status ≤2
5.
age 18 years or older
6.
patients must have the following baseline laboratory data:
a.
bilirubin ≤1.5 × upper limit of normal (ULN) or ≤3 × ULN for patients with Gilbert's 
disease or documented hepatic involvement with lymphoma
b.
alanine aminotransferase and aspartate aminotransferase ≤3 × ULN or ≤5 × ULN for 
patients with documented hepatic involvement with lymphoma
c.
creatinine clearance ≥30mL/min (calculated using the Cockcroft-Gault formula) 
d.
absolute neutrophil count ≥1000/µL (unless documented bone marrow involvement with 
lymphoma, in which case ANC ≥500/µL)
e.
platelet count ≥75,000/µL (unless documented bone marrow involvement with 
lymphoma, in which case platelets ≥50,000/µL)
f.
urine protein:creatinine ratio (UPC) ratio <1
7.
females of childbearing potential must have a negative serum or urine beta human chorionic 
gonadotropin pregnancy test result within 7 days prior to the first dose of study drug.  Females of 
non-childbearing potential are those who are postmenopausal for more than 1 year or who have 


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had a bilateral tubal ligation, hysterectomy, or bilateral oophorectomy
8.
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, as well as 12 months following the last dose of rituximab
9.
patients must provide written informed consent
Exclusion Criteria: If any of the following apply, the patient MUST NOT enter the study: 
1.
previous history of treated indolent lymphoma.  Newly diagnosed patients with DLBCL who are 
found to have small cell infiltration of the bone marrow or other diagnostic material (representing 
a discordant lymphoma) are eligible.
2.
history of another primary invasive cancer, hematologic malignancy, or myelodysplastic syndrome 
that has not been in remission for at least 3 years (exceptions include non-melanoma skin cancer, 
curatively treated localized prostate cancer, ductal carcinoma in situ, and cervical carcinoma in 
situ by biopsy or a squamous intraepithelial lesion by papanicolaou smear)
3.
history of progressive multifocal leukoencephalopathy (PML)
4.
cerebral/meningeal disease related to the underlying malignancy
5.
baseline peripheral neuropathy ≥Grade 2 (per the National Cancer Institute’s [NCI] Common 
Terminology Criteria for Adverse Events [CTCAE], Version 4.03) or patients with the 
demyelinating form of Charcot-Marie-Tooth syndrome
6.
left ventricular ejection fraction less than 45% or symptomatic cardiac disease (including 
symptomatic ventricular dysfunction, symptomatic coronary artery disease, and symptomatic 
arrhythmias), or myocardial infarction within the past 6 months or previous treatment with 
complete cumulative doses of doxorubicin or other anthracyclines
7.
patients with the following ocular conditions:
a.
corneal disorders: corneal dystrophies, history of corneal or limbal stem cell 
transplantation (including endothelial keratoplasty), evidence of limbal stem cell 
deficiency (ie, deep pannus, poor epithelial healing)
b.
monocular vision (ie, best corrected visual acuity ≥20/200 in one eye)
c.
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
8.
any active ≥Grade 3 (per the NCI CTCAE, Version 4.03) 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. females who are breastfeeding
11. known hypersensitivity to any excipient contained in any of the drug formulations of study 
treatments
12. patients with known urinary outflow obstruction
13. patients with a positive polymerase chain reaction assay who have also tested positive for 
hepatitis B surface antigen and/or anti-hepatitis B core antibody; patients with a negative 
polymerase chain reaction assay are permitted with appropriate anti-viral prophylaxis
14. known or suspected active hepatitis C infection or known human immunodeficiency virus 
infection
NUMBER OF SUBJECTS: Approximately 160 patients (24 patients in Part A and 136 patients in Part B)
STUDY TREATMENT:
Test Product, Dose and Mode of Administration:
Denintuzumab mafodotin at 3 mg/kg will be administered every 6 weeks via intravenous (IV) infusion to all 
patients in Part A and to patients in the Experimental Arm in Part B.  Denintuzumab mafodotin will be 
administered on Day 1 of Cycles 1, 3, and 5; the timing of denintuzumab mafodotin administration will be 
approximately 30 minutes, but no longer than 60 minutes, following rituximab completion on Day 1, after which 
it will then be followed by the remaining components of the combination therapy, ie, CHOP or CHP. 
Reference Therapy, Dose and Mode of Administration:
RCHOP: rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 
1.4 mg/m2 (dose capped at 2 mg total) will be administered IV on Day 1 of every 21-day cycle together 


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with prednisone 100 mg administered orally on Days 1 to 5 of every 21-day cycle
RCHP: rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, and doxorubicin 50 mg/m2 will be 
administered IV on Day 1 of every 21-day cycle together with prednisone 100 mg administered orally on 
Days 1 to 5 of every 21-day cycle
DURATION OF TREATMENT: Study treatment consist of up to six 21-day cycles of either RCHOP or 
RCHP with or without up to 3 doses of denintuzumab mafodotin given on Day 1 of Cycles 1, 3, and 5.  
STUDY EVALUATIONS:
Efficacy Assessment: Disease response will be assessed by the investigator, based on the Lugano 
classification criteria (Cheson, 2014). Radiographic assessments will include PET and diagnostic quality 
CT scans.  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 only and 
evaluated by CT-based response criteria per the Lugano classification criteria.  
Pharmacokinetic and Antitherapeutic Antibody Measurements: Concentrations of denintuzumab 
mafodotin antibody drug conjugate and released cysteine maleimidocaproyl monomethyl auristatin F in 
plasma and ATA in serum will be measured.  Concentrations of rituximab in serum will be measured.  
Pharmacokinetic samples will also be collected and archived for possible analysis of other denintuzumab 
mafodotin-related species.
Biomarker Assessments: Biomarker evaluations may include, but are not limited to, baseline pre- and 
post-treatment peripheral blood evaluation for circulating B cells by flow cytometry and for soluble 
mediator quantification, which may include soluble CD19. Peripheral blood will be collected and assessed 
for cell-free circulating tumor DNA to detect minimal residual disease.  Peripheral blood cell pellets will be 
collected for assessment of Fc-gamma receptor (FcγR) polymorphisms.  The evaluation of pre-treatment 
tumor biopsies may include, but is not limited to, therapeutic target CD19 and other immune cell marker 
expression by immunohistochemistry, COO by gene expression profiling, as well as somatic mutations that 
are prognostic or predictive of denintuzumab mafodotin response.
Safety Assessment:  Safety assessments will include the evaluation of the type, incidence, severity, 
seriousness, and relatedness of adverse events, and the type, incidence, and severity of laboratory test
abnormalities. Ophthalmologic exams and ocular health surveys will be conducted at protocol-specific 
time points.  
STATISTICAL METHODS: 
Sample Size Considerations
In Part A of the study, up to approximately 24 patients will be enrolled to receive denintuzumab mafodotin 
with either RCHOP or RCHP (approximately 12 patients per treatment arm).  With 12 patients in each arm, 
the probability of observing at least 1 patient with a clinically relevant adverse event is 72% if the true 
event rate is 10%.  The probability becomes 93% if the true event rate is 20%.  
In Part B of the study, with approximately 136 patients randomized in a 1:1 to each treatment arm 
(approximately 68 patients per treatment arm) for the primary analysis, the study is designed to have 
approximately 80% power to detect an increase in the CR rate of 18% (eg, from 70% in the RCHOP 
treatment arm to 88% in the denintuzumab mafodotin plus RCHOP (or RCHP) treatment arm. This 
calculation is based on a 2-sided chi-squared test with significance level of alpha =0.1 using EAST 6.3.1
Randomization
In Part A, randomization will be stratified by high-intermediate or high-risk disease.  
In Part B, randomization will be stratified based on the following factors for both randomization and 
analysis:
●COO by local immunohistochemical assessment per Hans algorithm (germinal center B [GCB] versus
non-GCB)
●IPI or aaIPI (high-intermediate risk versus high-risk disease)
Analysis Methods
The efficacy endpoints of response rates (CR rate and ORR) at EOT assessment will be summarized by 
descriptive statistics and exact 90% confidence intervals (CIs) will be calculated. The CR rate comparison 
between the 2 treatment arms for Part B will be performed using a Cochran-Mantel-Haenszel test stratified 
by the randomization strata at a 2-sided alpha level of 0.1. 


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EFS, PFS and OS will be estimated using the Kaplan-Meier methodology. 
The safety analysis will evaluate the type, incidence, severity, seriousness, and relatedness of adverse 
events, and the type, incidence, and severity of laboratory abnormalities for Parts A and B. 
DATE AND VERSION: 18 February 2016, Version 01


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3.
TABLE OF CONTENTS
1.
SIGNATURE .............................................................................................................2
2.
SYNOPSIS..................................................................................................................4
3.
TABLE OF CONTENTS..........................................................................................9
4.
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS.........................14
5.
ETHICS....................................................................................................................16
5.1
Ethics Committee ......................................................................................................16
5.2
Ethical Conduct of the Study.....................................................................................16
5.3
Patient Information and Consent...............................................................................16
6.
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ...........17
7.
INTRODUCTION...................................................................................................18
7.1
Disease Review .........................................................................................................18
7.2
CD19..........................................................................................................................19
7.3
Denintuzumab Mafodotin..........................................................................................19
7.3.1
Mechanism of Action ................................................................................................20
7.3.2
Preclinical Experience...............................................................................................20
7.3.3
Clinical Studies..........................................................................................................20
7.4
Clinical Study Rationale............................................................................................21
8.
STUDY OBJECTIVES ...........................................................................................23
8.1
Primary Study Objectives..........................................................................................23
8.2
Secondary Study Objectives......................................................................................23
8.3
Additional Objectives................................................................................................23
9.
INVESTIGATIONAL PLAN.................................................................................24
9.1
Overall Study Design and Plan..................................................................................24
9.1.1
Part A – Safety Evaluation ........................................................................................24
9.1.2
Part B – Randomized, Open-Label Phase 2...............................................................26
9.2
Discussion and Rationale for Study Design ..............................................................28
9.2.1
Method of Assigning Patients to Treatment Groups .................................................28
9.2.2
Rationale for Selection of Doses ...............................................................................29
9.2.3
Blinding.....................................................................................................................31
9.3
Patient Population......................................................................................................31
9.3.1
Inclusion Criteria.......................................................................................................31
9.3.2
Exclusion Criteria......................................................................................................32
9.3.3
Withdrawal and Replacement of Patients..................................................................33
9.3.3.1
Discontinuation of Study Drug..................................................................................33
9.3.3.2
Patient Withdrawal from Study.................................................................................33
9.3.3.3
Replacement of Patients ............................................................................................34
9.4
Treatment...................................................................................................................34
9.4.1
Treatment Administered............................................................................................34
9.4.2
Investigational Study Drug........................................................................................34
9.4.2.1
Description ................................................................................................................34
9.4.2.2
Dose and Administration...........................................................................................34
9.4.2.3
Storage and Handling ................................................................................................35


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9.4.2.4
Packaging and Labeling.............................................................................................35
9.4.2.5
Preparation.................................................................................................................36
9.4.3
Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone.............36
9.4.3.1
Description ................................................................................................................36
9.4.3.2
Method of Procurement.............................................................................................36
9.4.3.3
Dose and Administration...........................................................................................36
9.4.3.4
Storage and Handling ................................................................................................37
9.4.3.5
Packaging and Labeling.............................................................................................37
9.4.3.6
Preparation.................................................................................................................37
9.4.4
Required Premedication and Postmedication............................................................37
9.4.5
Prophylactic Steroid Eye Drops for Denintuzumab Mafodotin.................................38
9.4.6
Concomitant Therapy................................................................................................38
9.4.6.1
Required Concomitant Therapy.................................................................................38
9.4.6.2
Allowed Concomitant Therapy .................................................................................39
9.4.6.3
Prohibited Concomitant Therapy...............................................................................39
9.4.7
Management of Infusion Reactions...........................................................................40
9.4.8
Management of Suspected Progressive Multifocal Leukoencephalopathy (PML) ...40
9.4.9
Dose Modifications ...................................................................................................41
9.4.9.1
Dose Modifications for Ocular Events ......................................................................42
9.4.10
Treatment Compliance ..............................................................................................44
9.4.11
Assignment to Treatment...........................................................................................44
9.5
Efficacy and Safety Variables ...................................................................................44
9.5.1
Efficacy and Safety Measurements Assessed............................................................44
9.5.2
Pharmacokinetic and Antitherapeutic Antibody Measurements ...............................45
9.5.3
Biomarker Assessments.............................................................................................45
9.5.4
Safety Measurements.................................................................................................45
10.
STUDY EVALUATIONS BY VISIT.....................................................................46
10.1
Screening (Days -28 to 1)..........................................................................................46
10.2
Baseline (Days -7 to 1)..............................................................................................47
10.3
Randomization (Day -1 to Day 1) .............................................................................47
10.4
Treatment Period (Day 1 to Day 21) .........................................................................47
10.4.1
Cycles 1, 3, and 5 ......................................................................................................47
10.4.2
Cycles 2, 4, and 6 ......................................................................................................48
10.4.3
Part A Intense Sampling Schedule – Pharmacokinetic, Antitherapeutic Antibody, and 
Biomarker Assessments.............................................................................................49
10.4.3.1
Cycles 1 and 3 ...........................................................................................................49
10.4.3.2
Cycles 2 and 4 ...........................................................................................................49
10.4.3.3
Cycles 5 and 6 ...........................................................................................................50
10.4.4
Part B Intense Sampling Schedule – Pharmacokinetics, Antitherapeutic, Antibody, and 
Biomarker Assessments.............................................................................................50
10.4.4.1
Cycles 1 and 3 ...........................................................................................................50
10.4.4.2
Cycles 2 and 4 ...........................................................................................................51
10.4.4.3
Cycles 5 and 6 ...........................................................................................................51


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10.4.5
Part B Sparse Sampling Schedule – Pharmacokinetic, Antitherapeutic Antibody, and 
Biomarker Assessments.............................................................................................51
10.4.5.1
Cycles 1 to 6..............................................................................................................51
10.5
End of Treatment (30 to 37 Days After Last Dose of Study Treatment)...................52
10.6
End of Treatment Response Assessment (5 weeks [± 1 week] After Last Dose of Study 
Treatment) .................................................................................................................52
10.7
Long-Term Follow-Up ..............................................................................................53
10.8
End of Study/End of Follow-Up................................................................................54
11.
METHOD OF ASSESSMENT...............................................................................55
11.1
Medical History.........................................................................................................55
11.2
International Prognostic Index...................................................................................55
11.3
Lymphoma Disease Stage .........................................................................................55
11.4
B Symptoms ..............................................................................................................55
11.5
Histological Subtype and Cell of Origin Determination ...........................................55
11.6
Response and Efficacy Assessments .........................................................................56
11.7
Patient-Reported Outcomes – Ocular Health Survey................................................57
11.8
Pharmacokinetic and Antitherapeutic Antibody Assessments ..................................57
11.9
Biomarker Analysis...................................................................................................58
11.9.1
B-Cell Subset Analysis..............................................................................................58
11.9.2
Protein Markers in Blood ..........................................................................................58
11.9.3
Fc-γ Receptor (FcγR) Variants..................................................................................59
11.9.4
Characterization of Tumor Tissue .............................................................................59
11.10
Biospecimen Samples for Future Research...............................................................60
11.11
Appropriateness of Measurements ............................................................................60
12.
SAFETY MEASUREMENTS AND VARIABLES ..............................................61
12.1
Adverse Events..........................................................................................................61
12.1.1
Definition...................................................................................................................61
12.1.2
Procedures for Eliciting and Recording Adverse Events ..........................................63
12.1.3
Reporting Periods for Adverse Events and Serious Adverse Events.........................65
12.1.4
Serious Adverse Events Require Immediate Reporting ............................................65
12.1.5
Sponsor Safety Reporting Requirements...................................................................66
12.2
Vital Signs .................................................................................................................66
12.3
Clinical Laboratory Tests ..........................................................................................67
12.4
Physical Examination, Height, and Weight...............................................................68
12.5
Ocular Monitoring Plan.............................................................................................68
12.6
ECOG Performance Status........................................................................................68
12.7
Cardiac Evaluation ....................................................................................................68
13.
DATA MANAGEMENT AND STATISTICAL ANALYSIS..............................69
13.1
Data Management......................................................................................................69
13.2
Sample Size Estimation.............................................................................................69
13.3
Statistical Analysis Plan ............................................................................................69
13.4
Randomization...........................................................................................................70
13.5
Analysis Populations .................................................................................................70
13.5.1
Intent-to-Treat Population .........................................................................................70


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13.5.2
Safety Analysis Set....................................................................................................70
13.5.3
Per-Protocol Analysis Set..........................................................................................70
13.6
Statistical Methods ....................................................................................................71
13.6.1
Missing Data..............................................................................................................71
13.6.2
Demographic and Baseline Data ...............................................................................71
13.6.3
Patient Disposition.....................................................................................................71
13.6.4
Efficacy......................................................................................................................71
13.6.5
Pharmacokinetics, Antitherapeutic Antibody, and Biomarkers.................................72
13.6.6
Safety.........................................................................................................................73
13.6.7
Additional Data .........................................................................................................73
13.6.8
Interim Analysis ........................................................................................................73
13.6.9
Data Safety Monitoring Committee ..........................................................................73
14.
MONITORING PROCEDURES (QUALITY ASSURANCE)............................74
14.1
Routine Monitoring ...................................................................................................74
14.2
Inspections and Auditing Procedures ........................................................................74
15.
STUDY MANAGEMENT AND MATERIALS....................................................75
15.1
Electronic Case Report Forms...................................................................................75
15.2
Data Collection..........................................................................................................75
15.3
Source Documents Maintenance ...............................................................................76
15.4
Record Maintenance..................................................................................................76
15.5
Confidentiality...........................................................................................................77
16.
ADMINISTRATION PROCEDURES ..................................................................78
16.1
Regulatory Approval .................................................................................................78
16.2
Protocol Amendments ...............................................................................................78
16.3
Protocol Adherence and Deviations ..........................................................................78
16.4
Study Documentation, Privacy, and Records Retention............................................79
16.5
Publication Policy......................................................................................................79
16.6
Clinical Study Report ................................................................................................80
16.7
Contractual and Financial Details..............................................................................80
16.8
Insurance, Indemnity, and Compensation .................................................................80
16.9
Discontinuation of the Study.....................................................................................80
16.10
Study Center File Management .................................................................................80
17.
REFERENCE LIST ................................................................................................82
18.
APPENDICES..........................................................................................................85
18.1
Schedule of Events ....................................................................................................85
18.2
Response Assessment – The Lugano Classification..................................................93
18.3
Modified* CTCAE V4.03 Grading Scheme for Ocular Toxicity..............................96
18.4
International Prognostic Index Scales .......................................................................97
18.5
Eastern Cooperative Oncology Group Performance Status.......................................98
18.6
Common Terminology Criteria for Adverse Events (CTCAE; v 4.03).....................99


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LIST OF TABLES
Table 9-1:
Study Treatments by Arm in Part B.....................................................................27
Table 9-2:
Recommended Vincristine Dose Modifications for Treatment-associated Neuropathy
..............................................................................................................................41
Table 9-3:
Evaluation, Treatment, and Dose Modifications in the Event of Ocular Toxicity 
Associated with Denintuzumab Mafodotin Administration.................................43
Table 18-1:
Study Schedule.....................................................................................................85
Table 18-2:
Part A Intense Sampling Schedule – Pharmacokinetics, Antitherapeutic Antibody, 
and Biomarker Assessment (For all Patients enrolled in Part A).........................88
Table 18-3:
Part B Intense Sampling Schedule – Pharmacokinetics, Antitherapeutic Antibody, 
and Biomarker Assessments – (For the First 25 Patients in Each Arm) ..............90
Table 18-4:
Part B Sparse Sampling Schedule – Pharmacokinetics, Antitherapeutic Antibody, and 
Biomarker Assessments – (For the Remaining Patients in Part B Following the First 
25 Patients Enrolled in Each Arm).......................................................................92
LIST OF FIGURES
Figure 1:
Part A Study Schema............................................................................................25
Figure 2:
Part B Study Schema............................................................................................27


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4. LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
Term
Definition
aaIPI
age-adjusted International Prognostic Index
ADC
antibody-drug conjugate
ADL
activities of daily living
ATA
antitherapeutic antibody
CBC
complete blood count
CFR
Code of Federal Regulations
CHOP
cyclophosphamide, doxorubicin, vincristine, and prednisone
CI
confidence interval
CMR
complete metabolic response
COO
cell of origin
CR
complete response
CRO
Clinical Research Organization
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
cys-mcMMAF
cysteine maleimidocaproyl monomethyl auristatin F
DDT
dose-delaying toxicity
DLBCL
diffuse large B-cell lymphoma
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EFS
event-free survival
EOT
end of treatment 
FcγR
Fc-gamma receptor
FDA
Food and Drug Administration
FDG
fluorodeoxyglucose
FL
follicular lymphoma
GCB
germinal center B cell
GCP
Good Clinical Practice 
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
IHC
immunohistochemistry
IND
Investigational New Drug
INR
international normalized ratio
IP
immunophenotyping 
IPI
International Prognostic Index


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IRB
Institutional Review Board
ITT
intent-to-treat 
IV
intravenous(ly)
LDH
lactate dehydrogenase
MMAF
monomethyl auristatin F
MRD
minimal residual disease
MTD
maximum tolerated dose
MUGA
multigated acquisition 
NCI
National Cancer Institute 
NHL
Non-Hodgkin lymphoma
ORR
objective response rate
OS
overall survival
PD
pharmacodynamic 
PET
positron emission tomography
PK
pharmacokinetics 
PFS
progression-free survival
PML
progressive multifocal leukoencephalopathy
PMR
partial metabolic response
PT
prothrombin time
PTT
partial thromboplastin time
RCHOP
rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone 
RCHP
rituximab, cyclophosphamide, doxorubicin, and prednisone
SAE
serious adverse event
SAP
Statistical Analysis Plan
sCD19
soluble CD19
SCT
stem cell transplant 
SGN-CD19A
denintuzumab mafodotin
SNP
single-nucleotide polymorphism 
SMC
Safety Monitoring Committee 
ULN
upper limit of normal
UPC
urine protein:creatinine ratio
US
United States


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




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7.
INTRODUCTION
7.1 Disease Review
Non-Hodgkin lymphoma (NHL) is a heterogeneous group of lymphoproliferative disorders 
originating in the B-lymphocytes, T-lymphocytes, and natural killer cells.  In the US, the 
majority (80% to 85%) are of B-cell origin (Armitage, 1998).  Non-Hodgkin lymphoma is 
the most common hematological malignancy, and it was estimated that 71,850 new cases 
would be diagnosed in the US in 2015 and that 19,790 people would die as a result of the 
disease (American Cancer Society, 2015).  Diffuse large B-cell lymphoma (DLBCL) is a
subset of NHL that comprises 37% of cases of NHL (American Cancer Society, 2014), 
representing the most common lymphoid neoplasm in adults (Swerdlow, 2008).  According 
to the 2008 World Health Organization classification schema, DLBCL (not otherwise 
specified) is a heterogeneous grouping of lymphomas comprising neoplasms of large 
B-lymphoid cells that do not belong to other specific subtypes or disease entities (Swerdlow, 
2008).  DLBCL (not otherwise specified) cases can be further subclassified based on 
morphological, molecular, and immunophenotypical features.  Follicular lymphoma (FL) is 
the most common indolent form of NHL, and comprises approximately 20% to 30% of all 
NHLs (Lymphoma Research Foundation, 2015).  Grade 3b FL histologically is characterized 
by solid sheets of centroblasts, has an aggressive clinical course, and is typically treated 
similar to DLBCL (Cancer Research UK, 2015; Dreyling 2011). Over time, about 1 in 3 FLs 
transform into a fast-growing DLBCL (American Cancer Society, 2015).  
Outcomes for patients with DLBCL have improved over the past decade, with the addition of 
rituximab to standard anthracycline-based multi-agent chemotherapy.  The standard of care 
for newly diagnosed, treatment-naive patients with DLBCL consists of six 21-day cycles of 
rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP)
(Tilly, 2012).  In large randomized trials, the benefit of RCHOP has been demonstrated by a 
3-year progression-free survival (PFS) rate of approximately 70% and a 3-year overall 
survival (OS) rate of approximately 75% (Pfreundschuh, 2008; Cunningham, 2011).  
Complete response (CR) rates of 75% to 78% have been reported in analyses that included 
both high and low risk patients (Coiffier, 2002; Pfreundschuh, 2008).  Despite the good 
outcomes achieved with RCHOP in newly diagnosed patients with DLBCL, high-risk patient 
populations still remain underserved.  The International Prognostic Index (IPI) identifies 
patients with a score of 3 to 5 as having inferior outcomes compared to those with a score of 
0 to 2.  Higher-risk patients with an IPI score of 3 to 5 have a 3-year PFS rate of 
approximately 55%; these patients comprise approximately 40% of the frontline DLBCL 
population (25% IPI 3, 15% IPI 4 to 5) (Pfreundschuh, 2008).  Younger patients (≤60 years 
of age) with age-adjusted International Prognostic Index (aaIPI) scores of 2 to 3 have 
similarly inferior outcomes as the traditional higher risk patients with IPI scores 3 to 5
(Shipp, 1993; Ziepert 2010).
A component of multi-agent RCHOP chemotherapy is vincristine, which is an antitubulin 
vinca alkaloid.  Neurotoxicity is the dose-limiting toxicity of vincristine and appears to be 
cumulative.  Neurologic manifestations that have been associated with vincristine include 


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paresthesia, tingling of the hands and feet, numbness, sensory loss, neuritic pain, pharyngeal 
and parotid gland pain, loss of deep tendon reflexes, and difficulty in walking (gait 
disturbances), including slapping gait.  Infrequently, hoarseness of voice, ocular palsies, 
atony of the urinary bladder, and autonomic neuropathy presenting as postural hypotension 
have occurred (Tangun, 1977; Legha, 1986; Tobias, 1991).  As a result of toxic neuropathy, 
vincristine is often dose-reduced or eliminated after several cycles of RCHOP.  The expected 
incidence of peripheral neuropathy with vincristine, delivered as part of RCHOP, is 
approximately 50%; the majority of neuropathy events are sensory in nature and low grade 
(Grade 1 or 2).  Grade 3 peripheral sensory neuropathy is observed in approximately 10% of 
patients; Grade 3 peripheral motor neuropathy events have been infrequently reported in the 
literature and are typically rare in clinical practice (Coiffier, 2002; Pfreundschuh, 2008).  
There is a paucity of data supporting the use of vincristine as a single agent in relapsed or 
refractory lymphomas, with no available single-agent prospective studies or retrospective 
case series.  Vincristine sulfate liposome injection, a formulation of vincristine designed to 
provide targeted, increased, and sustained delivery to tumor tissues, was evaluated in a 
phase 2 study of patients with relapsed or refractory aggressive NHL (Rodriguez, 2009). In 
this study of 119 patients, 25% achieved an objective response; of these, 5% achieved CR.  
In addition, Grade 3 or 4 neurotoxicity was observed in 32% of patients.  While vincristine 
has not been evaluated as a single agent in either the frontline or relapsed/refractory setting, 
the contribution of activity to RCHOP appears minimal to moderate at best based on
response rate of vincristine sulfate liposome injection in the relapsed or refractory aggressive 
NHL setting.
RCHOP currently under-serves this high risk population, resulting in an unmet need, and an 
opportunity to introduce novel agents to improve the treatment paradigm.
7.2 CD19
CD19 is an internalizing transmembrane surface protein that is a member of the 
immunoglobulin superfamily, and is one of the earliest markers of B-cell differentiation.  It is 
not known to be expressed by any cell outside of the B-cell lineage.  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 (Huh, 2000; Del Nagro; 2005; Bryder, 
2010). 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 NHL and is found in almost all clinical immunohistochemistry (IHC) and flow 
cytometry diagnostic panels.
7.3 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 
humanized anti-CD19 monoclonal antibody that is chemically conjugated to a synthetic 
analog (monomethyl auristatin F [MMAF]) of the naturally occurring tubulin-disrupting 


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drug, dolastatin 10. The maleimidocaproyl 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.
7.3.1
Mechanism of Action
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 maleimidocaproyl 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.
7.3.2
Preclinical Experience
A complete summary of the preclinical data relevant to denintuzumab mafodotin is provided 
in the Investigator’s Brochure (IB).    
7.3.3
Clinical Studies
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 B-cell NHL 
(Protocol SGN19A-002).  Denintuzumab mafodotin is administered on Day 1 of 3-week 
cycles (doses 0.5 to 6 mg/kg) or on Day 1 of 6-week cycles (dose 3 mg/kg).  In the 
62 patients treated to date, including 54 patients with DLBCL, the maximum tolerated dose
(MTD) was not exceeded after escalating to 6 mg/kg every 3 weeks.  Toxicity profiles and 
antitumor activity were similar across both schedules.  Denintuzumab mafodotin was 
generally well tolerated, and the most common adverse events of any grade included blurred 
vision, dry eye, fatigue, and keratopathy.  Hematopoietic toxicity and peripheral neuropathy 
were uncommon.  Of the 60 patients evaluable for response, 23 patients (38%) achieved an 
objective response, including 14 patients (23%) with a complete remission
(Moskowitz, 2015). Antitumor activity appeared to be higher in those who achieved an 
objective response to their most recent therapy (ie, relapsed patients).  Of the 25 patients who 
relapsed to their most recent prior therapy, 15 patients (60%) achieved an objective response, 
including 10 patients (40%) with a best response of CR.
Please see the IB for complete clinical safety information. 


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7.4 Clinical Study Rationale
Overall, the rationale to evaluate the administration of denintuzumab mafodotin in 
combination with RCHOP as well as a substitution in place of vincristine in RCHOP (ie, 
RCHP) as frontline multiagent chemotherapy is manifold:

Denintuzumab mafodotin monotherapy has demonstrated preliminary activity in 
aggressive, relapsed or refractory DLBCL after failure of second-line salvage and 
beyond.  As discussed in Section 7.3.3, of the 60 patients evaluable for response, 
38% achieved an objective response with a CR rate of 23% (Moskowitz, 2015).  
Antitumor activity appeared to be higher in those who achieved an objective response 
to their most recent therapy; of 25 such patients, 60% achieved an objective response
with a CR rate of 40%.  Given the activity observed with denintuzumab mafodotin in 
the relapsed DLBCL setting, there is rationale to support the hypothesis that 
denintuzumab mafodotin will have substantial single-agent activity in patients with 
newly diagnosed DLBCL.  DLBCL patients with adverse risk factors (IPI score of 
3 or higher for patients >60 years of age or an aaIPI score of 2 or 3 for patients who 
are ≤60 years of age), have poor outcomes with RCHOP therapy and new agents are 
needed (Section 7.1).  It is hypothesized that a treatment approach combining 
denintuzumab mafodotin with RCHOP may yield an improved CR rate, with the 
potential to prolong PFS and OS.

Due to the neurotoxicity profile of vincristine when administered as a component of 
RCHOP, there is a potential concern for additive neurotoxicity in combination with 
another microtubule inhibitor, even though clinically denintuzumab mafodotin 
monotherapy was generally well tolerated and peripheral neuropathy was uncommon.  
With denintuzumab mafodotin monotherapy, the most common adverse events of any 
grade included blurred vision, dry eye, fatigue, and keratopathy.  Hematopoietic 
toxicity was infrequent.  The expected incidence of peripheral neuropathy with 
vincristine, delivered as part of RCHOP, is approximately 50%; the majority of 
neuropathy events are sensory in nature and low grade (Grade 1 or 2).  Grade 3 
peripheral sensory neuropathy is observed in approximately 10% of patients; Grade 3 
peripheral motor neuropathy events have been infrequently reported in the literature 
and are typically rare in clinical practice (Coiffier 2002; Pfreundschuh 2008).  In 
addition, denintuzumab mafodotin has demonstrated better single agent antitumor 
activity when compared to that published for vincristine sulfate liposomal injection.
Therefore, it is hypothesized that a treatment approach of substituting denintuzumab 
mafodotin for vincristine in RCHOP (ie, denintuzumab mafodotin plus RCHP) may 
also yield an improved CR rate with the potential to prolong PFS and OS. Thus, this 
study will evaluate both (1) the addition of denintuzumab mafodotin to RCHOP, as 
well as (2) the substitution of denintuzumab mafodotin for vincristine (which has at 
most a moderate contribution to activity in RCHOP).  The latter may be a safer
approach than administering the 2 agents concurrently, where doses of one or both 
agents may be limited by resultant neurotoxicity, without a decline in potential 
efficacy.


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
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 RCHOP.  In inherently denintuzumab mafodotin 
insensitive tumor xenograft models, the combined antitumor activity of both 
denintuzumab mafodotin and rituximab, and denintuzumab mafodotin and RCHOP 
was found to be considerably stronger than either agent or regimen alone in FL and 
DLBCL models, leading to prolonged tumor delay as well as complete remissions.  
Similarly, the combinations of denintuzumab mafodotin and CHOP demonstrated 
stronger antitumor activity in the DLBCL models when compared to denintuzumab 
mafodotin or CHOP 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 (Van Epps, 2015).
Taken together, these data support further evaluation of incorporating denintuzumab 
mafodotin as part of multi-agent front-line therapy such as RCHOP or RCHP and may yield 
an improvement in the CR rate, as well as PFS and OS benefit, in treatment naive DLBCL or 
FL Grade 3b patients.


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8.
STUDY OBJECTIVES
8.1 Primary Study Objectives

To compare the CR rate at the end of treatment (EOT) in treatment-naive patients 
with high-intermediate or high-risk systemic DLBCL or FL Grade 3b treated with 
denintuzumab mafodotin plus RCHOP or RCHP versus RCHOP alone (Part B)

To assess the safety profile of denintuzumab mafodotin administered in combination 
with RCHOP or RCHP in treatment-naive patients with high-intermediate or 
high-risk systemic DLBCL or FL Grade 3b (Part A and Part B)
8.2 Secondary Study Objectives

To compare event-free survival (EFS) between study arms (Part B)

To compare PFS between study arms (Part B)

To compare OS between study arms (Part B)

To compare the objective response rate (ORR) at EOT between study arms (Part B)

To compare the duration of objective response and of CR between study arms
(Part B)
8.3 Additional Objectives

To evaluate the pharmacokinetics (PK) of denintuzumab mafodotin administered in 
combination with RCHOP or RCHP (Parts A and B)

To evaluate the incidence of antitherapeutic antibodies (ATA) against denintuzumab 
mafodotin (Parts A and B)

To assess denintuzumab mafodotin-mediated pharmacodynamic (PD) effects and 
potential biomarkers of response to denintuzumab mafodotin in combination with 
RCHOP or RCHP (Parts A and B)


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9.
INVESTIGATIONAL PLAN
9.1 Overall Study Design and Plan
This is an open-label phase 2 multicenter study of denintuzumab mafodotin in combination 
with RCHOP or RCHP compared with RCHOP alone as frontline therapy in patients with 
DLBCL or FL Grade 3b.  This study has 2 parts (Part A and Part B).  Part A of the study is a 
safety evaluation of denintuzumab mafodotin in combination with either RCHOP or RCHP.  
Results from Part A will be used to determine the regimen (RCHOP or RCHP) to be tested in 
combination with denintuzumab mafodotin in Part B. Part B is a multicenter study designed 
to evaluate the antitumor activity and safety of denintuzumab mafodotin in combination with 
either RCHOP or RCHP compared with RCHOP alone.  
9.1.1
Part A – Safety Evaluation
In Part A of the study, up to approximately 24 patients will be randomized 1:1 to receive
denintuzumab mafodotin plus RCHOP or denintuzumab mafodotin plus RCHP to assess 
safety in these 2 combination regimens. Patient randomization will be stratified by 
high-intermediate or high-risk disease (see Section 9.2.1 for definition of high-intermediate 
and high-risk disease). Study treatment is up to six 21-day cycles of either RCHOP or RCHP 
combined with up to 3 doses of denintuzumab mafodotin administered on Day 1 of Cycles 1, 
3, and 5. The study schema for Part A is depicted in Figure 1.    


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Figure 1:
Part A Study Schema
CT = computed tomography; EOT = end of treatment; PET = positron emission tomography; RCHOP = rituximab, 
cyclophosphamide, doxorubicin, vincristine, prednisone; RCHP = rituximab, cyclophosphamide, doxorubicin, and 
prednisone
a
Administered on Day 1 of Cycles 1, 3, and 5
b
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 anti-cancer treatment, 
death, or study closure, whichever comes first.  Survival status follow-up until death or study closure, whichever comes 
first.  
The SMC, comprising the study investigators, medical monitor, and biostatistician, and 
Sponsor’s medical expert, will periodically monitor the safety of patients at predefined 
interim safety evaluations and at regular intervals during the treatment period.  Formal safety 
evaluations of cumulative data from both treatment groups will be conducted at the following 
6 time points in Part A of the study:

after 6, 12, and 24 patients have completed Cycle 1 

after 6, 12, and 24 patients have completed EOT 
At each interim safety evaluation, the SMC will review the cumulative safety data, including 
the incidence of dose-delaying toxicities (DDTs) that are associated with denintuzumab 
mafodotin in combination with RCHOP or RCHP, as well as the rates of adverse events of 
interest such as peripheral neuropathy in each treatment group. A DDT is defined as any 
study treatment-related toxicity that necessitates a delay of >14 days in the start of RCHOP 
or RCHP treatment in the next cycle. With respect to hematologic recovery, it is 
recommended that the next cycle of RCHOP or RCHP be given once the patient's absolute 
neutrophil count recovers to ≥ 1000/μL and the platelet count recovers to ≥75,000/μL, as 
applicable.  Upon its evaluation of the data, the SMC will make one of the following 
recommendations to the Sponsor:

continue the trial as planned


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
modify the dose of denintuzumab mafodotin in subsequently enrolled patients

temporarily halt enrollment for additional evaluation
If the SMC determines that the risks outweigh the benefits of the study treatment in both 
combination regimens, no further patients will be enrolled at that dose and schedule.
The evaluation of the safety and antitumor activity data at the end of Part A will be used to 
determine the regimen (RCHOP or RCHP) to be tested in combination with denintuzumab 
mafodotin in Part B. If Grade 3 neuropathy (sensory or motor) is observed in >20% of 
patients in the denintuzumab mafodotin plus RCHOP treatment group (n = 12), then that 
combination will have exceeded the stopping criteria for that regimen, and RCHP may be 
selected for administration in combination with denintuzumab mafodotin in Part B of the 
study, with the support of the overall safety and antitumor activity data from both arms.
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.
PET scans and computed tomography (CT) scans of the neck, chest, abdomen, and pelvis
with intravenous (IV) and oral contrast, will be assessed at baseline and at EOT. CT scans 
will be contrast-enhanced (unless contrast is contraindicated) and of diagnostic quality.
Follow-up assessments will be performed every 4 months from last scan until 24 months 
from EOT scan, then every 6 months until 48 months from EOT scan, and then annually until 
study closure. 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 
only. Follow-up assessments will continue until disease progression, initiation of a new 
anticancer treatment, or study closure, whichever comes first.
Results from a bone marrow biopsy will be recorded at screening and/or EOT, and at any 
time on study if a bone marrow biopsy is performed as part of standard of care. 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 comes 
first.
9.1.2
Part B – Randomized, Open-Label Phase 2
Part B of the study is a phase 2, randomized, open-label, multicenter study designed to 
evaluate the antitumor activity and safety of denintuzumab mafodotin in combination with 
either RCHOP or RCHP (Experimental Arm) compared with RCHOP alone (Comparator 
Arm). Approximately 136 patients will be randomized 1:1 to either the Experimental or 
Comparator Arm. Randomization will be stratified by high-intermediate or high-risk disease 
and by cell of origin (COO). The study treatments per arm are summarized in Table 9-1.
The study schema for Part B is depicted in Figure 2.  


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Table 9-1:
Study Treatments by Arm in Part B
Part B Study Treatment
Treatment Arm
Experimental
Comparator
RCHOP
X
RCHOP or RCHP (pending Part A analysis) plus denintuzumab 
mafodotin
X
RCHOP = rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; RCHP = rituximab, cyclophosphamide, 
doxorubicin, and prednisone
Figure 2:
Part B Study Schema
CT = computed tomography; EOT = end of treatment; PET = positron emission tomography; RCHOP = rituximab, 
cyclophosphamide, doxorubicin, vincristine, prednisone; RCHP = rituximab, cyclophosphamide, doxorubicin, and 
prednisone
a
Administered on Day 1 of Cycles 1, 3, and 5
b
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 anti-cancer treatment, 
death, or study closure, whichever comes first.  Survival status follow-up until death or study closure, whichever comes 
first.  
The SMC will continue to monitor the safety of the combination of denintuzumab mafodotin 
and either RCHOP or RCHP at predefined interim safety evaluations and during the 
treatment period. The SMC will review cumulative safety data after 10 patients in each arm 
(N=approximately 20) have completed treatment, after 20 patients in each arm 
(N=approximately 40) have completed treatment, and after all patients in both arms have 
completed treatment.   
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.
PET scans and CT scans of the neck, chest, abdomen, and pelvis with IV and oral contrast, 


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will be assessed at baseline and at EOT.  CT scans will be contrast-enhanced (unless contrast 
is contraindicated) and of diagnostic quality.  Follow-up assessments will be performed every 
4 months from the last scan until 24 months after the EOT scan, then every 6 months until 
48 months after the EOT scan, and then annually until study closure.  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 only.  Follow-up assessments will 
continue until disease progression, initiation of a new anticancer treatment, or study closure, 
whichever comes first. 
Results from a bone marrow biopsy will be recorded at screening and/or at EOT, and at any 
time on study if a bone marrow biopsy is performed as part of standard of care.  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 comes 
first. 
  
9.2 Discussion and Rationale for Study Design
The FDA’s Guidance on Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics (FDA, 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 EOT as 
assessed by the investigator utilizing the Lugano classification criteria (Cheson, 2014).  In 
this population where the ability to achieve a CR directly influences long-term outcomes, CR 
is the most appropriate endpoint to assess early treatment benefit.  Complete response, which
provides a direct comparison of the effectiveness of each treatment regimen, is directly 
correlated with the long-term clinical benefit of prolonging PFS and OS, and minimizes 
potential biases in interpretation.  Therefore, CR rate is the most appropriate primary 
endpoint in this phase 2, randomized, open-label clinical trial.
The endpoints of this study are appropriate for evaluating efficacy and safety in this patient 
population.  The frequency of blood draws for evaluation of PK is appropriate based on prior 
experience with denintuzumab mafodotin.
9.2.1
Method of Assigning Patients to Treatment Groups
In Part A, following informed consent and screening, patients will be randomly assigned to 
1 of 2 treatment regimens combined with denituzumab mafodotin in a 1:1 ratio using a 
centralized randomization system.  Randomization in this part of the study is for the purpose 
of evaluating the safety of denituzumab mafodotin in combination with RCHOP versus 
RCHP.  Patients will be stratified according to high-intermediate risk (IPI =3 for age 
>60 years and aaIPI =2 for age ≤60 years) versus high-risk (IPI =4 or 5 for age >60 years and 
aaIPI =3 for age ≤60 years) disease based on standard IPI for patients >60 years of age or 
aaIPI for patients ≤60 years of age.
In Part B, following informed consent and screening assessments, patients will be randomly 
assigned to 1 of 2 arms in a 1:1 ratio using a centralized randomization system.  


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Randomization in this part of the study is for the purpose of evaluating the efficacy and 
safety of denituzumab mafodotin in combination with either RCHP or RCHOP versus
RCHOP alone.  Randomization will be stratified by the following 2 factors:  

COO by local IHC assessment per Hans algorithm (germinal center B [GCB] versus 
non-GCB)

high-intermediate risk versus high-risk disease based on standard IPI for patients 
>60 years of age and aaIPI for patients ≤60 years of age
Randomization strata are specified in Section 9.4.11.  Randomization procedures are detailed 
in the study manual.
9.2.2
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 
IV every 3 weeks.  Denintuzumab mafodotin has been generally well tolerated, and the MTD 
was not exceeded at 6 mg/kg every 3 weeks. Following characterization of a mean 
terminal-phase half-life for denintuzumab mafodotin of approximately 2 weeks, the safety 
and antitumor efficacy of 3 mg/kg administered once every 6 weeks was evaluated.  The 
toxicity profiles and efficacy were similar across both schedules.  
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 or every 
6 weeks has demonstrated antitumor activity in 60 efficacy-evaluable patients with an ORR 
of 38% and CR rate of 23% (Moskowitz, 2015).  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, patients treated at 3 mg/kg every 3 weeks (n=14) had the same 
rate of response (CR/partial remission) as those at the higher dose levels (unpublished data).  
A similar response rate was observed in patients treated with 3 mg/kg every 6 weeks (n=10) 
(4 CR out of 9 efficacy-evaluable patients) (Moskowitz, 2015).  Additionally, the 3 mg/kg 
dose level was well tolerated with fewer Grade 3 or 4 hematological adverse events than that 
observed with higher doses.  Thus, 3 mg/kg every 6 weeks is expected to be a safe and 
efficacious dose of denintuzumab mafodotin for evaluation in combination with RCHOP or 
RCHP.
The dose of rituximab (375 mg/m2) is the standard approved dose for patients with 
previously untreated DLBCL when given in combination with CHOP or other 
anthracycline-based chemotherapy regimens.  Additionally, the selected dose and schedule 
have been safely and effectively employed in combination with various single- and 
multi-agent chemotherapy regimens for this patient population (Gisselbrecht, 2012;
Tilly, 2012).  In theory, rituximab and denintuzumab mafodotin are partly eliminated via 
binding to CD19/CD20-positive B-cells, therefore changes in this cell population could 
potentially alter the PK of these molecules.  In patients with relapsed/refractory NHL, 


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denintuzumab mafodotin demonstrated linear PK in the dose range of 1 to 6 mg/kg every 
3 weeks.  However, treatment naïve NHL patients generally have more normal circulating 
B-cells than relapsed/refractory NHL patients.  Therefore, it is expected that in the current 
study of treatment naïve NHL patients, part of the rituximab and denintuzumab mafodotin 
doses will bind to the normal circulating B-cells, resulting in potentially reduced systemic 
exposures. However, dose adjustment of rituximab based on pre-treatment CD19 count is 
not necessary (Rituxan Prescribing Information, 2013).  The reduction in denintuzumab 
mafodotin exposure is expected to be mild and transient because the dose of denintuzumab 
mafodotin (3 mg/kg) may be high enough to overcome this target-mediated disposition.  
Furthermore, both denintuzumab mafodotin and rituximab deplete the normal circulating 
B-cells after a single dose so that these are unlikely to affect the PK of denintuzumab 
mafodotin beyond the first cycle of treatment.
The doses of cyclophosphamide (750 mg/m2), doxorubicin (50 mg/m2), and 
vincristine (1.4 mg/m2) (dose capped at 2 mg total) are the standard doses when given in a 
combination setting that will be administered IV on Day 1 of every 21-day cycle together 
with prednisone 100 mg administered orally on Days 1 to 5 of every 21-day cycle.    
Additional considerations for these dosing regimens include the following:  

Cyclophosphamide is excreted unchanged in the urine (approximately 10% to 20%) 
and converted to active metabolite(s) (approximately 75%) by multiple cytochrome 
P450 (CYP) enzymes, with CYP2B6 showing the highest activity.  The active 
metabolite(s) can undergo oxidation/inactivation by aldehyde dehydrogenases 
(Cyclophosphamide Prescribing Information, Baxter, March 2013). 

Doxorubicin is eliminated predominantly by metabolism (by CYP3A4 and CYP2D6) 
and biliary excretion (by P-glycoprotein 1) (Doxorubicin Prescribing Information, 
Pfizer, October 2013).

Vincristine is predominantly eliminated by the liver either by CYP 3A metabolism or 
biliary excretion (Vincristine Prescribing Information, Hospira, July 2013).

Prednisone is completely converted by CYP3A4 to the active metabolite 
prednisolone, which is further metabolized mainly in the liver and excreted in the 
urine as sulfate and glucuronide conjugates (Prednisone Prescribing Information, 
Horizon Pharma USA, June 2013).
Cys-mcMMAF at the concentration of 0.1 µM was a substrate of multiple transporters 
including P-glycoprotein 1 in vitro. Cys-mcMMAF was 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), did not inhibit multiple 
CYP enzymes including CYP2B6, CYP2D6, or CYP3A4/5, nor induce CYP2B6 or 
CYP3A4/5 in vitro (denintuzumab mafodotin IB). 
Based on known metabolism and elimination information for denintuzumab mafodotin
(ADC), cys-mcMMAF, rituximab, cyclophosphamide, doxorubicin, vincristine, and 
prednisone, the risk of drug-drug interactions between RCHOP/RCHP components and 
denintuzumab mafodotin is considered low, therefore standard RCHOP/RCHP doses are 
considered appropriate.


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9.2.3
Blinding
This study is not blinded.
9.3 Patient Population
Patients cannot be enrolled or randomized before all inclusion and exclusion criteria 
(including test results) are met.
9.3.1
Inclusion Criteria
Patients MUST satisfy all of the following entry criteria before they will be allowed to 
participate in the study:
1. treatment-naive patients with histologically confirmed systemic de novo or transformed 
DLBCL (from follicular or marginal zone lymphoma), or FL Grade 3b; patients must 
have high-intermediate or high-risk disease based on standard IPI (score ≥3 for patients 
>60 years of age) or aaIPI (score 2 or 3 for patients ≤60 years of age), and stage IAX 
(bulk defined as single lymph node mass >10 cm in diameter)–IV disease
2. tumor tissue available from most recent biopsy to determine COO by IHC using Hans 
algorithm, as assessed by site pathologist.  In addition, tumor tissue must be submitted for 
central pathological review during the trial; if such tissue is not available, a fresh biopsy 
must be obtained.  
3. fluorodeoxyglucose (FDG)-avid disease by positron emission tomography (PET) based 
on the Lugano classification criteria (Cheson, 2014) (Appendix 18.2), and measurable 
disease of at least 1 nodal lesion greater than 1.5 cm in the longest diameter or a 
non-nodal tumor lesion greater than 1.0 cm in the longest diameter by CT, as assessed by 
the site radiologist
4. an Eastern Cooperative Oncology Group (ECOG) performance status ≤2
5. age 18 years or older
6. patients must have the following baseline laboratory data:
a.
bilirubin ≤1.5 × upper limit of normal (ULN) or ≤3 × ULN for patients with Gilbert's 
disease or documented hepatic involvement with lymphoma
b. alanine aminotransferase and aspartate aminotransferase ≤3 × ULN or ≤5 × ULN for 
patients with documented hepatic involvement with lymphoma
c.
creatinine clearance ≥30mL/min (calculated using the Cockcroft-Gault formula) 
d. absolute neutrophil count ≥1000/µL (unless documented bone marrow involvement 
with lymphoma, in which case ANC ≥500/µL)
e.
platelet count ≥75,000/µL (unless documented bone marrow involvement with 
lymphoma, in which case platelets ≥50,000/µL)
f.
urine protein:creatinine ratio (UPC) ratio <1
7. females of childbearing potential must have a negative serum or urine beta human 
chorionic gonadotropin pregnancy test result within 7 days prior to the first dose of study 
drug.  Females of non-childbearing potential are those who are postmenopausal for more 


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than 1 year or who have had a bilateral tubal ligation, hysterectomy, or bilateral 
oophorectomy.
8. 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, as well as 12 months following the last dose of 
rituximab
9. patients must provide written informed consent
9.3.2
Exclusion Criteria
If any of the following apply, the patient MUST NOT enter the study:
1. previous history of treated indolent lymphoma.  Newly diagnosed patients with DLBCL 
who are found to have small cell infiltration of the bone marrow or other diagnostic 
material (representing a discordant lymphoma) are eligible.
2. history of another primary invasive cancer, hematologic malignancy, or myelodysplastic 
syndrome that has not been in remission for at least 3 years (exceptions include 
non-melanoma skin cancer, curatively treated localized prostate cancer, ductal carcinoma 
in situ, and cervical carcinoma in situ by biopsy or a squamous intraepithelial lesion by
papanicolaou smear)
3. history of progressive multifocal leukoencephalopathy (PML)
4. cerebral/meningeal disease related to the underlying malignancy
5. baseline peripheral neuropathy ≥Grade 2 (per the National Cancer Institute’s [NCI]
Common Terminology Criteria for Adverse Events [CTCAE], Version 4.03) or patients 
with the demyelinating form of Charcot-Marie-Tooth syndrome
6. left ventricular ejection fraction less than 45% or symptomatic cardiac disease (including 
symptomatic ventricular dysfunction, symptomatic coronary artery disease, and 
symptomatic arrhythmias), or myocardial infarction within the past 6 months or previous 
treatment with complete cumulative doses of doxorubicin or other anthracyclines
7. patients with the following ocular conditions:
a.
corneal disorders: corneal dystrophies, history of corneal or limbal stem cell 
transplantation (including endothelial keratoplasty), evidence of limbal stem cell 
deficiency (ie, deep pannus, poor epithelial healing)
b. monocular vision (ie, best corrected visual acuity ≥20/200 in one eye)
c.
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
8. any active ≥Grade 3 (per the NCI CTCAE, Version 4.03) 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. females who are breastfeeding
11. known hypersensitivity to any excipient contained in any of the drug formulations of 
study treatments
12. patients with known urinary outflow obstruction


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13. patients with a positive polymerase chain reaction assay who have also tested positive for 
hepatitis B surface antigen and/or anti-hepatitis B core antibody; patients with a negative 
polymerase chain reaction assay are permitted with appropriate anti-viral prophylaxis
14. known or suspected active hepatitis C infection or known human immunodeficiency virus 
infection
9.3.3
Withdrawal and Replacement of Patients
In accordance with the Declaration of Helsinki and applicable regulations, a patient has the 
right to discontinue treatment or withdraw from the study at any time and for any reason 
without prejudice to his or her future medical care by the physician or at the institution.
PRA 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 the electronic Case Report Form (eCRF).
9.3.3.1 Discontinuation of Study Drug
A patient’s treatment with study drug may be discontinued for any of the following reasons:

completed treatment

progressive disease 

adverse event

investigator decision

patient decision, non-adverse event

study termination by Sponsor

other, non-adverse event
The reason for treatment discontinuation will be recorded in the clinical records and the 
eCRF.  All patients who discontinue treatment will undergo an EOT visit (see Section 10.5)
and EOT response assessments (see Section 10.6). These patients will remain on study and
continue to be followed for survival and disease status (see Section 10.7) unless they 
withdraw from study (see Section 9.3.3.2).  Withdrawn/discontinued patients will not be 
replaced.
9.3.3.2
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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Patients who withdraw consent will not be further contacted.  
9.3.3.3 Replacement of Patients
Patients who discontinue from treatment or study will not be replaced.
9.4 Treatment
9.4.1
Treatment Administered
In Part A, patients will be randomized 1:1 to receive denintuzumab mafodotin plus RCHOP or 
denintuzumab mafodotin plus RCHP.  In Part B, patients will be randomized 1:1 to receive 
denintuzumab mafodotin plus either RCHOP or RCHP, or RCHOP alone.  
9.4.2
Investigational Study Drug
Denintuzumab mafodotin, 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 Manual.
9.4.2.1 Description 
Denintuzumab mafodotin is a sterile, preservative-free, white to off-white lyophilized cake or 
powder for reconstitution for IV administration.  Denintuzumab mafodotin is supplied by 
Seattle Genetics in single-use glass vials.  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, 
United States Pharmacopeia, the denintuzumab mafodotin product consists of 5 mg/mL.  The 
pH of the reconstituted product is approximately 6.0.  Before administration, reconstituted 
denintuzumab mafodotin must be diluted.
9.4.2.2
Dose and Administration
Denintuzumab mafodotin at 3 mg/kg will be administered every 6 weeks via IV infusion given 
over approximately 30 minutes to all patients in Parts A and to patients in the Experimental Arm 
in Part B.  The dose of denintuzumab mafodotin may be modified upon recommendation of the 
SMC.  Dosing of denintuzumab mafodotin is based on patient weight obtained according to the 


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institutional standard; however, doses must be adjusted for patients who have a ≥10% change in 
weight from baseline.  If rounding, doses must be rounded to the nearest milligram.
Denintuzumab mafodotin should be administered immediately after and on the same day as 
rituximab (the first component of RCHOP and RCHP). Denintuzumab mafodotin will be 
administered on Day 1 of Cycles 1, 3, and 5 within approximately 30 minutes of completing 
treatment with rituximab (see Section 9.4.3.3 for more details). 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 to 45 minutes).
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.  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.
9.4.2.3
Storage and Handling
Single-use vials containing denintuzumab mafodotin must be stored under refrigeration set to 
2°C 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°C 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°C 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°C to 8°C.  
Drug product vials and solutions should be protected from light until the time of use.  
Reconstituted vials and solutions must not be shaken.
Drug accountability instructions are provided in the Pharmacy Manual.
9.4.2.4
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 and the International 
Nonproprietary Name, or as SGN-CD19A, the compound code; the 2 names can be used 
interchangeably.


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9.4.2.5
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 Manual.
9.4.3
Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone
In Part A, RCHOP or RCHP is administered with denintuzumab mafodotin.  In Part B, either 
RCHOP or RCHP (depending on the evaluation of data from Part A) is administered with 
denintuzumab mafodotin in the Experimental Arm, or RCHOP is administered alone in the 
Comparator Arm.  
9.4.3.1
Description
RCHOP is a standard chemo-immunotherapy regimen consisting of rituximab, 
cyclophosphamide, doxorubicin, vincristine, and prednisone.  RCHP is a modified version 
that omits vincristine.  Rituximab is a CD20-directed cytolytic antibody.  Cyclophosphamide 
is a nitrogen mustard alkylating agent.  Doxorubicin is a cytoxic anthracycline antibiotic.  
Vincristine is a vinca alkaloid with a mechanism of action related to the inhibition of 
microtubule formation in the mitotic spindle.  Prednisone is a synthetic corticosteroid.  
9.4.3.2
Method of Procurement
Agents contained in the RCHOP regimen are commercially available and approved by the 
United States FDA and other regulatory agencies for use in treating patients with multiple 
types of cancer.
Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone 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).
9.4.3.3
Dose and Administration
In Part A, study treatment is six 21-day cycles of either RCHOP or RCHP combined with 
3 doses of denintuzumab mafodotin administered on Day 1 of Cycles 1, 3, and 5. The 
sequence of administration of the different components of the combination therapy should be
the following: rituximab administration should be the first component of RCHOP/RCHP; 
denintuzumab mafodotin administration should be initiated approximately 30 minutes, but no 
longer than 60 minutes, after the completion of rituximab on Day 1; approximately 
30 minutes after the completion of denintuzumab mafodotin the remaining components 
CHOP or CHP should be administered in an order per institutional standard of care.


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In Part B of the Experimental Arm, study treatment is six, 21-day cycles of either RCHOP or 
RCHP (as determined following evaluation of the safety and efficacy data from Part A) with 
3 doses of denintuzumab mafodotin administered on Day 1 of Cycles 1, 3, and 5.  The 
sequence of administration of the different components of the combination therapy should be 
the same as specified in Part A in the paragraph above. Study treatment in the Comparator 
Arm is 6 cycles of RCHOP alone; rituximab should be administered on Day 1 as the first 
component, while the remaining components of RCHOP may be administered as per 
institutional standard of care.
RCHOP:  rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and 
vincristine 1.4 mg/m2 (dose capped at 2 mg total) will be administered IV on Day 1 of every 
21-day cycle together with prednisone 100 mg administered orally on Days 1 to 5 of every 
21-day cycle.  
RCHP:  rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, and doxorubicin 50 mg/m2
will be administered IV on Day 1 of every 21-day cycle together with prednisone 100 mg 
administered orally on Days 1 to 5 of every 21-day cycle.
Dosing should be based on the patient’s baseline (predose, Cycle 1 Day 1) height and weight 
or per institutional standards at the site.
9.4.3.4
Storage and Handling 
Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone should be stored and 
handled per their package inserts.  
9.4.3.5
Packaging and Labeling 
Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone are commercially 
available in the US.
9.4.3.6
Preparation
Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone should be prepared 
per their package inserts.  
9.4.4
Required Premedication and Postmedication
Routine premedication is not necessary for the prevention of infusion-related reactions before 
the first dose of denintuzumab mafodotin.  However, patients who have a Grade 1 or Grade 2 
infusion-related reaction may receive subsequent denintuzumab mafodotin infusions with 
premedication as described in Section 9.4.7.  Patients who have a Grade 3 or Grade 4
infusion-related reaction may potentially receive additional treatment with denintuzumab 
mafodotin at the discretion of the investigator after discussion with the Sponsor.


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Acetaminophen and an antihistamine should be given within 15 to 90 minutes before
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.
There is no protocol-required pre- or post-medications for cyclophosphamide, doxorubicin, 
vincristine or prednisone.  Routine anti-emetic prophylaxis regimen should be administered 
with each cycle of RCHOP or RCHP per institutional standard.
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.
9.4.5
Prophylactic Steroid Eye Drops for Denintuzumab Mafodotin
Prophylactic steroid eye drops must be administered daily for 7 days with each dose of 
denintuzumab mafodotin.  Eye drops should consist of prednisolone 1%, or equivalent, 
administered 4 times daily, 1 drop in each eye.  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 (eg, in the setting of intolerability, contraindication, or toxicity secondary to 
steroid eye drops) upon 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 9.4.9.1 and Table 9-3.  See Section 12.5 for the ocular 
safety monitoring plan.  
Patients should avoid use of contact lenses while on denintuzumab mafodotin.
9.4.6
Concomitant Therapy 
All concomitant medications, blood products, and radiotherapy administered will be 
collected from Day 1 (predose) through the safety reporting period (Section 12.1.3).  Any 
concomitant medication given for a study protocol-related adverse event should be recorded 
from the time of informed consent.
9.4.6.1
Required Concomitant Therapy
Patients with a negative hepatitis B PCR assay who also tested positive for hepatitis B 
surface antigen and/or hepatitis B core antibody must begin antiviral prophylaxis prior to 
receiving study treatment and continue 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.


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See Section 9.4.4 for required rituximab pre- and post-medications. See Section 9.4.5 for 
required denintuzumab mafodotin prophylactic steroid eye drops.
9.4.6.2
Allowed Concomitant Therapy
The use of corticosteroids to treat conditions other than DLBCL is permitted per institutional 
standard.  Systemic corticosteroids may be used to keep DLBCL-related symptoms under 
control prior to Cycle 1 Day 1 as long as the duration of steroid use is no longer than 14 days. 
Routine infectious prophylaxis for Pneumocystis jiroveci pneumonia should be considered 
for all patients per standard of care.  In addition, the JNCCN 2012 guideline for the 
prevention and treatment of cancer-related infections is recommended (Baden, 2012).
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.
The use of transfusions, platelet and/or colony-stimulating factors per the American Society 
of Clinical Oncology guideline for the use of white blood cell growth factors is 
recommended for the management of neutropenia and febrile neutropenia (Smith, 2015).  
Intrathecal prophylactic treatment for cerebral/meningeal disease is permitted at the 
discretion of the investigator.
The use of colony-stimulating factors and/or chemotherapy for stem-cell collection to enable 
a future autologous stem cell transplant (SCT) is permitted per institutional standard.  
Chemo-mobilization of stem cells is only permitted after EOT procedures are completed.
Consolidative radiotherapy or SCT may be given at the investigator’s discretion after EOT 
procedures are completed.  At least 6 cycles of study treatment should be given prior to 
initiating post-treatment consolidative radiotherapy or SCT.
Any other treatment (not explicitly excluded) considered necessary for the subject’s welfare 
may be given at the discretion of the Investigator.  Administration of concomitant 
medications must be reported in the appropriate section of the eCRF along with dates of 
administration and reasons for use.
9.4.6.3
Prohibited Concomitant Therapy
Patients may not receive other investigational drugs, immunosuppressive medications, 
radiotherapy, or systemic anti-neoplastic therapy from Day 1 through EOT (the treatment 
phase of the study).  Exceptions are noted in Section 9.4.6.2.


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9.4.7
Management of Infusion Reactions 
Infusion reactions related to rituximab, cyclophosphamide, doxorubicin, and vincristine
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 a Grade 1 or Grade 2 infusion-related reaction should be 
premedicated for subsequent infusions.  Premedication may include acetaminophen, 
an antihistamine, and a corticosteroid administered 30 to 60 minutes prior to each 
infusion or according to institutional standards.

Patients who have a Grade 3 infusion-related reaction may potentially receive 
additional treatment with denintuzumab mafodotin at the discretion of the investigator 
after discussion with the Sponsor.

If a Grade 4 infusion-related reaction occurs, denintuzumab mafodotin administration 
should be immediately discontinued.  It is recommended that for Grade 4 infusion 
reactions that it be permanently discontinued. Patients may potentially receive 
additional treatment with denintuzumab mafodotin at the discretion of the investigator 
after discussion with the Sponsor.

If anaphylaxis occurs, denintuzumab mafodotin administration should be immediately 
and permanently discontinued.
See Section 12.1.2 for details regarding recording adverse events.
9.4.8
Management of Suspected Progressive Multifocal Leukoencephalopathy
(PML)
Progressive multifocal leukoencephalopathy has been associated with rituximab treatment
(Rituxan Prescribing Information, 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 (RCHOP/RCHP and denintuzumab 
mafodotin) and undertake a diagnostic work-up including (but not limited to):
●
neurologic examinations, as warranted


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●
brain radiologic features by magnetic resonance imaging 
●
PCR analysis: John Cunningham virus DNA detectable in cerebrospinal fluid
If PML is confirmed, permanently discontinue study treatment with denintuzumab mafodotin 
and rituximab.
9.4.9
Dose Modifications
Dose modifications of rituximab, cyclophosphamide, doxorubicin, vincristine, or prednisone 
due to hematologic and non-hematologic toxicity are allowed per institutional standards and 
according to the product-specific United States Prescribing Information, or other relevant
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 RCHOP/RCHP chemo-immunotherapy and 
should not be used as the basis for dose reduction or elimination of denintuzumab mafodotin.  
All patients may receive growth factor support to shorten the duration of neutropenia.  If 
adequate myeloid recovery has not occurred per institutional standard of care, initiation of 
the next cycle may be postponed.  Administration of Cycle 2 onwards should not be delayed 
if there has been adequate recovery of peripheral blood counts (ie, it is recommended that 
absolute neutrophil count is ≥800/μL and platelets is ≥50,000/μL).    
See Table 9-2 for the recommended vincristine dose modifications for treatment-associated 
neuropathy. Doses reduced for treatment-related neuropathy should not be re-escalated 
without discussion with the sponsor.  
Table 9-2:
Recommended Vincristine Dose Modifications for Treatment-associated 
Neuropathy
Gradea of 
Treatment-
Associated 
Neuropathy
Recommended Dose Modification
Sensory Neuropathy
Motor Neuropathy
1
Continue study treatment at same dose level
Continue study treatment at same dose level
2
Continue study treatment at same dose level  Reduce dose levels of vincristinea
3
Hold vincristine; restart vincristineb at 
reduced dose after recovery to Grade 1
Discontinue treatment with vincristine
4
Discontinue treatment with vincristine
Discontinue treatment with vincristine
a Severity of grade is per National Cancer Institute Common Terminology Criteria for Adverse Events v4.03.
b The reduced dose of vincristine is 1 mg.
If RCHOP or RCHP chemo-immunotherapy will be delayed at the start of the subsequent 
cycle due to myelosuppression or other DDT, then denintuzumab mafodotin infusion will be 
delayed as well.  A delay of more than 14 days in starting RCHOP or RCHP in Cycles 2 and 


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beyond is discouraged; delays of more than 21 days are not allowed without discussion with 
the medical monitor.
If RCHOP or RCHP chemo-immunotherapy is discontinued in its entirety, no further 
denintuzumab mafodotin will be given and the patient will be discontinued from study 
treatment.
Denintuzumab mafodotin infusion may be delayed at the start of Cycle 3 or 5 due to ocular 
toxicity (see Section 9.4.9.1). Per-patient dose modifications of denintuzumab mafodotin are 
permitted upon discussion with the medical monitor as described in Section 9.4.9.1. In the 
absence of myelosuppression or other DDT, RCHOP or RCHP chemo-immunotherapy 
should be administered as planned on Day 1 of 3-week cycles.
9.4.9.1
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 
(Appendix 18.3). Table 9-3 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 (ie, dry eyes), preservative-free artificial tears may be 
administered 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 12.5 for additional details of the ocular safety monitoring plan.  Refer to 
Appendix 18.3 for information regarding the grading of ocular events related to the cornea.


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Table 9-3:
Evaluation, Treatment, and Dose Modifications in the Event of Ocular 
Toxicity Associated with Denintuzumab Mafodotin Administration
CTCAEa
Evaluation and Treatment
Dose Modificationsb
Ocular Symptoms
Grade 1
Start administration of preservative-free 
artificial tears
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)
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 combination treatment, 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 combination 
treatment, skip dose of denintuzumab mafodotin for this 
cycle and, with the medical monitor, re-evaluate the timing 
of denintuzumab mafodotin administration at the start of the 
next cycle.  
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).
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 combination treatment, 
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 combination 
treatment, skip dose of denintuzumab mafodotin for this 
cycle and, with the medical monitor, re-evaluate the timing 
of denintuzumab mafodotin administration at the start of the 
next cycle.    
CTCAE = Common Terminology Criteria for Adverse Events  
a
Modified CTCAE grading scheme; see Appendix 18.3.
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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9.4.10
Treatment Compliance
Denintuzumab mafodotin, RCHOP, and RCHP will be administered by qualified study site 
staff, and administration information will be recorded in source documents and the eCRF.
9.4.11
Assignment to Treatment
In Part A, patients will be randomized 1:1 to denintuzumab mafodotin plus RCHOP or 
denintuzumab mafodotin plus RCHP. Patient randomization will be stratified by 
high-intermediate risk or high-risk disease based on IPI (if age >60 years) or aaIPI (if age 
≤60 years).  
In Part B, patients will be randomized 1:1 to receive denintuzumab mafodotin in combination 
with either RCHOP or RCHP or RCHOP alone. Randomization will be stratified by 
high-intermediate risk or high-risk disease and by COO per site pathologist.   
After eligibility is determined patients are randomized within 1 business day prior to the 
planned first dose of Cycle 1, Day 1 of study treatment in Part A and Part B.  Patients will be 
randomly assigned to a treatment arm using a centralized randomization system.
9.5 Efficacy and Safety Variables
9.5.1
Efficacy and Safety Measurements Assessed
Primary Efficacy Variable:
The primary efficacy endpoint is the CR rate at the EOT as determined by investigators.
CR rate is defined as the proportion of patients who achieve complete metabolic response 
(CMR) by PET/CT or CR by CT scans only.  Disease response will be assessed by the 
investigator, based on the Lugano Classification Revised Staging System for malignant 
lymphoma (Cheson, 2014) (Appendix 18.2).  Patients whose disease responses are not 
evaluable/not evaluated will be regarded as non-responders for calculating the CR rate.    
Secondary Efficacy Variables:
The secondary efficacy endpoints are the following:  

EFS

PFS

OS

ORR following the completion of EOT 

duration of objective response

duration of CR


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See Section 13.6.4 for definitions.
9.5.2
Pharmacokinetic and Antitherapeutic Antibody Measurements 
Concentrations of denintuzumab mafodotin ADC and released cys-mcMMAF in plasma and 
ATA in serum will be measured.  Concentrations of rituximab in serum will be measured.  
PK samples will also be collected and archived for possible analysis of other denintuzumab 
mafodotin-related species.
9.5.3
Biomarker Assessments
Biomarker evaluations may include but are not limited to baseline pre- and post-treatment 
peripheral blood evaluation for circulating B cells by flow cytometry for soluble mediator 
quantification, which may include soluble CD19 (sCD19).  Peripheral blood will be collected 
and assessed for cell-free circulating tumor DNA to detect minimal residual disease (MRD).  
Peripheral blood cell pellets will be collected for assessment of Fc-gamma receptor (FcγR) 
polymorphisms.  The evaluation of pre-treatment tumor biopsies may include, but is not 
limited to, therapeutic target CD19 and other immune cell marker expression by IHC, COO
by gene expression profiling, as well as somatic mutations that are prognostic or predictive of 
denintuzumab mafodotin response.
9.5.4
Safety Measurements
Safety assessments will include the evaluation of the type, incidence, severity, seriousness, 
and relatedness of adverse events, and the type, incidence, and severity of laboratory test
abnormalities. Ophthalmologic exams and ocular health surveys will be conducted at 
protocol-specific time points. 
Safety will be monitored over the course of the study by an SMC as described in 
Section 9.1.1.  


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10.
STUDY EVALUATIONS BY VISIT
Adverse events and concomitant medications will be recorded from Day 1 (predose) through 
the safety reporting period (see Section 12.1.3).  Any study protocol-related adverse events
should be recorded from the time of informed consent as well as any concomitant 
medications given for the treatment of the adverse events.  
A schedule of safety and efficacy procedures for the screening and treatment periods is 
provided in Table 18-1. PK, ATA, and biomarker assessments are provided in Table 18-2
(Part A Intense Sampling Schedule), Table 18-3 (Part B Intense Sampling Schedule) and 
Table 18-4 (Part B Sparse Sampling Schedule).
Study activities are listed by visit in this section, and descriptions of all study assessments are 
presented in Section 11 and Section 12.  
10.1
Screening (Days -28 to 1)
The following procedures will be performed within 28 days before beginning treatment:  

informed consent

study eligibility per inclusion/exclusion criteria (Section 9.3)

medical history (includes a review of inflammatory conditions) (Section 11.1)

collection/acquisition of tumor specimen (fresh or archived) for central pathology 
review (eligibility will be assessed using a local pathology lab) (Section 11.5)

IPI or aaIPI score (Section 11.2)

echocardiogram or multigated acquisition (MUGA) scan (Section 12.7)

serology for hepatitis B surface antigen and anti-hepatitis B core antibody; if positive, 
PCR for hepatitis B viremia must also be performed (Section 12.3)

CT scan of diagnostic quality of the neck, chest, abdomen, and pelvis with IV and 
oral contrast (Section 11.6)

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) (Section 11.6)

collection of bone marrow aspirate/biopsy result, if performed as part of standard of 
care; the result from a biopsy collected within 60 days prior to the first dose of study 
treatment should be submitted (Section 11.5)

ophthalmologic exam (Section 9.4.9.1)

ocular health survey (±2 days from the ophthalmology exam) (Section 11.7)

collection of COO/MRD/CD19 tumor tissue (representative tissue from fresh tumor 
specimen for study entry and biomarker analysis.  Archived tumor tissue from the 
initial biopsy is also required; if such tissue is not available, a fresh biopsy must be 
obtained) (see Table 18-2 [Part A Intense Sampling Schedule], Table 18-3 [Part B 
Intense Sampling Schedule], and Table 18-4 [Part B Sparse Sampling Schedule])  


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10.2
Baseline (Days -7 to 1)
The following procedures will be performed within 7 days before beginning treatment:  

electrocardiogram (ECG)

serum or urine pregnancy test for females of childbearing potential (Section 12.3)

B symptom assessment (Section 11.4)

physical examination, height and weight (Section 12.4) 

ECOG performance status (Section 12.6)

serum chemistry panel (Section 12.3)

complete blood count (CBC) with differential (Section 12.3)

prothrombin time (PT)/partial thromboplastin time (PTT)/international normalized 
ratio (INR) (Section 12.3)

spot urine for UPC ratio (Section 12.3)
10.3
Randomization (Day -1 to Day 1)
Randomization is to occur after eligibility is determined and within 1 business day prior to 
the planned first dose of Cycle 1 Day 1 using a centralized randomization system.  
10.4
Treatment Period (Day 1 to Day 21)
Prophylactic steroid eye drops must be administered daily for 7 days with each dose of 
denintuzumab mafodotin.  Eye drop prophylaxis should begin 1 day prior to denintuzumab 
mafodotin dose (see Section 9.4.5).  In Cycle 1, however, if this is not possible then begin the 
prophylaxis on Day 1 of Cycle 1.
10.4.1
Cycles 1, 3, and 5

Day 1 (±1 day), pretreatment (all Day 1 assessments should be completed before 
study drug administration)
o
denintuzumab mafodotin administration (for all patients in Part A and if 
applicable in Part B) 

Note:  Prophylactic steroid eye drop administration required.  Seven 
days of steroid eye drop prophylaxis should begin 1 day prior to 
denintuzumab mafodotin dose (see Section 9.4.5)  

Denituzumab mafodotin administration will be approximately 
30 minutes, but no longer than 60 minutes, following rituximab, after 
which it will then be followed by the remaining components of the 
combination therapy, ie, CHOP or CHP.
o
RCHOP or RCHP (Parts A and B) administration (prednisone on Days 1 to 5)
o
B symptom assessment (not required at Cycle 1 Day 1)
o
physical examination and weight (not required at Cycle 1 Day 1)
o
ECOG (not required at Cycle 1 Day 1)


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o
serum chemistry 
o
CBC with differential 
o
PT/PTT/INR 
o
spot urine for UPC ratio

if UPC >2:  24-hour urine collection (prior to next cycle dosing, or 
prior to EOT visit if discontinuing study treatment)
o
vitals (Section 12.2)
If the Baseline Visit activities occur within 1 day prior to Cycle 1 Day 1, then 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.

Day 8 (± 1 day) and Day 15 (± 1 day)
o
serum chemistry panel
o
CBC with differential
o
spot urine for UPC ratio

if UPC >2:  24-hour urine collection (prior to next cycle dosing, or 
prior to EOT visit if discontinuing study treatment)
10.4.2
Cycles 2, 4, and 6

Day 1 (± 1 day), pretreatment (all Day 1 assessments should be completed before 
study drug administration)
o
RCHOP or RCHP administration (prednisone on Days 1 to 5)
o
B symptom assessment
o
physical examination and weight
o
ECOG performance status
o
serum chemistry
o
CBC with differential
o
PT/PTT/INR
o
spot urine for UPC ratio

if UPC >2:  24-hour urine collection (prior to next cycle dosing, or 
prior to EOT visit if discontinuing study treatment)
o
vitals

Day 8 (± 1 day)
o
serum chemistry
o
CBC with differential
o
spot urine for UPC ratio

if UPC >2:  24-hour urine collection (prior to next cycle dosing, or 
prior to EOT visit if discontinuing study treatment)

Day 15 (± 1 day), pretreatment
o
serum chemistry
o
CBC with differential
o
spot urine for UPC ratio


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
if UPC >2:  24-hour urine collection (prior to next cycle dosing, or 
prior to EOT visit if discontinuing study treatment)
o
ophthalmologic exam (window Day 15 to 21 of Cycles 2, 4, and 6, unless 
alternate schedule is approved by the medical monitor, see Section 12.5.  
Review exam results before next dosing of denituzumab mafodotin; dose 
modifications should be made based on ocular toxicity grading (see 
Appendix 18.3).
o
ocular health survey ± 2 days from the ophthalmology exam
10.4.3
Part A Intense Sampling Schedule – Pharmacokinetic, Antitherapeutic 
Antibody, and Biomarker Assessments
For all patients enrolled in Part A.  
10.4.3.1 Cycles 1 and 3

Day 1, pre-dose
o
denintuzumab mafodotin PK and rituximab PK (Section 11.8)
o
ATA (Section 11.8)
o
biomarker samples – immunophenotyping (IP)/MRD (whole blood),
sCD19/cytokines  (serum/plasma), single-nucleotide polymorphism (SNP)
(cell pellet; Cycle 1 only) (Section 11.8)

Day 1, end of rituximab infusion
o
rituximab PK

Day 1, end of denintuzumab mafodotin infusion
o
denintuzumab mafodotin PK

Day 1, 8 hours after the end of denintuzumab mafodotin infusion
o
denintuzumab mafodotin PK

Days 4, 8, and 15
o
denintuzumab mafodotin PK and rituximab PK
o
biomarker samples - IP/MRD (whole blood), sCD19 /cytokines 
(serum/plasma)

Day 22 (for patients not beginning the subsequent cycle on this day)
o
denintuzumab mafodotin PK and rituximab PK
10.4.3.2 Cycles 2 and 4

Day 1, pre-dose of rituximab
o
denintuzumab mafodotin PK and rituximab PK
o
biomarker samples - IP/MRD (whole blood), sCD19/cytokines 
(serum/plasma)

Day 1, end of rituximab infusion
o
rituximab PK


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
Days 8 and 15
o
denintuzumab mafodotin PK and rituximab PK

Day 22 (for patients not beginning the subsequent cycle on this day)
o
denintuzumab mafodotin PK and rituximab PK
10.4.3.3 Cycles 5 and 6

Day 1, pre-dose
o
denintuzumab mafodotin PK and rituximab PK
o
ATA (for Cycle 5 only)
o
biomarker samples - IP/MRD (whole blood), sCD19/cytokines 
(serum/plasma) 

Day 1, end of rituximab infusion
o
rituximab PK

Day 1, end of denintuzumab mafodotin infusion
o
denintuzumab mafodotin PK

Day 22 (for patients not beginning the subsequent cycle on this day)
o
denintuzumab mafodotin and rituximab PK
10.4.4
Part B Intense Sampling Schedule – Pharmacokinetics, Antitherapeutic, 
Antibody, and Biomarker Assessments
For the first 25 patients enrolled in each arm.
10.4.4.1 Cycles 1 and 3

Day 1, pre-dose
o
denintuzumab mafodotin PK and rituximab PK (Section 11.8)
o
ATA (Section 11.8)
o
biomarker samples - IP/MRD (whole blood), sCD19/cytokines  
(serum/plasma), SNP (cell pellet; Cycle 1 only)  (Section 11.8)

Day 1, end of rituximab infusion
o
rituximab PK 

Day 1, end of denintuzumab mafodotin infusion
o
denintuzumab mafodotin PK 

Day 1, 8 hours after the end of denintuzumab mafodotin infusion
o
denintuzumab mafodotin PK 

Days 4, 8, and 15 
o
denintuzumab mafodotin PK and rituximab PK 
o
biomarker samples - IP/MRD (whole blood), sCD19 /cytokines 
(serum/plasma) 

Day 22 (for patients not beginning the subsequent cycle on this day)
o
denintuzumab mafodotin PK and rituximab PK


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10.4.4.2 Cycles 2 and 4

Day 1, pre-dose of rituximab 
o
denintuzumab mafodotin PK and rituximab PK 
o
biomarker samples - IP/MRD (whole blood), sCD19/cytokines 
(serum/plasma)

Day 1, end of rituximab infusion
o
rituximab PK

Days 8 and 15
o
denintuzumab mafodotin PK and rituximab PK 

Day 22 (for patients not beginning the subsequent cycle on this day)
o
denintuzumab mafodotin PK and rituximab PK
10.4.4.3 Cycles 5 and 6

Day 1, pre-dose
o
denintuzumab mafodotin PK and rituximab PK 
o
ATA (for Cycle 5 only) 
o
biomarker samples - IP/MRD (whole blood), sCD19/cytokines 
(serum/plasma), 

Day 1, end of rituximab infusion
o
rituximab PK 

Day 1, end of denintuzumab mafodotin infusion
o
denintuzumab mafodotin PK 

Day 22 (for patients not beginning the subsequent cycle on this day)
o
denintuzumab mafodotin and rituximab PK
10.4.5
Part B Sparse Sampling Schedule – Pharmacokinetic, Antitherapeutic 
Antibody, and Biomarker Assessments
For the remaining patients in Part B following the first 25 patients enrolled in each arm.  
10.4.5.1 Cycles 1 to 6

Day 1, pre-dose
o
denintuzumab mafodotin PK and rituximab PK
o
ATA (for Cycles 1, 3, and 5 only)
o
biomarker samples - IP/MRD (whole blood), sCD19/cytokines  
(serum/plasma), SNP (cell pellet; cycle 1 only)

Day 1, end of rituximab infusion
o
rituximab PK

Day 1, end of denintuzumab mafodotin infusion
o
denintuzumab mafodotin PK


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
Day 22 (samples obtained only for patients not starting the next cycle on Day 22)
o
denintuzumab mafodotin PK and rituximab PK
10.5
End of Treatment (30 to 37 Days After Last Dose of Study Treatment)
EOT visits should occur 30 to 37 days after the last dose of study treatment. However, EOT 
evaluations must be performed before initiation of a new therapy.  If EOT evaluations are 
completed before 30 days after the last study treatment, the patient will be contacted 30 to 37 
days following the last treatment to assess for adverse events.
At the EOT visit, the following assessments/procedures will be performed:

review of inflammatory conditions (only required for patients with certain 
inflammatory conditions of interest at Screening/Baseline)

ECG

pregnancy test only for females of childbearing potential

B symptom assessment  

physical examination and weight

ECOG performance status

serum chemistry

CBC with differential

PT/PTT/INR

spot urine for UPC ratio
o
if UPC >2:  24-hour urine collection (within 5 days after urine protein 
creatinine PC assessment)

ophthalmologic exam (not required if an exam was performed within 4 weeks prior to
EOT and following the last dose of study treatment)

ocular health survey (± 2 days from the ophthalmology exam)

Blood samples for PK, ATA, and biomarker assessments (see Table 18-2 for Part A 
and Table 18-3 and Table 18-4 for Part B)
10.6
End of Treatment Response Assessment (5 weeks [± 1 week] After Last Dose of 
Study Treatment)
An EOT response assessment will be performed 5 weeks ± 1 week after the last dose of study 
treatment. These procedures can be performed at the same time as the EOT procedures if 
they occur within the appropriate visit window.  At the EOT response assessment visit, the 
following assessments/procedures will be performed:

bone marrow biopsy result, if bone marrow biopsy is performed as part of standard of 
care.  In addition, bone marrow results will be recorded at any time on study if 
performed as part of standard of care.

optional malignant lymphoma biopsy (Note: only for patients who are discontinuing 
treatment due to disease progression and who consent to the procedure.  If a tumor 


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biopsy was performed at the time of disease progression as part of standard of care, 
then submit sample of tumor specimen, if available [see Section 9.5.3])

CT scan of diagnostic quality of the neck, chest, abdomen, and pelvis with IV and 
oral contrast

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) physical 
examination and weight (can be the same as the EOT examination if within the 
appropriate window)
10.7
Long-Term Follow-Up
Patients who discontinue from study treatment will remain on the study for follow-up until 
they withdraw from the study (see Section 9.3.3).

Optional malignant lymphoma biopsy (Note: only for patients who are discontinuing 
treatment due to disease progression and who consent to the procedure.  If a tumor 
biopsy was performed at the time of disease progression as part of standard of care, 
then submit sample of tumor specimen, if available [see Section 9.5.3])

Patients who discontinue study treatment for any reason other than disease 
progression or initiation of a non-protocol therapy for treatment of lymphoma will 
have PET scans and CT scans of diagnostic quality of the neck, chest, abdomen, and 
pelvis with IV and oral contrast every 4 months after the last scan for the first 2 years 
and every 6 months until 48 months and then annually thereafter until disease 
progression, death, or study closure, whichever comes first.  Once disease becomes 
PET negative during the course of the study, PET scans are no longer required and all 
subsequent response assessments can be followed by CT scans of diagnostic quality 
only.

All patients who receive at least one dose of study drug will be followed for survival 
and disease status at 4-month intervals after their last scan for the first 2 years, and at 
6 month intervals until 48 months and then annually thereafter until death or study 
closure, whichever comes first.

MRD will be evaluated at each response assessment for the first year after EOT 
(blood draw)

Information will also be collected regarding subsequent anti-cancer therapies received
Patients who have disease progression or receive alternative NHL treatment will only be 
followed for survival thereafter.
In addition, for patients who develop ocular toxicity during study treatment, ophthalmologic 
exams and ocular health survey should be conducted monthly during the follow-up period 
(unless discussed with the medical monitor) until resolution or return to baseline.


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10.8
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 9.3.3).


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11.
METHOD OF ASSESSMENT
Only patients who meet all inclusion and exclusion criteria specified in Section 9.3 will be 
enrolled in this study.
11.1
Medical History
A full medical history, including a thorough review of significant past medical history and 
current conditions, any treatment for prior malignancies, and any concomitant medications, 
will be performed at screening.  Medical history also included 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.
11.2
International Prognostic Index
For patients >60 years of age at randomization, patient IPI scores should be calculated based 
on the International Non-Hodgkin Lymphoma Prognostic Factors Project (Shipp, 1993) to 
determine eligibility (see Appendix 18.4), and used for randomization into study arms.  The 
IPI is calculated by scoring 5 prognostic factors:  age, stage of disease, lactate dehydrogenase 
(LDH) level, ECOG score, and number of extranodal sites.  For patients who are ≤60 years 
of age at randomization, patient aaIPI scores should be calculated based on the method 
initially published by Shipp et al to be used for randomization (Shipp, 1993; Ziepert, 2010).  
The aaIPI is calculated by scoring 3 prognostic factors: stage of disease, LDH, and ECOG 
score.  
Refer to the Study Manual for details and scoring sheets.
11.3
Lymphoma Disease Stage
Patient disease stage is to be calculated at baseline to determine eligibility, per the Cotswolds 
Modification of Ann Arbor Staging System (Lister, 1989).
11.4
B Symptoms
B symptoms are defined as unexplained fevers >38°C, drenching night sweats, or weight loss 
>10% of body weight.
11.5
Histological Subtype and Cell of Origin Determination
Histologically confirmed DLBCL or FL Grade 3b must be determined by local pathology 
assessment.  Also, COO by IHC using Hans algorithm must be determined by local 
pathologist. Submission of the tumor block or approximately 15 unstained slides from a 
biopsy of disease is required for subsequent central pathology review and evaluation of 
additional molecular biomarkers.  The biopsy specimen must be from a malignant lymph 


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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 additional bone marrow biopsy/aspirate samples are available at baseline, if performed at 
EOT or at progression as part of standard of care, or at any time while the patient is on study 
treatment, a sample will be collected (if available) to evaluate response at the cellular level 
and potential resistant biomarkers (see Section 10.5).  
11.6
Response and Efficacy Assessments
Lymphoma assessments are to be performed at the time points outlined in Section 10 and 
Appendix 18.1.  An adequate focused lymphoma assessment consists of the following:
●
patient medical history, including a thorough review of the patient’s current signs and 
symptoms, including B symptoms (fever, night sweats, or weight loss >10%) and 
concomitant medications
●
physical examination, including evaluation of skin, head, eyes, ears, nose, and throat,
and lymph nodes, heart, lungs, abdomen, back, extremities, and neurology
Radiographic assessments (PET and CT of diagnostic quality of the neck, chest, abdomen, 
and pelvis with IV and oral contrast) will be performed at protocol-specified time points or if 
disease progression is suspected (Appendix 18.2).  After the patient is withdrawn from study 
treatment for any reason, a response assessment will be performed if an assessment has not 
been performed within the prior 6 weeks.  Assessment of lymphoma progression will be 
made according to the Lugano Classification Revised Staging System for malignant 
lymphoma (see Appendix 18.2) (Cheson, 2014).  Treatment decisions by the investigator will 
be based on these assessments.  PET and CT scans are required per protocol as directed in 
Table 18-1.  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.  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, stable disease, partial remission, or complete 
remission 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 
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 


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quality only and evaluated by CT-based response criteria per the Lugano classification 
criteria.  CT and/or PET scans may also be obtained throughout the study if clinically 
indicated.
If cutaneous lesions are the sole site of progressive disease, a biopsy must be obtained to 
histologically confirm progression.
Results from a bone marrow biopsy will be recorded at the screening and/or EOT visit and at 
any time on study, if performed as part of standard of care.  A result from a biopsy performed 
within 60 days of the first dose of study treatment, as part of clinical care, may be submitted 
for the screening visit.  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 collected.  
Bone marrow results will also be collected at any time on study if performed as part of 
standard of care.
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 eCRF source verification.  Copies of all tumor 
imaging studies must be submitted to independent review facility as described in the study 
manual.
11.7
Patient-Reported Outcomes – Ocular Health Survey
The Visual Function Questionnaire 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 10 and should be 
completed at or around the time of each ophthalmology exam (± 2 days).
11.8
Pharmacokinetic and Antitherapeutic Antibody Assessments
Sensitive, qualified assays will be used to measure concentrations of denintuzumab 
mafodotin ADC and released cys-mcMMAF in plasma, and concentrations of rituximab in 
serum.  PK samples will also be collected and archived for possible analysis of other 
denintuzumab mafodotin-related species.  The assays will include enzyme-linked 
immunosorbent assays and liquid chromatography/tandem mass spectrometry assays, as well 
as other assays if further characterization is required.  A qualified electrochemiluminescence 
assay will be used to determine the levels of ATA.
The PK parameters to be estimated include, but are not limited to, maximum plasma/serum
concentration, area under the plasma/serum concentration-time curve, plasma/serum
concentrations at trough, terminal half-life, clearance, steady-state volume of distribution, 
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The ATA incidence rate is defined as the proportion of patients who develop ATA at any 
time during the study.  
  
Pharmacokinetic, ATA, and biomarker samples will be collected at time points outlined in 
Table 18-2 (Part A Intense Sampling Schedule), Table 18-3 (Part B Intense Sampling 
Schedule), and Table 18-4 (Part B Sparse Sampling Schedule). 
11.9
Biomarker Analysis
Samples from patients in both treatment arms in Part A and Part B 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 PD markers of denintuzumab mafodotin activity and compared to that in the
RCHOP Comparator Arm.  Circulating proteins such as sCD19 will be assessed at baseline 
and post treatment to understand their potential prognostic and predictive value to 
denintuzumab mafodotin treatment.  Blood sampling time points for biomarker analyses are 
listed in Table 18-2 (Part A Intense Sampling Schedule), Table 18-3 (Part B Intense 
Sampling Schedule), and Table 18-4 (Part B Sparse Sampling Schedule).
Biomarker evaluation may include but not be limited to baseline pre- and post-treatment 
peripheral blood evaluation for circulating B cells by flow cytometry for soluble mediator 
quantification, which may include sCD19.  Peripheral blood will be collected and assessed 
for cell-free circulating tumor DNA to detect MRD.  Peripheral blood cell pellets will be 
collected for assessment of FcγR polymorphisms.  The evaluation of pre-treatment tumor 
biopsies may include but not be limited to therapeutic target CD19 and other immune cell 
marker expression by IHC, COO by gene expression profiling, and somatic mutations that 
are prognostic or predictive of denintuzumab mafodotin response.
11.9.1
B-Cell Subset 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 PD marker of 
denintuzumab mafodotin activity.  Flow cytometry measurements will include but are not 
limited to the following:  CD3, CD10, CD14, CD19, CD20, CD27, CD38, CD45, CD56, 
CD269, and IgD.
11.9.2
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 patient with 
DLBCL at baseline may be predictive of denintuzumab mafodotin treatment response.  


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Soluble CD19 will be measured pre- and post-treatment with denintuzumab mafodotin to 
understand its value as a potential predictive marker as well as a PD marker.  
Circulating proteins related to tumor burden or other potentially prognostic characteristics of 
the disease may also be monitored.  In addition, MRD evaluation will be carried out to 
understand the depth of response to therapy and may be correlated with PFS and other patient 
outcomes.  Peripheral blood will be collected and assessed for cell-free circulating tumor 
DNA to detect MRD.    
11.9.3
Fc-γ Receptor (FcγR) Variants
Peripheral blood cell pellets will be collected for assessment of 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 
antitumor 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; therefore, enhanced antibody-dependent cellular cytotoxicity in patients 
with high-affinity FcγR variants may contribute to better antitumor activity.
Germline SNPs that may inform efficacy and toxicity may also be explored from patients 
who give optional pharmacogenomics 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.  No additional blood 
draw is necessary.
11.9.4
Characterization of Tumor Tissue
Fresh or archived tumor tissue from initial diagnosis will be collected at screening to evaluate 
biomarkers potentially predictive of response to denintuzumab mafodotin treatment; if such 
tissue is not available, a fresh biopsy must be obtained.  Collection of tumor biopsies/samples 
are not required pre-treatment or during treatment, but if they are collected then they are to 
be submitted.  If a biopsy on residual tumor is performed at EOT 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 10.5).  Tumor biopsies may be evaluated 
for CD19, CD20, CD21, and other immune-cell marker expression by 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 COO and additional gene expression analyses may also be evaluated.  Cell of origin 
gene expression profiling of DLBCL can be used to classify the germinal center B-cell and 
activated B-cell subtypes, which have different prognoses.  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.  If samples are available, correlation of response to 


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denintuzumab mafodotin with rates of these known mutations, as well as immune cell 
infiltrates, may be evaluated.
Refer to the Central Laboratory Manual for information on collection, processing, storage, 
and shipment of samples.
11.10
Biospecimen Samples for Future Research
Any remaining de-identified unused blood and tissue will be retained by Seattle Genetics and 
used for future research for patients who provide consent.  The planned future research 
includes, but is not limited to, the identification of targets for novel ADCs, the biology of 
ADC sensitivity and resistance mechanisms, and the identification of predictive PD
biomarkers of response to ADCs.  Blood and tissue samples donated for future research will 
be retained for 25 years.  Outside the US or if additional consent is not granted, any blood 
and tissue samples remaining after all study testing is completed will be destroyed following 
study closure.
11.11
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.  Adverse events 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 time points 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 time points.
Antitherapeutic antibody 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.


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12.
SAFETY MEASUREMENTS AND VARIABLES
The assessment of safety during the course of this study will consist of the surveillance and 
recording of adverse events including serious adverse events (SAEs), recording of 
concomitant medication and measurements of protocol-specified physical examination 
findings and laboratory tests.  Ophthalmologic examinations and ocular health survey will be 
conducted. 
Safety will be monitored over the course of the study by an SMC as described in 
Section 9.1.1.
12.1
Adverse Events
12.1.1
Definition
Adverse Events
According to the ICH E2A guideline Definitions and Standards for Expedited Reporting, and 
21 CFR 312.32, Investigational New Drug (IND) Safety Reporting, an adverse event is any 
untoward medical occurrence in a patient or clinical investigational patient administered a 
medicinal product and which does not necessarily have a causal relationship with this 
treatment.
The following information should be considered when determining whether or not to record a 
test result, medical condition, or other incident on the Adverse Events and Pre-existing 
Conditions eCRF:
•
From the time of informed consent through the day prior to study Day 1, only study 
protocol-related adverse events should be recorded.  A protocol-related adverse event
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 adverse events (regardless of relationship to study drug) should be recorded from 
study Day 1 (during and postdose) through the end of the safety reporting period (see 
Section 12.1.3.  Complications that occur in association with any procedure (eg, 
biopsy) should be recorded as adverse events whether or not the procedure was 
protocol mandated.  
•
Changes in medical conditions and adverse events, including changes in severity, 
frequency, or character, during the safety reporting period should be recorded.
•
In general, an abnormal laboratory value should not be recorded as an adverse event
unless it is associated with clinical signs or symptoms, requires an intervention, 
results in an SAE, or results in study termination or interruption/discontinuation of 
study treatment.  When recording an adverse event resulting from a laboratory 


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abnormality, the resulting medical condition rather than the abnormality itself should 
be recorded (eg, record “anemia” rather than “low hemoglobin”).
Serious Adverse Events
An adverse event should be classified as an SAE if it meets one of the following criteria:
Fatal:
Adverse event resulted in death
Life threatening:
The adverse event placed the patient at immediate risk of death.  This 
classification does not apply to an adverse event that hypothetically 
might cause death if it were more severe.
Hospitalization:
The adverse event 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 adverse event did not meet any of the above criteria, but could 
have jeopardized the patient and might have required medical or 
surgical intervention to prevent one of the outcomes listed above or 
involves suspected transmission via a medicinal product of an 
infectious agent.
Adverse Event Severity
Adverse event severity should be graded using the NCI CTCAE, version 4.03 
(Appendix 18.6), with the exception of ocular adverse events which will be graded according 
to a modified CTCAE version 4.03 scheme (Appendix 18.3).  The CTCAE criteria are 
provided in the study manual or may be accessed at http://ctep.cancer.gov/reporting/ctc.html.
Adverse event severity and seriousness are assessed independently.  “Severity” characterizes 
the intensity of an adverse event.  “Serious” is a regulatory definition and serves as a guide to 
the Sponsor for defining regulatory reporting obligations (see definition for SAEs).


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Relationship of the Adverse Event to Study Treatment
The relationship of each adverse event to each study drug (denintuzumab mafodotin or any 
component of or protocol-required chemotherapy [ie, rituximab, cyclophosphamide, 
doxorubicin hydrochloride, vincristine sulfate, or prednisone]) should be evaluated by the 
Investigator using the following criteria:
Related:
There is evidence to suggest a causal relationship between the drug 
and the adverse event, such as:
•
An event that is uncommon and known to be strongly 
associated with drug exposure (eg, angioedema, hepatic injury, 
Stevens-Johnson Syndrome)
•
An event that is not commonly associated with drug exposure, 
but is otherwise uncommon in the population exposed to the 
drug (eg, tendon rupture)
Unrelated:
Another cause of the adverse event is more plausible (eg, due to 
underlying disease or occurs commonly in the study population), or a 
temporal sequence cannot be established with the onset of the adverse 
event and administration of the study treatment, or a causal 
relationship is considered biologically implausible
12.1.2
Procedures for Eliciting and Recording Adverse Events
Investigator and study personnel will report all adverse events and SAEs, whether elicited 
during patient questioning, discovered during physical examination, laboratory testing, 
and/or other means by recording them on the eCRF and/or SAE form, as appropriate.
Eliciting Adverse Events
An open-ended or non-directed method of questioning should be used at each study visit to 
elicit the reporting of adverse events.
Recording Adverse Events
The following information should be recorded on the Adverse Events and Pre-existing 
Conditions eCRF:

description including onset and resolution dates

whether it met serious criteria

severity

relationship to study treatment or other causality

outcome


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Diagnosis Versus Signs or Symptoms
In general, the use of a unifying diagnosis is preferred to the listing of individual symptoms. 
Grouping of symptoms into a diagnosis should only be done if each component sign and/or 
symptom is a medically confirmed component of a diagnosis as evidenced by standard 
medical textbooks. If any aspect of a sign or symptom does not fit into a classic pattern of 
the diagnosis, report the individual symptom as a separate adverse event.
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 adverse event. If multiple signs or 
symptoms occur with a given infusion-related event, each sign or symptom should be 
recorded separately with its level of severity.
Recording 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 Section 18.3.
Recording Serious Adverse Events
For SAEs, record the primary event on both the eCRF and an SAE form; events occurring 
secondary to the primary event should be described on the SAE form in the narrative 
description of the case.
The following should be considered when recording SAEs:
•
Death is an outcome of an event. The event that resulted in the death should be 
recorded and reported on both an SAE form and eCRF.
•
For hospitalizations, surgical, or diagnostic procedures, the illness leading to the 
surgical or diagnostic procedure should be recorded as the SAE, not the procedure 
itself. The procedure should be captured in the narrative as part of the action taken in 
response to the illness.
Progression of the Underlying Cancer
Do not use the term “disease progression” when reporting an adverse event, including SAEs,
because it is too general. 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 (eg, “malignant pleural effusion”, “spinal bone metastases”, “lymphadenopathy 
from underlying NHL”, “brain metastases”).  Otherwise, it is acceptable to report the specific 
disease (eg, non-Hodgkin lymphoma) as an SAE.


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Pregnancy
Notification to Drug Safety: Complete a Pregnancy Report Form for all pregnancies that 
occur from the time of first study drug dose until 6 months after the last dose of study 
drug(s), including any pregnancies that occur in the partner of a male study patient. Only 
report pregnancies that occur in a male patient’s partner if the estimated date of conception is 
after the male patient’s first study drug dose. Fax or email the Sponsor’s Drug Safety 
Department within 48 hours of becoming aware of a pregnancy.
All pregnancies will be monitored for the full duration; all perinatal and neonatal outcomes 
should be reported. Infants should be followed for a minimum of 8 weeks.
Collection of data on the eCRF: All pregnancies (as described above) that occur within 
30 days of the last dose of study drug(s) will also be recorded on the Adverse Events and 
Pre-Existing Conditions eCRF.
Abortion, whether accidental, therapeutic, or spontaneous, should be reported as an SAE. 
Congenital anomalies or birth defects, as defined by the ‘serious’ criterion above (see 
definitions Section 12.1.1) should be reported as SAEs.
12.1.3
Reporting Periods for Adverse Events and Serious Adverse Events
The safety reporting period for all adverse events and SAEs is from study Day 1 (predose) 
through the EOT visit or 30 days after the last dose of study treatment (denintuzumab 
mafodotin or any component of or protocol-required chemotherapy [ie, rituximab, 
cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, or prednisone], whichever 
is later).  However, all study protocol-related adverse events are to be collected from the time 
of informed consent. 
All SAEs that occur after the end of safety reporting period (ie, more than 30 days after the 
last dose of study treatment) and are considered treatment-related in the opinion of the 
Investigator should also be reported to the Sponsor.
SAEs will be followed until significant changes return to baseline, the event stabilizes 
(recovering/resolving) or is no longer considered clinically significant by the Investigator, or 
the patient dies or withdraws consent, or study closure. All non-SAEs will be followed 
through the safety reporting period. Certain ongoing non-SAEs of interest (including, but not 
limited to, neuropathy and ocular adverse events) may be followed until resolution, return to 
baseline, or study closure.
12.1.4
Serious Adverse Events Require Immediate Reporting
Within 24 hours of observing or learning of an SAE, Investigators are to report the event to 
the Sponsor, regardless of the relationship of the event to the study treatment regimen.


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For initial SAE reports, available case details are to be recorded on an SAE form. At a 
minimum, the following should be included:

patient number 

date of event onset

description of the event

study treatment, if known
The completed SAE form and SAE Fax Cover Sheet are to be faxed to the Drug Safety 
Department within 24 hours.  Refer to the contact information provided on the SAE report 
form.
Relevant follow-up information is to be submitted to the Sponsor as soon as it becomes 
available.
12.1.5
Sponsor Safety Reporting Requirements 
Investigators are required to report all SAEs, including anticipated SAEs, to the sponsor (see 
Section 12.1.3).
The sponsor will report all SAEs to regulatory authorities as required per local regulatory 
reporting requirements.  In the US, endpoints that assess disease-related mortality or major 
morbidity as well as other SAEs that are not study endpoints, but are known consequences of 
the underlying disease or condition that are anticipated to occur in the study population 
should not be reported to the FDA as individual IND safety reports per the final rule 
amending the IND safety reporting requirements under  21 CFR 312.32 and the FDA’s final 
guidance Safety Reporting Requirements for INDs and Bioavailability and Bioequivalence 
Studies (December 2012) and draft guidance Safety Assessment for IND Safety Reporting 
(December 2015).
In this study, the SAEs that do not require individual IND safety reports are disease 
progression events.  This anticipated SAE 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 arms (denintuzumab mafodotin plus 
either RCHOP or RCHP), then an IND safety report for the SAE will be submitted to the 
FDA.  
The Sponsor or its designee will report relevant SAEs to the relevant regulatory authorities, 
and participating investigators, in accordance with FDA regulations (21 CFR 312.32), ICH 
guidelines, European Clinical Trials Directive (Directive 2001/20/EC), and/or local 
regulatory requirements.
12.2
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should be collected per institutional standard for RCHOP infusion.  For patients who receive
denintuzumab mafodotin and RCHOP or RCHP, vital signs will be measured and recorded 
before 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.
12.3
Clinical Laboratory Tests
Samples will be drawn for local laboratory testing, which 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 time points 
(Table 18-1) during the course of the study:

Serum chemistry panel, including alanine aminotransferase, albumin, alkaline 
phosphatase, aspartate aminotransferase, blood urea nitrogen, calcium, creatinine, 
chloride, glucose, LDH, magnesium, phosphorous, potassium, sodium, total bilirubin, 
and uric acid.  

The CBC with differential is to include the following tests:  white blood cell count 
with five-part differential (neutrophils, lymphocytes, monocytes, eosinophils, and 
basophils), platelet count, hemoglobin, and hematocrit.  Manual differential should be 
completed when clinically indicated.

PT/PTT/INR

Hepatitis B surface antigen and anti-hepatitis B core antibody testing; if positive, 
PCR for hepatitis B viremia must also be performed

A serum or urine beta human chorionic gonadotropin pregnancy test for females of 
childbearing potential

Urine samples will be tested protein and creatinine; these laboratory results will be 
used to calculate a UPC ratio.

24-hour urine collection 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.
Additional laboratory assessments may be performed by certified local laboratories.  
Documentation of certification and laboratory normal ranges will be filed with study 
documentation.
Additional and repeat laboratory safety testing may be performed at the discretion of the 
Investigator.  


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12.4
Physical Examination, Height, and Weight
Physical examinations should include assessment of the following body parts/systems:  
abdomen, extremities, head, heart, lungs, neck, and neurological.  
Body weight will be measured and recorded at baseline and Day 1 of each cycle.  Height will 
be determined at screening to assess body surface area (to be recorded in the eCRF).
12.5
Ocular Monitoring Plan
In order to assess the effects of denintuzumab mafodotin on the eye, patients will have 
complete ophthalmology assessments at protocol-defined time points (Table 18-1).  
Ophthalmology assessments are to include, but are not limited to the following:

visual acuity and slit lamp examination.  

baseline dilated fundus examination is required; subsequent dilated fundus 
examinations are to be conducted as clinically indicated  

corneal epithelium changes must be assessed at each time point  

evaluation of steroid eye drop-induced changes including, but not limited to, 
intraocular pressure measurements and subcapsular cataracts

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 9.4.9.1
and Appendix 18.3) following discussion with the medical monitor.
Ophthalmology exams and ocular health surveys are required at screening, during Cycles 2, 
4, and 6 (Days 15 to 21), EOT (not required if conducted within 4 weeks of EOT, and 
following the last dose of study treatment), and during long-term follow-up.  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.
12.6
ECOG Performance Status
ECOG performance status will be evaluated at protocol-specified time points indicated in 
Table 18-1.  See Appendix 18.5 for the ECOG scale.
12.7
Cardiac Evaluation
Cardiac function will be determined by performing either an echocardiogram or a MUGA 
scan, and an ECG at protocol-specified time points (see Table 18-1).


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13.
DATA MANAGEMENT AND STATISTICAL ANALYSIS
The data management and statistical analysis of this study will be performed by an external 
CRO, PRA Health Sciences.
13.1
Data Management
An eCRF will be used for the current study and a data management plan will be prepared by 
the CRO PRA Health Sciences.  PRA Health Sciences will provide eCRF Completion 
Guidelines for eCRF data entry.  Study specific data management procedures will be 
maintained in the data management plan.  Queries resulting from edit checks and/or data 
verification procedures will be posted electronically in the eCRF.
Previous and concomitant medications will be coded using the latest available World Health 
Organization Drug Reference Dictionary. Coexistent diseases and adverse events will be 
coded using the Medical Dictionary for Regulatory Activities.
13.2
Sample Size Estimation
In Part A of the study, up to approximately 24 patients will be enrolled to receive 
denintuzumab mafodotin with either RCHOP or RCHP (approximately 12 patients per 
treatment arm). With 12 patients in each arm, the probability of observing at least 1 patient 
with a clinically relevant adverse event is 72% if the true event rate is 10%. The probability 
becomes 93% if the true event rate is 20%. In evaluating the grade 3 peripheral neuropathy, 
the observed incidence rate for patients treated with RCHOP is approximately 10%. 
One criterion for selecting the study treatment for Part B of the study is that the addition of 
denintuzumab mafodotin, which is another microtubule inhibitor similar to vincristine, to 
RCHOP should not cause significant additive neurotoxicity, and Grade 3 peripheral 
neuropathy should not exceed 20%.  With 12 patients in each arm, if the true incidence rate is 
15%, the probability of observing at least 3 patients having the event is 26%; if the true 
incidence rate is 25%, this probability becomes 61%.    
In Part B of the study, approximately 136 patients will be randomized 1:1 to each treatment 
arm (approximately 68 patients per treatment arm).  It is assumed that the underlying CR 
rates for the denintuzumab mafodotin plus RCHOP (or RCHP) treatment group is 88% and 
RCHOP treatment group is 70%. With a sample size of 136, an 18% improvement in CR 
rate in the denintuzumab mafodotin plus RCHOP (or RCHP) treatment group would provide 
approximately 80% power. This calculation is based on a 2-sided chi-squared test with 
significance level of alpha = 0.1 using EAST 6.3.1.
13.3
Statistical Analysis Plan
A Statistical Analysis Plan (SAP) will be written and finalized prior to any lock of the study 
database. The SAP will provide a detailed description of the statistical methods and expand 


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on the details provided in the protocol. Additional analyses may be added. Tables, listing 
and figures shells will also be provided.
13.4
Randomization
In Part A, patients will be randomized 1:1 to denintuzumab mafodotin plus RCHOP or 
denintuzumab mafodotin plus RCHP. Patient randomization will be stratified by 
high-intermediate or high-risk disease.  
In Part B, patients will be randomized 1:1 to receive denintuzumab mafodotin in combination 
with either RCHOP or RCHP or RCHOP alone. Randomization will be stratified by high 
intermediate or high-risk disease, and by COO.  
13.5
Analysis Populations
13.5.1
Intent-to-Treat Population 
The intent-to-treat (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. Stratified analyses will be based on the stratification factor as recorded at 
randomization. 
13.5.2
Safety Analysis Set
The safety analysis set will include all patients from Parts A and B who receive any amount 
of denintuzumab mafodotin or any component of RCHOP or RCHP.  Treatment group will 
be determined using the actual treatment received, regardless of the randomization treatment 
assignment.  In Part B, patients who received any amount of denintuzumab mafodotin will be 
assigned to the denintuzumab mafodotin in combination with either RCHOP or RCHP actual 
treatment arm.
13.5.3
Per-Protocol Analysis Set
The per-protocol analysis set will include patients in Part B who received at least of 1 cycle 
of study treatment, and had both a baseline and post-baseline evaluable response assessment 
(per the Lugano classification criteria (Cheson, 2014) (Appendix 18.2) or determination of 
clinical disease progression per the investigator), and no other major protocol deviations that 
affect response assessment.  The per-protocol analysis set is a subset of the ITT analysis set, 
and patients will be grouped in the same manner as the ITT analysis set.


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13.6
Statistical Methods
13.6.1
Missing Data
Missing data will not be imputed, with the exception of missing or partial dates or missing 
response assessments; imputation rules for missing or partial dates will be specified in the 
SAP.  Patients whose responses are not evaluable/not evaluated postbaseline will be counted 
as non-responders in the analysis of CR rate and ORR.
13.6.2
Demographic and Baseline Data
Demographic and baseline data will be summarized descriptively by treatment arm for Part A 
and Part B.  Details will be provided in the Statistical Analysis Plan.  
13.6.3
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 listed.
13.6.4
Efficacy
The efficacy endpoints of response rates (CR rate and ORR) at treatment completion will be 
analyzed based on the ITT analysis set.  CR rate is defined as the proportion of patients who 
achieve CMR by PET/CT or CR by CT.  The ORR is defined as the proportion of patients 
who achieved CMR or partial metabolic response (PMR) by PET/CT, or CR or PR by CT. 
Patients whose response is not evaluable/not evaluated postbaseline will be regarded as 
non-responders.  The response rates will be summarized by descriptive statistics, and exact 
90% confidence intervals (CIs) will be calculated for Part B only. The CR rate comparison 
for Part B only between the 2 treatment arms will be performed using a 
Cochran-Mantel-Haenszel test stratified by the randomization strata at a 2-sided alpha level 
of 0.1.  
EFS, PFS, and OS will be analyzed based on the ITT analysis set for Part B only.  EFS is 
defined as the time from randomization to the first documentation of disease progression, 
investigator-assessed clinical progression, initiation of subsequent anti-cancer therapy, or 
death, whichever is earliest.  PFS is defined as the time from randomization to the first 
documentation of disease progression, investigator-assessed clinical progression, or death, 
whichever is earliest. OS is defined as the time from randomization to death of any cause.  
EFS, PFS, and OS will be summarized using the Kaplan-Meier method.  The median EFS, 
PFS, and OS and their 2-sided 90% CIs using the complementary log-log transformation 
method (Collett, 1994) will be calculated as appropriate.  Hazard ratio may also be estimated 
by the stratified Cox regression model, if appropriate.


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Duration of objective response is defined as the time from the documentation of objective 
response at the EOT assessment to the first documentation of disease progression, 
investigator assessed clinical progression, initiation of subsequent anti-cancer therapy, or 
death, whichever is earliest.  Duration of objective response will be calculated for the 
subgroup of patients achieving CR or PR at the EOT assessment.  
Duration of CR is defined as the time from the documentation of CR at the EOT assessment 
to the first documentation of disease progression, investigator assessed clinical progression, 
initiation of subsequent anti-cancer therapy, or death, whichever is earliest.  Duration of CR 
will be calculated for the subgroup of patients achieving CR at the EOT assessment.  
Duration of OR and CR will be analyzed using the Kaplan-Meier method.  The median 
duration and its 2-sided 90% CI using the complementary log-log transformation method
(Collett, 1994) will be calculated as appropriate. 
As sensitivity analyses, the un-stratified analyses, and the stratified analyses using strata as 
recorded at baseline will be performed.  Efficacy analyses will also be performed based on 
the safety analysis set and the PP analysis set. 
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:

COO (GCB versus non-GCB)

IPI/aaIPI (high-intermediate versus high-risk)
Detailed methodology will be provided in the Statistical Analysis Plan.  
The primary analysis of CR rates between the 2 treatment arms is planned to occur after all 
patients have completed the EOT response assessment, which occurs approximately 5 weeks 
after last study treatment. 
13.6.5
Pharmacokinetics, Antitherapeutic Antibody, and Biomarkers
The individual plasma concentrations of denintuzumab mafodotin ADC and unconjugated 
drug (cys-mcMMAF) and serum concentrations of rituximab will be summarized with 
descriptive statistics at each PK sampling time point. Individual PK parameters will be 
estimated using noncompartmental analysis methods (where data allow), and summarized 
with descriptive statistics for each dose cohort. Additional PK and PK/PD analyses may be 
conducted and presented in a separate report.  
The incidence of ATA to denintuzumab mafodotin will be summarized. The impact of ATA 
on PK, efficacy and safety may be assessed.
The biomarker data will be summarized. 


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13.6.6
Safety
The safety analysis will evaluate the type, incidence, severity, seriousness, and relatedness of 
adverse events, and the type, incidence, and severity of laboratory abnormalities for Parts A 
and B.  The incidence, duration, and resolution of ocular adverse events (Sponsor-defined 
Query Terms) and neuropathy (Standardised Medical Dictionary for Regulatory Activities 
Queries, sensory and motor) will be summarized.  The incidence and severity of 
infusion-related and hypersensitivity reactions will also be summarized. 
13.6.7
Additional Data
All data collected on the eCRFs will be included in data listings. Additional summaries may 
be defined in the SAP.
13.6.8
Interim Analysis
No formal interim analysis is planned for this study.  An SMC will monitor the trial for 
safety and will convene regularly during both parts of the study (for complete details, see 
Section 13.6.9).
An ongoing real-time review of SAEs in both parts of the study will be conducted by the 
Seattle Genetics Program Safety Monitoring Team.  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.
13.6.9
Data Safety Monitoring Committee
Members of the SMC will include the study investigators, medical monitor, and 
biostatistician, and Sponsor’s medical expert.  The primary role of this SMC will be to 
monitor safety data during Part A. 
Formal safety evaluations of cumulative data from both treatment groups will be conducted 
at predefined interim safety evaluations in both Part A and Part B of the study (for complete 
details see Section 9.1.1 for Part A and Section 9.1.2 for Part B).  
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.


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14.
MONITORING PROCEDURES (QUALITY ASSURANCE)
The Sponsor has ethical, legal, and scientific obligations to conduct this study in accordance 
with established research principles and ICH GCP guidelines. As such, in order to fulfill
these obligations and to maintain current of study progress, the Sponsor's monitors or 
representatives will visit the investigative sites during study conduct, with frequency 
dependent on the rate of enrollment and workload at each site, in addition to maintaining 
telephone and written communication. During monitoring visits, the Seattle Genetics 
representative may review regulatory documentation, eCRFs, source documentation, and 
investigational product storage, preparation, and accountability, as applicable.  On-site visits, 
telephone calls, and regular inspection of the CRFs will be conducted in order to assess 
patient enrollment, compliance with protocol procedures, completeness and accuracy of data 
entered on the eCRFs, verification of eCRF data against original source documents, and 
occurrence of adverse events. The Investigator must provide the monitor with full access to 
all source and study 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 Sponsor or its designated monitors and by 
quality assurance auditors, or representatives of regulatory authorities.
14.1
Routine Monitoring
The site must complete the eCRFs in a timely manner and on an ongoing basis to allow 
regular review by the study monitor.
Whenever a patient name is revealed on a document that is to be collected for the Sponsor, 
the name must be blacked out permanently by the site personnel, leaving the initials visible, 
and annotated with the patient number as identification.
14.2
Inspections and Auditing Procedures
The Sponsor or its representative may conduct audits at the investigative sites including, but 
not limited to, drug supply, presence of required documents, the informed consent process, 
and comparison of eCRFs with source documents. All medical records (progress notes) must 
be available for audit. The Investigator agrees to participate with audits conducted at a 
convenient time in a reasonable manner.
Government regulatory authorities may also inspect the Investigator during or after the study. 
The Investigator or designee should contact the Sponsor/CRO immediately if this occurs. 
The Investigator must cooperate fully with regulatory authorities or other audits conducted at 
a convenient time in a reasonable manner.
The purpose of an audit is to assess whether ethics, regulatory and quality requirements are 
fulfilled.


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


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


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


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16.
ADMINISTRATION PROCEDURES
16.1
Regulatory Approval
Seattle Genetics, Inc., or their appointed agents will be responsible for ensuring that 
appropriate regulatory authority approvals are obtained, according to local country
requirements.
No patient may enter the study until this approval has been obtained. A copy of the approval 
(where one is provided, according to local country requirements) will be provided to the 
Investigator and to the IRB(s).
16.2
Protocol Amendments
In accordance with ICH Topic E 6 (R1) Guideline for GCP the Investigator should not 
implement any deviation from, or changes of the protocol without agreement by the Sponsor 
and documented approval from the IRB of a protocol amendment, except where necessary to 
eliminate an immediate hazard(s) to study patients, or when the change(s) involves only 
logistical or administrative aspects of the study (eg, change in monitor[s], change of 
telephone number[s]). 
Any change to the protocol must be handled as a protocol amendment. Any potential 
amendment must be approved by the Sponsor. A written amendment must be submitted to 
the appropriate regulatory authorities and to the IRB assuming this responsibility. The 
Investigator must await IRB approval of protocol amendments before implementing the 
changes, except where necessary to eliminate apparent immediate hazard to patients. In 
these cases, the IRB must be notified within 5 days of the change.
All amendments to the protocol must be approved in writing by both the appropriate 
regulatory authorities and the IRB, except for administrative amendments, which require 
notification but not written approval. Once approved, the protocol amendment will be
distributed to all recipients of the original protocol, with instructions to append the 
amendment to the protocol.
If, in the judgment of the local IRB, the Investigator and/or Sponsor, the protocol amendment 
alters the study design, procedures and/or increases the potential risk to the patient, the 
currently approved written informed consent form will require modification. The modified 
informed consent form must also be reviewed and approved by the Sponsor, appropriate 
regulatory authorities, and the IRB. In such cases, repeat informed consent must be obtained 
from patients enrolled in the study before participation continues.
16.3
Protocol Adherence and Deviations
The protocol must be read thoroughly by all site personnel participating in the trial and the 
instructions must be followed. No routine protocol waivers will be granted. However, 


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exceptions will be made in emergency situations when the protection, safety, and well-being 
of the patient requires immediate intervention based on the judgment of the Investigator or a 
responsible, appropriately trained, and credentialed professional(s) designated by the 
Investigator as a sub-investigator. 
In the event of a significant protocol deviation due to an emergency, accident, or error, the 
Investigator or designee must contact the Medical Monitor at the earliest possible time by 
telephone. This allows for an early joint decision to be made as to whether or not the patient 
should continue study treatment. The Investigator, the Sponsor, and the Medical Monitor 
will document this decision.
16.4
Study Documentation, Privacy, and Records Retention
Government agency regulations and directives require that all study documentation 
pertaining to the conduct of a clinical trial must be retained by the Investigator until notified 
by the Sponsor in writing that retention is no longer necessary.
To protect the safety of participants in the study and to ensure accurate, complete, and 
reliable data, the Investigator will keep records of laboratory tests, clinical notes, and patient 
medical records in the patient files as original source documents for the study. If requested, 
the Investigator will provide the Sponsor, its licensees and collaborators, applicable 
regulatory agencies, and the applicable IRB with direct access to original source documents 
or certified copies.
Records containing patient medical information must be handled in accordance with the 
requirements of the Health Information Portability and Accountability Act Privacy Rule and 
be consistent with the terms of the patient authorization contained in the informed consent 
document for the study (the Authorization). Care should be taken to ensure that such records 
are not shared with any person or for any purpose not contemplated by the Authorization. 
Furthermore, case report forms and other documents to be transferred to the Sponsor should 
be completed in strict accordance with the instructions provided by the Sponsor, including 
the instructions regarding the coding of patient identities.
In compliance with local and/or regional regulations, this trial may be registered and trial 
results may be posted on public registries, such as ClinicalTrials.gov.
16.5
Publication Policy
The details of the processes of producing and reviewing publications and presentations based 
on the data from this study will be described in the Clinical Trial Agreement between Seattle 
Genetics, Inc., and the institution of the Investigator.


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16.6
Clinical Study Report
A final clinical study report will be prepared according to the ICH guideline on Structure and 
Contents of Clinical Study Reports.  A final clinical study report will be prepared regardless 
of whether the study is completed or prematurely terminated. 
16.7
Contractual and Financial Details
The Investigator (and/or, as appropriate, the hospital administrative representative) and the 
Sponsor will sign a clinical study agreement prior to the start of the study, outlining overall 
Sponsor and Investigator responsibilities in relation to the study. The contract should 
describe whether costs for pharmacy, laboratory, and other protocol-required services are 
being paid directly or indirectly. 
16.8
Insurance, Indemnity, and Compensation
Seattle Genetics, Inc. undertakes to maintain an appropriate clinical study insurance policy.
Deviations from the study protocol - especially the prescription of a dose other than that 
scheduled in the study protocol, other modes of administration, other indications, and longer 
treatment periods - are not permitted and shall not be covered by the statutory patient 
insurance scheme.
16.9
Discontinuation of the Study
This study may be terminated by the Sponsor. The study may also be terminated prematurely 
at any time when agreed to by both the Investigator and the Sponsor as being in the best 
interests of patients and justified on either medical or ethical grounds. In terminating the 
study, Seattle Genetics, Inc., the CRO (PRA Health Sciences), and the Investigator will 
ensure that adequate consideration is given to the protection of the patients’ interests.
16.10
Study Center File Management
The Investigator is responsible for assuring that the Study Center File is maintained. The 
Study Center File will contain, but will not be limited to, the information listed below:
1. Investigator’s Brochure
2. current, signed version of the protocol and any previous versions of the protocol
3. protocol amendments (if applicable)
4. operations manual (if applicable)


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5. current informed consent form (blank) and any previous versions of the informed 
consent form
6. curricula vitae of Investigator(s) and sub-Investigator (s) and photocopy of their 
respective license(s) where required by law; Original US FDA Form 1572 (for all 
studies conducted under US IND regulations), signed by all Principal Investigators. 
The names of any sub-Investigators must appear on this form. Investigators must also 
complete all regulatory documentation as required by ICH GCP and by local or 
national regulations
7. documentation of IRB approval of the protocol, the informed consent form, any 
protocol amendments, and any informed consent form revisions
8. all correspondence between the Investigator, IRB, and the Sponsor/CRO relating to 
study conduct
9. laboratory certification(s)
10. monitoring log
11. study drug invoices
12. site signature and duty delegation log


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17.
REFERENCE LIST
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Cancer Society, 2015.  Available at: http://www.cancer.org.  Accessed 30 Decembers 2015.
American Cancer Society. Cancer Treatment and Survivorship Facts & Figures 2014-2015. 
Atlanta, GA US: American Cancer Society. 2014. Available at: http://www.cancer.org. 
Accessed 04 February 2016.
Armitage JO, Weisenburger DD. New approach to classifying non-Hodgkin's lymphomas: 
clinical features of the major histologic subtypes.  Non-Hodgkin's Lymphoma Classification 
Project.  J Clin Oncol. 16 (8): 2780-95, 1998.
Baden LR, Bensinger W, Angarone M, et al.  Prevention and treatment of cancer-related 
infections.  J Natl Compr Canc Netw. 10:1412-1445, 2012.    
Bryder D, Sigvardsson M.  Shaping up a lineage-lessons from B lymphopoesis. Curr Opin 
Immunol.  22: 148-53. 2010.
Cancer Research UK.  Different types of non-Hodgkin lymphoma.  London, UK.  Available 
at:  http://www.cancerresearchuk.org/about-cancer/type/non-hodgkins-
lymphoma/about/types/the-most-common-types-of-non-hodgkins-lymphoma.  Accessed 05 
November 2015.    
Cheson BD, Fisher RI, Barrington SF, et al.  Recommendations for Initial Evaluation, 
Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano 
Classification.  J Clin Oncol. 32(27): 3059-67, 2014.
Chu PG, Chen YY, Molina A, et al.  Recurrent B-cell neoplasms after rituximab therapy: an 
immunophenotypic and genotypic study.  Leuk Lymphoma. 43: 2335-41, 2002.
Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with 
CHOP alone in elderly patients with diffuse large-B-cell lymphoma.  N Engl J Med. 346 (4): 
235-42, 2002. 
Collett D. Modeling Survival Data in Medical Research, London: Chapman & Hall. 1994
Cunningham D, Smith P, Mouncey P, et al. R-CHOP14 versus R-CHOP21: result of a 
randomized phase III trial for the treatment of patients with newly diagnosed diffuse large 
B-cell non-Hodgkin lymphoma.  J Clin Oncol 29:504s, abstr 8000, 2011.
Cyclophosphamide Prescribing Information, Baxter, March 2013.
Del Nagro CJ, Otero DC, Anzelon AN, et al. CD19 function in central and peripheral B-cell 
development. Immunol Res. 31:119-31, 2005.
Dreyling M, Ghielmini M, Marcus R, et al.  Newly diagnosed and relapsed follicular 
lymphoma:  ESMO clinical practice guidelines for diagnosis, treatment and follow-up.  Ann 
Oncol 22(6): vi59-vi63, 2011.    
Doxorubicin Prescribing Information, Pfizer, October 2013.  
Echeverri C, Fisher S, King D et al.  Immunophenotypic variability of B-cell non-Hodgkin 
lymphoma: a retrospective study of cases analyzed by flow cytometry. Am J Clin Pathol. 
117: 615-20, 2002.
FDA.  U.S. Department of Health and Human Services Food and Drug Administration.  
Safety Assessment for IND Safety Reporting.  December 2015.  Available at:  


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http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/u
cm477584.pdf    
FDA.  U.S. Department of Health and Human Services Food and Drug Administration.  
Safety Reporting Requirements for INDs and Bioavailability and Bioequivalence Studies.  
December 2012.  Available at:  
http://www.fda.gov/downloads/Drugs/.../Guidances/UCM227351.pdf
FDA.  U.S. Department of Health and Human Services Food and Drug Administration.  
Guidance for Industry Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics.  May 2007.  Available at:  
http://www.fda.gov/downloads/Drugs/.../Guidances/ucm071590.pdf
Gervasi F, Lo Verso R, Giambanco C, et al. Flow cytometric immunophenotyping analysis 
of patterns of antigen expression in non-Hodgkin’s B cell lymphoma in samples obtained 
from different anatomic sites. Ann N Y Acad Sci. 1028: 457-62. 2004.
Gisselbrecht C, Glass B, Mounier N, et al. Salvage regimens with autologous transplantation 
for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol. 28: 4184-90, 2012.  
Hamlin PA, Zelenetz AD, Kewalramani T, et al. Age-adjusted International Prognostic Index 
predicts autologous stem cell transplantation outcome for patients with relapsed or primary 
refractory diffuse large B-cell lymphoma. Blood. 2003;102:1989–96.
Huh YO, Ibrahim S.  Immunophenotypes in adult acute lymphocytic leukemia:  role of flow 
cytometry in diagnosis and monitoring of disease. Hematol Oncol Clin North Am. 14: 
1251-1265, 2000.
Legha SS.  Vincristine neurotoxicity.  Pathophysiology and management.  Med Toxicol. 1: 
421-427, 1986.  
Lister TA, Crowther D, Sutcliffe SB, et al.  Report of a committee convened to discuss the 
evaluation and staging of patients with Hodgkin’s disease:  Cotswolds meeting. J Clin Oncol 
7: 1630-1636, 1989.
Lymphoma Research Foundation.  Follicular Lymphoma.  New York, NY.  Available at:  
http://www.lymphoma.org/site/pp.asp?c=bkLTKaOQLmK8E&b=6300155.  Accessed 05 
November 2015.    
Mangione CM, Lee PP, Gutierrez PR, et al. National Eye Institute Visual Function 
Questionnaire Field Test I. Development of the 25-item National Eye Institute Visual 
Function Questionnaire.  Arch Ophthalmol.  119: 1050-8, 2001.
Moskowitz CH, Fanale MA, Shah BJ, et al.  A phase 1 study of denintuzumab mafodotin 
(SGN-CD19A) in relapsed/refractory B-lineage non-Hodgkin lymphoma.  57th American 
Society of Hematology Annual Meeting and Exposition, Orlando FL USA.  Abstract 182; 06 
December 2015.   
Pfreundschuh M, Schubert J, Zipert M, et al. Six versus eight cycles of bi-weekly CHOP-14 
with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a 
randomised control trial (RICOVER-60).  Lancet Oncol. 9: 105-116, 2008.  
Prednisone Prescribing Information, Horizon Pharma USA, June 2013.  
Rituxan Prescribing Information, Genentech, September 2013.


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Rodriguez, MA, Pytlik R, Kozak T, et al.  Vincristine sulfate liposomes injection (Marqibo) 
in heavily pretreated patients with refractory aggressive non-Hodgkin lymphoma: report of 
the pivotal phase 2 study.  Cancer.  115: 3475-3482, 2009.  
Shipp MA. A predictive model for aggressive non-Hodgkin's lymphoma. The International 
Non-Hodgkin′s Lymphoma Prognostic Factors Project. N Engl J Med. 329:987–994, 1993.
Smith TJ, Bohlke K, Lyman GH et al. Recommendations for the use of WBC growth factors: 
American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 33 
(28): 3199-3212. 2015.
Swerdlow SH, Campo E, Harris NL, et al.  Chapter 10: mature B-cell neoplasms.  WHO 
classification of tumours of haematopoietic and lymphoid tissues.  Lyon, France, 
International Agency for Research on Cancer: 179-268, 2008. 
Tangun Y, Atamer T.  More on vincristine in treatment of ITP.  N Engl J Med.  297:  894, 
1977.    
Tilly H, Vitolo U, Walewski J.  Diffuse large B-cell lymphoma (DLBCL):  ESMO clinical 
practice guidelines for diagnosis, treatment and follow-up.  Ann Oncol.  22(6):vi59-vi63.    
Tobias JD, Bozeman PM.  Vincristine-induced recurrent laryngeal nerve paralysis in 
children.  Intensive Care Med.  17:304-305, 1991.  
Van Epps HA, Klussman K, Anderson M, et al.  Preclinical results of SGN-CD19A in 
combination with R-ICE or R-CHOP in non-Hodgkin lymphoma models.  American 
Association for Cancer Research Annual Meeting 2015, Philadelphia, PA USA.  
Abstract 2541; 18-22 April 2015.    
Vincristine Prescribing Information, Hospira, July 2013.  
World Medical Association, Inc.  Declaration of Helsinki – Ethical principles for medical 
research involving human subjects.  Ferney-Voltaire, France.  WMA The World Medical 
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Accessed 02 December 2015.  
Ziepert M, Hasenclever D, Kuhnt E, et al. Standard International Prognostic Index remains a 
valid predictor of outcome for patients with aggressive CD20+ B-cell lymphoma in the 
rituximab era. J Clin Oncol. 28:2373–2380, 2010.


 
 
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18. 
APPENDICES 
18.1 
Schedule of Events 
Table 18-1: 
Study Schedule 
Page 1 of 2 
Please refer to footnotes on the following page. 
SCHEDULE OF EVENTS 
Screening Baseline 
Enrollment 
Cycles 1, 3, & 5 
Cycles 2, 4, & 6 
EOTH 
EOT 
Response 
Assessment 
Long-
term 
follow-
up 
Visit Window 
D –28 to 1 
D –7 to 1 
D –7 to 1 
D1  
(±1 day) 
D8  
(±1 day) 
D15  
(±1 day) 
D1  
(±1 day) 
D8  
(±1 day) 
D15  
(±1 day) 
30+7 days 
post last 
dose 
5 wks  
(±1 wk)  
post last dose 
Q4 mos  
after last 
scan for 
1st 2 yrs 
then Q6 
mosR 
Screening/ 
Baseline 
Assessments 
Informed consent 
X 
 
Eligibility documentation submitted to  
Sponsor prior to study start 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
Inflammatory conditions review 
X 
 
 
 
 
 
 
 
XQ 
 
 
Tumor specimen 
collection/acquisitionI 
X 
 
 
 
 
 
 
 
 
 
 
IPI or age-adjusted IPI score 
X 
 
 
 
 
 
 
 
 
 
 
Height  
 
X 
 
 
 
 
 
 
 
 
 
Electrocardiogram 
 
X 
 
 
 
 
 
 
X 
 
 
Echo or MUGA scan 
X 
 
 
 
 
 
 
 
 
 
 
Serology for hepatitis BJ 
X 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
 
X 
 
 
 
 
 
 
X 
 
 
Treatment 
Denintuzumab mafodotinD   
 
 
X 
 
 
 
 
 
 
 
 
RCHOP or RCHP 
 
 
X 
 
 
XU 
 
 
 
 
 
Research 
SampleA 
PK/ATA samples 
 
 
See Table 18-2 to Table 18-4 
X 
 
Soluble CD19 
 
 
 
Biomarker blood samples 
 
 
 
MRD 
 
 
XV 
Biomarker bone marrow sample 
 
 
 
 
 
 
 
 
 
XR 
 
Optional malignant lymphoma 
biopsy 
 
 
 
 
 
 
 
 
 
XS 
XS 
Response 
Assessments 
CT (neck, chest, abdomen, 
pelvis)B, C 
X 
 
 
 
 
 
 
 
 
XG 
X 
PETC 
X 
 
 
 
 
 
 
 
 
XG 
XF 
Bone marrow aspirate/biopsy E 
XE 
 
 
 
 
 
 
 
 
 
 
B symptoms 
 
X 
XP 
 
 
X 
 
 
X 
 
 
Survival status  
 
 
 
 
 
 
 
 
 
 
X 


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Table 18-1:
Study Schedule
Page 2 of 2
ATA = antitherapeutic antibodies; CBC = complete blood count; CT = computerized tomography; D = day; echo = echocardiogram; ECOG = Eastern Cooperative Oncology Group; EOT = end of treatment; INR = 
international normalized ratio; IPI = International Prognostic Index; IV = intravenous; mos = months; MRD = minimal residual disease; MUGA = multigated acquisition scan; PET = positron emission tomography; 
PK = pharmacokinetics; PT = prothrombin time; PTT = partial thromboplastin time; RCHOP = rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate; prednisone; RCHP = rituximab, 
cyclophosphamide, doxorubicin hydrochloride, prednisone; UPC = urine protein creatinine; wk = week(s); Q = every
A.  Refer to Table 18-2 to Table 18-4 for sampling schedules.
B.  Diagnostic quality CT of neck, chest, abdomen, and pelvis with IV and oral contrast.
C.  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.
D.  All patients in Part A and if applicable in Part B.  Note:  Prophylactic steroid eye drop administration required.  Seven days of steroid eye drop prophylaxis should begin 1 day prior to denintuzumab mafodotin.  
Denintuzumab mafodotin administration will be approximately 30 minutes, but no longer than 60 minutes, following rituximab, after which it will then be followed by the remaining components of the 
combination therapy, ie, CHOP or CHP.    
E.  If performed as part of standard of care; the result from a biopsy collected within 60 days prior to the first dose of study treatment should be submitted
F.  If PET scan negativity was previously achieved during the course of the study, PET scans are not required during long-term follow-up and/or can be discontinued once PET scan negativity is achieved during 
long-term follow-up.  Instead, CT scans only are acceptable.
G.  Should be obtained if not done within the previous 6 weeks.
H.  EOT evaluations should be done before initiation of non-protocol therapy.  If done <30 days after the last dose of study treatment, conduct a phone screen 30 to 37 days post last treatment to ensure no change in 
the adverse event profile has occurred.  EOT and EOT response assessments can be performed at the same time if it is within the 30 to 37 day window.
I.  Tumor specimen (fresh or archived) must be submitted for central pathology review (eligibility will be assessed using a local pathology lab).
J.  Hepatitis B surface antigen and anti-hepatitis B core antibody; if positive, PCR for hepatitis B viremia must also be performed
K.  Window Day 15 to 21 of Cycles 2, 4, and 6.
L.  Not required if conducted within 4 weeks of EOT, and following the last dose of study treatment.
M. In the event of ocular toxicity, continue at least monthly in follow up until resolution or return to baseline.
N.  Prior to next cycle dosing or within 5 days of UPC if discontinuing study treatment.  
O. If baseline activities occur within 1 day prior to Cycle 1 Day 1, assessment does not need to be repeated.
P.  Not required at Cycle 1 Day 1.
Q.  Only required for patients with certain inflammatory conditions of interest at Screening/Baseline.
R.  Recorded if bone marrow biopsy is performed as part of standard of care.  In addition, bone marrow results will be recorded at any time on study if performed as part of standard of care.
SCHEDULE OF EVENTS
Screening
Baseline
Enrollment
Cycles 1, 3, & 5
Cycles 2, 4, & 6
EOTH
EOT
Response 
Assessment
Long-
term 
follow-
up
Visit Window
D –28 to 1
D –7 to 1
D –7 to 1
D1 
(±1 day)
D8 
(±1 day)
D15 
(±1 day)
D1 
(±1 day)
D8 
(±1 day)
D15 
(±1 day)
30+7 days 
post last 
dose
5 wks 
(±1 wk) 
post last dose
Q4 mos 
after last 
scan for 
1st 2 yrs 
then Q6 
mosR
Safety 
Assessments
Physical exam and weight
X
XP
X
X
X
ECOG
X
XP
X
X
Serum chemistry
X
XO
X
X
X
X
X
X
CBC with differential
X
XO
X
X
X
X
X
X
PT/PTT/INR
X
XO
X
X
Spot urine for UPC ratio
X
XO
X
X
X
X
X
X
24-hr urine collection if UPC >2
XN,O
XN
XN
XN
XN
XN
XN
Vitals
X
X
Ophthalmologic exam
X
XK
XL
XM
Ocular health survey
XT
XT
XL,T
XM
Concomitant medication & 
adverse events
Collect any related to 
study procedures
Collect from Day 1 (predose) thru 30 days post last dose or EOT visit, whichever is later


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S.  Only for patients who are discontinuing treatment due to disease progression and who consent to the procedure. If a tumor biopsy was performed at the time of disease progression as part of standard of care, then 
submit sample of tumor specimen, if available.  
T.  ±2 days from the ophthalmology exam
U.  Prednisone on Days 1 to 5
V.  Collected for the first year of follow-up only. 


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Table 18-2:
Part A Intense Sampling Schedule – Pharmacokinetics, Antitherapeutic Antibody, and Biomarker Assessment -
(For all Patients enrolled in Part A)
Biomarker Samples
COO/MRD/CD19 –
Tumor Tissue
Blood Samples
Study Day
Time
Window
Relative TimeA
Denintuzumab 
mafodotin PKB Rituximab 
PK
ATA
IP/MRD –
Whole Blood
sCD19/
Cytokines –  
Serum/Plasma
SNP –
Cell Pellet
Screening/ 
Baseline
Day
–28 to 1
N/A
N/A
N/A
XC
Cycles 1, 3
Day 1
Pre-dose
Within 8 hrs prior 
to start of infusionE
Start of infusion
X
X
XF
X
X
XG
End of rituximab 
infusion
Within 5 min post 
end of infusion
End of infusion
X
End of 
denintuzumab 
mafodotin infusion
Within 5 min post 
end of infusion
End of infusion
X
8 hr after the end of 
denintuzumab 
mafodotin infusion
± 30 min
End of infusion
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
Day 15
336 hr
± 24 hr
Start of infusion
X
X
X
X
Day 22D
504 hr
± 24 hr
Start of infusion
X
X
Cycles 2, 4
Day 1
Pre-dose of 
rituximab
Within 8 hr
Start of infusion
X
X
X
X
End of rituximab 
infusion
Within 5 min post 
end of infusion
End of infusion
X
Day 8
168 hr
± 24 hr
Start of infusion
X
X
Day 15
336 hr
± 24 hr
Start of infusion
X
X
Day 22D
504 hr
± 24 hr
Start of infusion
X
X
Cycles 5, 6
Day 1
Pre-dose
Within 8 hr
Start of infusion
X
X
XF
X
X
End of rituximab 
infusion
Within 5 min post 
end of infusion
End of infusion
X
End of 
denintuzumab 
mafodotin infusion
Within 5 min post 
end of infusion
End of infusion
X
Day 22D
504 hr
± 24 hr
Start of infusion
X
X
EOT
X
X
X
XH
X
X
Please refer to footnotes on the following page.


Study SGN19A-004
Protocol V01
18 February 2016
Denintuzumab mafodotin
Seattle Genetics, Inc. – Confidential
Page 89 of 99
ATA = antitherapeutic antibodies; COO = cell or origin; EOT = end of treatment; IP = immunophenotyping; MRD = minimal residual disease; N/A = not applicable; PK = pharmacokinetics; sCD19 = soluble CD19; 
SNP = single-nucleotide polymorphism
A.  For patients receiving denintuzumab mafodotin plus RCHOP or RCHP: odd-cycle relative time is based on the denintuzumab mafodotin infusion, except the rituximab PK samples at the end of 
rituximab infusion; even-cycle relative time is based on the rituximab infusion.  
B.  For patients receiving denintuzumab mafodotin plus RCHOP or RCHP.
C.  Representative tissue from fresh tumor specimen for study entry and biomarker analysis.  If available, archived tumor tissue from the initial biopsy is also required.
D.  Sample obtained only for patients not starting the next cycle on that day 
E.  Cycle 1 Day 1 pre-dose window is 24 hours.
F.  For Cycles 1, 3 and 5 only
G.  For Cycle 1 only
H.  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.


Study SGN19A-004
Protocol V01
18 February 2016
Denintuzumab mafodotin
Seattle Genetics, Inc. – Confidential
Page 90 of 99
Table 18-3:
Part B Intense Sampling Schedule – Pharmacokinetics, Antitherapeutic Antibody, and Biomarker Assessments
– (For the First 25 Patients in Each Arm)
Biomarker Samples
COO/MRD/CD19 –
Tumor Tissue
Blood Samples
Study Day
Time
Window
Relative TimeA
Denintuzumab 
mafodotin PKB Rituximab 
PK
ATA
IP/MRD –
Whole Blood
sCD19/
Cytokines –  
Serum/Plasma
SNP –
Cell Pellet
Screening/ 
Baseline
Day
–28 to 1
N/A
N/A
N/A
XC
Cycles 1, 3
Day 1
Pre-dose
Within 8 hrs prior 
to start of infusionE
Start of infusion
X
X
XF
X
X
XG
End of rituximab 
infusion
Within 5 min post 
end of infusion
End of infusion
X
End of 
denintuzumab 
mafodotin infusion
Within 5 min post 
end of infusion
End of infusion
X
8 hr after the end of 
denintuzumab 
mafodotin infusion
± 30 min
End of infusion
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
Day 15
336 hr
± 24 hr
Start of infusion
X
X
X
X
Day 22D
504 hr
± 24 hr
Start of infusion
X
X
Cycles 2, 4
Day 1
Pre-dose of 
rituximab
Within 8 hr
Start of infusion
X
X
X
X
End of rituximab 
infusion
Within 5 min post 
end of infusion
End of infusion
X
Day 8
168 hr
± 24 hr
Start of infusion
X
X
Day 15
336 hr
± 24 hr
Start of infusion
X
X
Day 22D
504 hr
± 24 hr
Start of infusion
X
X
Cycles 5, 6
Day 1
Pre-dose
Within 8 hr
Start of infusion
X
X
XF
X
X
End of rituximab 
infusion
Within 5 min post 
end of infusion
End of infusion
X
End of 
denintuzumab 
mafodotin infusion
Within 5 min post 
end of infusion
End of infusion
X
Day 22D
504 hr
± 24 hr
Start of infusion
X
X
EOT
X
X
X
XH
X
X
Please refer to footnotes on the following page.


Study SGN19A-004
Protocol V01
18 February 2016
Denintuzumab mafodotin
Seattle Genetics, Inc. – Confidential
Page 91 of 99
ATA = antitherapeutic antibodies; COO = cell or origin; EOT = end of treatment; IP = immunophenotyping; MRD = minimal residual disease; N/A = not applicable; PK = pharmacokinetics; sCD19 = soluble CD19; 
SNP = single-nucleotide polymorphism
A.  For patients receiving denintuzumab mafodotin plus RCHOP or RCHP: odd-cycle relative time is based on the denintuzumab mafodotin infusion, except the rituximab PK samples at the end of 
rituximab infusion; even-cycle relative time is based on the rituximab infusion.  For patients receiving RCHOP: relative time is based on the rituximab infusion for all cycles.  
B.  For patients receiving denintuzumab mafodotin plus RCHOP or RCHP.
C.  Representative tissue from fresh tumor specimen for study entry and biomarker analysis.  If available, archived tumor tissue from the initial biopsy is also required.
D.  Sample obtained only for patients not starting the next cycle on that day 
E.  Cycle 1 Day 1 pre-dose window is 24 hours.
F.  For Cycles 1, 3 and 5 only
G.  For Cycle 1 only
H.  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.


Study SGN19A-004
Protocol V01
18 February 2016
Denintuzumab mafodotin
Seattle Genetics, Inc. – Confidential
Page 92 of 99
Table 18-4:
Part B Sparse Sampling Schedule – Pharmacokinetics, Antitherapeutic Antibody, and Biomarker Assessments –
(For the Remaining Patients in Part B Following the First 25 Patients Enrolled in Each Arm)  
Biomarker Samples
COO/MRD/
CD19 –
Tumor Tissue
Blood Samples
Study 
Day
Time
Window
Relative TimeB
Denintuzumab 
mafodotin PKC Rituximab 
PK
ATA
IP/MRD –
Whole Blood
sCD19/
Cytokines –
Serum/Plasma
SNP –
Cell Pellet
Screening
/ Baseline
Day
–28 to 1
N/A
N/A
N/A
XD
Cycles
1-6
Day 1
Pre-dose
Within 8 hrs prior to 
start of infusionA
Start of infusion
X
X
XF
X
X
XH
End of 
rituximab 
infusion
Within 5 min post 
end of infusion
End of infusion
X
End of 
denintuzumab 
mafodotin 
infusion
Within 5 min post 
end of infusion
End of infusion
X
Day 22E
504 hr
± 24 hr
Start of infusion
X
X
EOT
X
X
X
XG
X
X
ATA = antitherapeutic antibodies; COO = cell or origin; EOT = end of treatment; IP = immunophenotyping; MRD = minimal residual disease; N/A = not applicable; PK = pharmacokinetics; sCD19 = soluble CD19; 
SNP = single-nucleotide polymorphism
A.  Cycle 1 Day 1 pre-dose window is 24 hours. 
B.  Odd-cycle relative time is based on the denintuzumab mafodotin infusion, except the rituximab PK samples at the end of rituximab infusion; even-cycle relative time is based on the rituximab 
infusion.
C.  For patients receiving denintuzumab mafodotin plus RCHOP or RCHP.
D.  Representative tissue from fresh tumor specimen for study entry and biomarker analysis.  If available, archived tumor tissue from the initial biopsy is also required.
E.  Sample obtained only for patients not starting the next cycle on that day 
F.  For Cycles 1, 3 and 5 only.
G.  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.
H. For Cycle 1 only.  


Study SGN19A-004
Protocol V01
18 February 2016
Denintuzumab mafodotin
Seattle Genetics, Inc. – Confidential
Page 93 of 99
18.2
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 (eg, with chemotherapy or myeloid 
colony-stimulating factors), uptake may be greater than 
normal mediastinum and/or liver.  In this circumstance, 
complete metabolic response may be inferred if uptake at 
sites of initial involvement is no greater than surrounding 
normal tissue even if the tissue has high physiologic 
uptake
Target nodes/nodal masses must regress to ≤1.5 cm in LDi
No extralymphatic sites of disease
Nonmeasured lesion
Not applicable
Absent
Organ enlargement
Not applicable
Regress to normal
New lesions
None
None
Bone marrow
No evidence of FDG-avid disease in marrow
Normal by morphology; if indeterminate, IHC negative
Partial Response
Partial metabolic response 
Partial remission (all of the following)
Lymph nodes and 
extralymphatic sites
Score 4 or 5b with reduced uptake compared with baseline 
and residual mass(es) of any size
At interim, these findings suggest responding disease
When a lesion is too small to measure on CT, assign 5 mm × 
5 mm as the default value
When no longer visible, 0 × 0 mm
For a node >5 mm × 5 mm, but smaller than normal, use actual 
measurement for calculation
Nonmeasured lesion
Not applicable
Absent/normal, regressed, but no increase
Organ enlargement
Not applicable
Spleen must have regressed by >50% in length beyond normal
New lesions
None
None


Study SGN19A-004
Protocol V01
18 February 2016
Denintuzumab mafodotin
Seattle Genetics, Inc. – Confidential
Page 94 of 99
Response Assessment – The Lugano Classification (continued)
Partial Response
Partial metabolic response 
Partial remission (all of the following)
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
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


Study SGN19A-004
Protocol V01
18 February 2016
Denintuzumab mafodotin
Seattle Genetics, Inc. – Confidential
Page 95 of 99
Response Assessment – The Lugano Classification (continued)
Progressive Disease
Progressive metabolic disease 
Progressive disease requires at least 1 of the following
Individual target nodes/nodal 
masses
Score 4 or 5 with an increase in intensity of uptake from 
baseline 
and/or
PPD progression
Extranodal lesions
New FDG-avid foci consistent with lymphoma at interim 
or EOT assessment
An individual node/lesion must be abnormal with:
LDi >1.5 cm
and
Increase by ≥50% from PPD nadir
and
An increase in LDi or SDi from nadir
0.5 cm for lesions ≤2 cm
1.0 cm for lesions >2 cm
In the setting of splenomegaly, the splenic length must increase 
by >50% of the extent of its prior increase beyond baseline (eg, 
a 15-cm spleen must increase to >16 cm).  If no prior 
splenomegaly, must increase by at least 2 cm from baseline
Nonmeasured lesion
None
New or clear progression of preexisting nonmeasured lesions
New lesions
New FDG-avid foci consistent with lymphoma rather than 
another etiology (eg, infection, inflammation).  If 
uncertain regarding etiology of new lesions, biopsy or 
interval scan may be considered
Regrowth of previously resolved lesions
A new node >1.5 cm in any axis
A new extranodal site >1.0 cm in any axis; if <1.0 cm in any 
axis, its presence must be unequivocal and must be attributable 
to lymphoma
Assessable disease of any size unequivocally attributable to 
lymphoma
Bone marrow
New or recurrent FDG-avid foci
New or recurrent involvement 
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.
The Lugano Classification (Cheson 2014).  


Study SGN19A-004
Protocol V01
18 February 2016
Denintuzumab mafodotin
Seattle Genetics, Inc. – Confidential
Page 96 of 99
18.3
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 (ie, preparing 
meals, shopping for 
groceries or clothes, 
using the telephone 
or computer, 
managing money, 
driving, etc.)
Affects self-care 
ADL (ie, 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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Protocol V01
18 February 2016
Denintuzumab mafodotin
Seattle Genetics, Inc. – Confidential
Page 97 of 99
18.4
International Prognostic Index Scales
International Prognostic Index (IPI, for patients >60 years of age)
1 point for any of the following:
●
Age >60
●
Serum LDH >1 x ULN
●
ECOG Performance Status ≥2
●
Stage III or IV
●
Extranodal involvement ≥2 sites
Risk Category:
●
Low:
0–1
●
Low-intermediate:
2
●
High-intermediate:
3
●
High:
4–5
From the International Non-Hodgkin’s Lymphoma Prognostic Factors Project (Shipp, 1993).
Age-adjusted International Prognostic Index (aaIPI, for patients ≤60 years of age) 
1 point for any of the following:
●
Serum LDH >1 x ULN
●
ECOG Performance Status ≥2
●
Stage III or IV
Risk Category:
●
Low:
0
●
Low-intermediate:
1
●
High-intermediate:
2
●
High:
3
Based on Shipp 1993; Moscowitz 1999; Hamlin 2003


Study SGN19A-004
Protocol V01
18 February 2016
Denintuzumab mafodotin
Seattle Genetics, Inc. – Confidential
Page 98 of 99
18.5
Eastern Cooperative Oncology Group Performance Status
Grade
Criterion
0
Fully active, able to carry on all pre-disease activities without restriction.
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, for example light housework or office work.
2
Ambulatory and capable of all self-care but unable to carry out work activities. Up and about 
more than 50% of waking hours.
3
Capable of only limited self-care, confined to bed or chair 50% or more of waking hours.
4
Completely disabled, cannot carry on any self-care, totally confined to bed or chair.
5
Death


Study SGN19A-004
Protocol V01
18 February 2016
Denintuzumab mafodotin
Seattle Genetics, Inc. – Confidential
Page 99 of 99
18.6
Common Terminology Criteria for Adverse Events (CTCAE; v 4.03)
The current version of the NCI CTCAE (Version 4.03) can be viewed on-line at the NCI web 
site:
http://ctep.cancer.gov/reporting/ctc.html

SAP_001.pdf: 
CONFIDENTIAL INFORMATION
Page 1 of 30
Statistical Analysis Plan
Sponsor:
Seattle Genetics, Inc.
Protocol No:
SGN19A-004
PRA Project Id:
SGB1B219-1B219A
Version Date:
30JAN2018
Version Number:
1.0
APPROVALS
Sponsor Name:
Seattle Genetics, Inc.
Name of Sponsor 
Representative/Title:
 
Signature of Sponsor 
Representative /Date:
Name of PRA Project 
Manager/Title:
Signature of PRA Project 
Manager/Date:
Name of  PRA Biostatistician 
/Title:
Signature of PRA Biostatistician 
/Date:
                   
Sponsor:  Seattle Genetics, Inc.
Statistical Analysis Plan
Protocol no:  SGN19A-004
30JAN2018 Version 1.0


CONFIDENTIAL INFORMATION
Page 2 of 30
TABLE OF CONTENTS
Approvals....................................................................................................................................... 1
Table of Contents .......................................................................................................................... 2
1.
Introduction ........................................................................................................................... 4
1.1
Changes from Protocol..................................................................................................... 4
2.
Study Objectives.................................................................................................................... 4
2.1
Primary Study Objectives................................................................................................. 4
2.2
Secondary Study Objectives............................................................................................. 5
2.3
Additional  Objectives...................................................................................................... 5
3.
Study Design........................................................................................................................... 5
3.1
Overall Study Design and Plan ........................................................................................ 5
3.1.1
Part A – Safety Evaluation.......................................................................................... 6
3.1.2
Part B – Randomized, Open-Label Phase 2................................................................ 7
3.2
Sample Size Considerations............................................................................................. 8
3.3
Randomization ................................................................................................................. 9
3.4
Blinding............................................................................................................................ 9
4.
Study Variables and Covariates........................................................................................... 9
4.1
Primary Variables............................................................................................................. 9
4.1.1
Efficacy....................................................................................................................... 9
4.1.2
Safety ........................................................................................................................ 10
4.2
Secondary variables........................................................................................................ 10
4.2.1
Efficacy..................................................................................................................... 10
4.3
Additional Variables ...................................................................................................... 10
4.3.1
Pharmacokinetic and Immunogenicity Variables ..................................................... 10
4.3.2
Biomarker Assessment Variables ............................................................................. 10
4.4
Predetermined Covariates and Prognostic Factors......................................................... 10
5.
Definitions ............................................................................................................................ 10
6.
Analysis Sets......................................................................................................................... 12
6.1
Intent-to-Treat ................................................................................................................ 12
6.2
Safety Analysis Set......................................................................................................... 12
7.
Interim Analyses.................................................................................................................. 13
8.
Data Review ......................................................................................................................... 13
8.1
Data Handling and Transfer........................................................................................... 13
8.2
Data Screening ............................................................................................................... 13
9.
Statistical Methods .............................................................................................................. 14
9.1
Subject Disposition ........................................................................................................ 14
9.2
Demographic and Baseline Characteristics.................................................................... 14
                   
Sponsor:  Seattle Genetics, Inc.
Statistical Analysis Plan
Protocol no:  SGN19A-004
30JAN2018 Version 1.0


CONFIDENTIAL INFORMATION
Page 3 of 30
9.3
Protocol Deviations and Violations ............................................................................... 15
9.4
Treatments...................................................................................................................... 15
9.4.1
Extent of Study Drug Exposure ................................................................................ 15
9.4.2
Prior and Concomitant Medications ......................................................................... 15
9.5
Efficacy Analyses........................................................................................................... 15
9.6
Pharmacokinetic, Antitherapeutic Antibody Measurements and Biomarkers ............... 15
9.7
Handling of Dropouts and Missing Data........................................................................ 16
9.8
Safety Analyses.............................................................................................................. 16
9.8.1
Adverse Events and Serious Adverse Events ........................................................... 16
9.8.2
Adverse Events of Special Interest ........................................................................... 18
9.8.3
Deaths ....................................................................................................................... 18
9.8.4
Laboratory Data ........................................................................................................ 18
9.8.5
Vital Signs................................................................................................................. 19
9.8.6
Physical Examinations, ECGs, ECOG, and Other Observations Related to Safety. 19
9.8.7
Ocular Examinations and Visual Function Survey................................................... 19
10.
Validation ......................................................................................................................... 19
11.
References......................................................................................................................... 19
Appendix 1
Glossary of Abbreviations ................................................................................ 20
Appendix 2
Imputation of Partially Unknown Adverse Event Dates............................... 23
Appendix 3
Treatment Emergent Adverse Event Programming Guide .......................... 27
Appendix 4
Ocular AEs of Interest SSQ Definition ........................................................... 29
                   
Sponsor:  Seattle Genetics, Inc.
Statistical Analysis Plan
Protocol no:  SGN19A-004
30JAN2018 Version 1.0


CONFIDENTIAL INFORMATION
Page 4 of 30
1. INTRODUCTION
This statistical analysis plan (SAP) describes the statistical methods to be used during the 
reporting and analyses of data collected under Seattle Genetics, Inc., Protocol SGN19A-004, 
entitled “An open-label phase 2 study of denintuzumab mafodotin (SGN-CD19A) in 
combination with RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and 
prednisone) or RCHP (rituximab, cyclophosphamide, doxorubicin, and prednisone) compared 
with RCHOP alone as frontline therapy in patients with diffuse large B-cell lymphoma (DLBCL) 
or follicular lymphoma (FL) Grade 3b”. Results of the proposed analyses will become the basis 
of the final clinical study report for this protocol.
This SAP should be read in conjunction with the study protocol and case report form (CRF). 
This version of the plan has been developed using the protocol dated 18 February, 2016 and CRF 
dated 24 August, 2016. Any further changes to the protocol or CRF may necessitate updates to 
the SAP.
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 be reflected in amendments to this plan before the database lock, 
detailed below, or specifically documented in the clinical study report. 
The SAP is to be developed in two stages. The purpose is to “finalize” a SAP so that 
programming can begin earlier in the process. Versions of the SAP up to initial sponsor approval 
will be known as SAP1. Changes following approval of SAP1 will be tracked in the SAP Change 
Log and a final version of the SAP, known as SAP2, will be issued for sponsor approval prior to 
database lock.
1.1
CHANGES FROM PROTOCOL
Seattle Genetics will end the study early after Part A, and therefore only a subset of the analyses 
planned in the protocol will be produced in order to prepare an abbreviated clinical study report 
(CSR). Analyses for the abbreviated CSR will focus on patient disposition, demographics, 
exposure and safety. Secondary efficacy endpoints will not be calculated or summarized as they 
pertain to Part B only. Biomarker endpoints will be described in a separate report. 
2. STUDY OBJECTIVES
2.1
PRIMARY STUDY OBJECTIVES

To compare the complete response (CR) rate at the end of treatment (EOT) in treatment-
naive patients with high-intermediate or high-risk systemic DLBCL or FL Grade 3b 
treated with denintuzumab mafodotin plus RCHOP or RCHP versus RCHOP alone (Part 
B)
                   
Sponsor:  Seattle Genetics, Inc.
Statistical Analysis Plan
Protocol no:  SGN19A-004
30JAN2018 Version 1.0


CONFIDENTIAL INFORMATION
Page 5 of 30

To assess the safety profile of denintuzumab mafodotin administered in combination with 
RCHOP or RCHP in treatment-naive patients with high-intermediate or high-risk 
systemic DLBCL or FL Grade 3b (Part A and Part B)
2.2
SECONDARY STUDY OBJECTIVES

To compare event-free survival (EFS) between study arms (Part B) 

To compare progression-free survival (PFS) between study arms (Part B)

To compare overall survival (OS) between study arms (Part B)

To compare the objective response rate (ORR) at EOT between study arms (Part B)

To compare the duration of objective response (OR) and of CR between study arms 
(Part B)
2.3
ADDITIONAL OBJECTIVES

To evaluate the pharmacokinetics (PK) of denintuzumab mafodotin administered in 
combination with RCHOP or RCHP (Parts A and B)

To evaluate the incidence of antitherapeutic antibodies (ATA) against denintuzumab 
mafodotin (Parts A and B) 

To assess denintuzumab mafodotin-mediated pharmacodynamic (PD) effects and 
potential biomarkers of response to denintuzumab mafodotin in combination with 
RCHOP or RCHP (Parts A and B)
•
3. STUDY DESIGN
3.1
OVERALL STUDY DESIGN AND PLAN
This is an open-label, phase 2, multicenter study of denintuzumab mafodotin in combination 
with RCHOP or RCHP compared with RCHOP alone as frontline therapy in patients with 
DLBCL or FL Grade 3b.  This study has 2 parts (Part A and Part B).  Part A of the study is a 
safety evaluation of denintuzumab mafodotin in combination with either RCHOP or RCHP.  
Results from Part A will be used to determine the regimen (RCHOP or RCHP) to be tested in 
combination with denintuzumab mafodotin in Part B.  Part B is a multicenter study designed to 
evaluate the antitumor activity and safety of denintuzumab mafodotin in combination with either 
RCHOP or RCHP compared with RCHOP alone.
In Part A and Part B, lymphoma response and progression will be assessed using the Lugano 
Classification Revised Staging System (Cheson, 2014) for malignant lymphoma. Diagnostic 
quality computed tomography (CT) scans (neck, chest, abdomen, and pelvis with intravenous 
and oral contrast) and positron emission tomography (PET) scans will be performed at baseline 
and at 5 weeks after the last dose of study treatment; all other EOT evaluations will be assessed 
30 to 37 days after the last dose. Follow-up assessments will be performed every 4 months from 
the last scan until 24 months, then every 6 months until 48 months, and then annually until study 
                   
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closure. For all follow-up assessments, both PET and CT scans are required until disease is PET 
negative; responses will then be followed by CT scan only. A CT scan will also be performed at 
the time of suspected clinical progression. Follow-up assessments will continue until disease
progression, initiation of a new anti-cancer treatment, or study closure, whichever comes first. 
Survival status follow-up will continue until patient death or study closure, whichever comes 
first.
A schedule of safety and efficacy procedures for the screening and treatment periods for part A 
and B is provided in Table 18-1 of the protocol.  PK, ATA, and biomarker assessments are 
provided in Table 18-2 (Part A Intense Sampling Schedule), Table 18-3 (Part B Intense 
Sampling Schedule) and Table 18-4 (Part B Sparse Sampling Schedule) of the protocol
3.1.1 Part A – Safety Evaluation
In Part A of the study, up to approximately 24 patients will be randomized 1:1 to receive 
denintuzumab mafodotin plus RCHOP or denintuzumab mafodotin plus RCHP to assess safety 
in these 2 combination regimens.  Patient randomization will be stratified by high-intermediate 
or high-risk disease.  Study treatment is up to six 21-day cycles of either RCHOP or RCHP 
combined denintuzumab mafodotin administered on Day 1 of Cycles 1, 3, and 5.  The study 
schema for Part A is depicted in Figure 1.
Figure 1:
Part A Study Schema 
a
CT = computed tomography; EOT = end of treatment; PET = positron emission tomography; RCHOP = rituximab, 
cyclophosphamide, doxorubicin, vincristine, prednisone; RCHP = rituximab, cyclophosphamide, doxorubicin, and 
prednisone
b
Administered on Day 1 of Cycles 1, 3, and 5
c
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 anti-cancer treatment, 
death, or study closure, whichever comes first.  Survival status follow-up until death or study closure, whichever comes first.  
                   
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The Safety Monitoring Committee (SMC), comprising the study investigators, medical monitor, 
and biostatistician and Sponsor’s medical expert, will periodically monitor the safety of patients 
at predefined interim safety evaluations and at regular intervals during the treatment period.  
Formal safety evaluations of cumulative data from both treatment groups will be conducted at 
the following 6 time points in Part A of the study:

after 6, 12, and 24 patients have completed Cycle 1 

after 6, 12, and 24 patients have completed EOT  
At each interim safety evaluation, the SMC will review the cumulative safety data, including the 
incidence of dose-delaying toxicities (DDTs) that are associated with denintuzumab mafodotin in 
combination with RCHOP or RCHP, as well as the rates of adverse events of interest such as 
peripheral neuropathy (PN) in each treatment group.  A DDT is defined as any study 
treatment-related toxicity that necessitates a delay of >14 days in the start of RCHOP or RCHP 
treatment in the next cycle.  With respect to hematologic recovery, it is recommended that the 
next cycle of RCHOP or RCHP be given once the patient's absolute neutrophil count recovers to 
≥ 1000/μL and the platelet count recovers to ≥75,000/μL, as applicable.  Upon its evaluation of 
the data, the SMC will make one of the following recommendations to the Sponsor:

continue the trial as planned

modify the dose of denintuzumab mafodotin in subsequently enrolled patients

temporarily halt enrollment for additional evaluation 
If the SMC determines that the risks outweigh the benefits of the study treatment in both 
combination regimens, no further patients will be enrolled at that dose and schedule.  
The evaluation of the safety and antitumor activity data at the end of Part A will be used to 
determine the regimen (RCHOP or RCHP) to be tested in combination with denintuzumab 
mafodotin in Part B.  If Grade 3 neuropathy (sensory or motor) is observed in >20% of patients 
in the denintuzumab mafodotin plus RCHOP treatment group (n = 12), then that combination 
will have exceeded the stopping criteria for that regimen, and RCHP may be selected for 
administration in combination with denintuzumab mafodotin in Part B of the study, with the 
support of the overall safety and antitumor activity data from both arms.
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.
3.1.2 Part B – Randomized, Open-Label Phase 2
Part B of the study is a phase 2, randomized, open-label, multicenter study designed to evaluate 
the antitumor activity and safety of denintuzumab mafodotin in combination with either RCHOP 
or RCHP (Experimental Arm) compared with RCHOP alone (Comparator Arm).  Approximately 
136 patients will be randomized 1:1 to either the Experimental or Comparator Arm.  
Randomization will be stratified by high-intermediate or high-risk disease and by cell of origin 
(COO).  The study schema for Part B is depicted in Figure 2.  
                   
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Figure 2:
Part B Study Schema
d
CT = computed tomography; EOT = end of treatment; PET = positron emission tomography; RCHOP = rituximab, 
cyclophosphamide, doxorubicin, vincristine, prednisone; RCHP = rituximab, cyclophosphamide, doxorubicin, and 
prednisone
a
Administered on Day 1 of Cycles 1, 3, and 5
b
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 anti-cancer treatment, 
death, or study closure, whichever comes first.  Survival status follow-up until death or study closure, whichever comes first.  
The SMC will continue to monitor the safety of the combination of denintuzumab mafodotin and 
either RCHOP or RCHP at predefined interim safety evaluations and during the treatment period.  
The SMC will review cumulative safety data at the following timepoints:

after 10 patients in each arm (N=approximately 20) have completed treatment, 

after 20 patients in each arm (N=approximately 40) have completed treatment, and 

after all patients in both arms have completed treatment.   
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
SAMPLE SIZE CONSIDERATIONS
In Part A of the study, up to approximately 24 patients will be enrolled to receive denintuzumab 
mafodotin with either RCHOP or RCHP (approximately 12 patients per treatment arm).  With 12 
patients in each arm, the probability of observing at least 1 patient with a clinically relevant 
adverse event is 72% if the true event rate is 10%.  The probability becomes 93% if the true 
event rate is 20%.  In evaluating the grade 3 peripheral neuropathy, the observed incidence rate 
for patients treated with RCHOP is approximately 10%.  
One criterion for selecting the study treatment for Part B of the study is that the addition of 
denintuzumab mafodotin, which is another microtubule inhibitor similar to vincristine, to 
                   
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RCHOP should not cause significant additive neurotoxicity, and Grade 3 peripheral neuropathy 
should not exceed 20%.  With 12 patients in each arm, if the true incidence rate is 15%, the 
probability of observing at least 3 patients having the event is 26%; if the true incidence rate is 
25%, this probability becomes 61%.    
In Part B of the study, approximately 136 patients will be randomized 1:1 to each treatment arm 
(approximately 68 patients per treatment arm).  It is assumed that the underlying CR rates for the 
denintuzumab mafodotin plus RCHOP (or RCHP) treatment group is 88% and RCHOP 
treatment group is 70%.  With a sample size of 136, an 18% improvement in CR rate in the 
denintuzumab mafodotin plus RCHOP (or RCHP) treatment group would provide approximately 
80% power.  This calculation is based on a 2-sided chi-squared test with significance level of 
alpha = 0.1 using EAST 6.3.1. 
3.3
RANDOMIZATION
In Part A, following informed consent and screening, patients will be randomly assigned to 1 of 
2 treatment regimens combined with denituzumab mafodotin in a 1:1 ratio using a centralized 
randomization system.  Randomization in this part of the study is for the purpose of evaluating 
the safety of denituzumab mafodotin in combination with RCHOP versus RCHP.  Patients will 
be stratified according to high-intermediate risk (International Prognostic Index ([IPI)] =3 for age 
>60 years and age-adjusted International Prognostic Index (aaIPI) =2 for age ≤60 years) versus 
high-risk (IPI =4 or 5 for age >60 years and age-adjusted International Prognostic Index [aaIPI]
=3 for age ≤60 years) disease.
In Part B, following informed consent and screening assessments, patients will be randomly 
assigned to 1 of 2 arms in a 1:1 ratio using a centralized randomization system.  Randomization 
in this part of the study is for the purpose of evaluating the efficacy and safety of denituzumab 
mafodotin in combination with either RCHP or RCHOP versus RCHOP alone.  Randomization 
will be stratified by the following 2 factors:  

COO by local immunohistochemistry (IHC) assessment per Hans algorithm (germinal 
center B [GCB] versus non-GCB)

high-intermediate risk versus high-risk disease based on standard IPI for 
patients >60 years of age and aaIPI for patients ≤60 years of age
3.4
BLINDING
This is an open label study.
4. STUDY VARIABLES AND COVARIATES
4.1
PRIMARY VARIABLES
4.1.1 Efficacy 

CR rate at the EOT as determined by investigators
                   
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4.1.2 Safety

Adverse events (AEs, type, incidence, severity, seriousness, and relatedness) 

Laboratory abnormalities (type, incidence, and severity)

Ophthalmologic exams and ocular health surveys
4.2
SECONDARY VARIABLES
4.2.1 Efficacy 
Secondary efficacy variables for include: Event-free survival (EFS), Progression-free 
survival (PFS), Overall survival (OS), Objective response rate (ORR) following the 
completion of EOT, Duration of objective response and Duration of CR. These variables will 
not be calculated or presented. 
4.3
ADDITIONAL VARIABLES
4.3.1 Pharmacokinetic and Immunogenicity Variables

Plasma concentrations of denintuzumab mafodotin antibody-drug conjugate (ADC)
and released cysteine maleimidocaproyl monomethyl auristatin F (cys-mcMMAF)

Serum concentrations of rituximab

Serum denintuzumab mafodin ATA
4.3.2 Biomarker Assessment Variables
Biomarker assessment variables will be defined and summarized in a separate report. 
4.4
PREDETERMINED COVARIATES AND PROGNOSTIC FACTORS
Randomization will be stratified by high-intermediate or high-risk disease in Part A, and by high 
intermediate or high-risk disease and by COO in Part B to insure some level of balance between 
treatment arms. These stratification factors at randomization will be used as covariates in 
statistical models for the primary analysis.
5. DEFINITIONS  
Age will be calculated with the SAS INTCK function using informed consent date and birth date.
                   
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Baseline: Unless otherwise specified, baseline is the last measurement taken prior to first dose of 
any study drug at Screening and/or Cycle 1 Day 1 visits.
Body Mass Index (BMI) (kg/m2) = weight (kg) / [height (m)]2.
Body Surface Area (BSA) (m2) = (weight (kg) * height (cm)/3600) 0.5.
Cumulative Dose (mg): is defined as sum of actual doses received for denintuzumab mafodotin, 
rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone, 
respectively
Dose Intensity, Absolute (ADI): is defined as the actual dose (mg/kg or mg/m2) per unit of time 
that the subject received over the entire treatment period, where the treatment time is calculated 
as: 
([Last Cycle day 1 dose date + 21] – first dose date (of any treatment))/7.
Dose Intensity, Intended (IDI): is the intended dose of drug (mg/kg or mg/m2) per unit time.
For denintuzumab mafodotin (DM), IDI= assigned DM dose level (mg/kg)/6 weeks..
For the components of RCHP/RCHOP, IDI is the intended dose of drug (mg/kg or mg/m2)/3 
weeks. 
Dose Intensity, Relative (RDI): ADI divided by IDI *100.
Dose Modification: is defined as any elimination, delay, reduction, or unplanned dose 
adjustment
Duration of Treatment (days): is defined as time from the first dose of any treatment to 21 days 
after the last Cycle day 1 study dose,
[Last cycle day 1 dose date + 21] – first dose date.
If death occurs less than 21 days after the last cycle day 1 dose date, duration of treatment is 
defined as, 
Date of death – first dose date + 1.
Height (cm): Height is reported in centimeters (cm). The following conversion will be used as 
necessary to convert height measurements collected in inches (in) to cm:
Height (cm) = Height (in) x 2.54
Time Unit Conversion: is defined as follows:

Weeks = Days/7

Months= Days/30.4375

Years = Days/365.25
Time Since Diagnosis (days): is defined as Date of Informed Consent - Date of initial 
pathologic diagnosis from the disease diagnosis CRF.
                   
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Weight (kg): Weight will be tabulated in kilograms (kg). The following conversion will be used 
as necessary to convert weight measurements collected in pounds (lb) to kg:
Weight (kg) = Weight (lb) / 2.205
AEs of Special Interest:
Improvement of Peripheral Neuropathy(SMQ): is defined for events that are not resolved
(defined below) as decrease by at least one grade from worst grade as of the latest assessment.  
Improvement of Ocular AEs (SSQ): is defined for events that are not resolved (defined below) 
as All grade 3 or 4 AEs of interest have improved to grade 2 or better, and all grade 2 AEs of 
interest have improved to grade 1 or better as of the latest assessment. If multiple preferred terms 
under the SSQ exist, the preferred terms will be reviewed jointly, eg if one preferred term is 
improved, but another is not, at a subject level the subject will be counted as not improved.   
Resolution of adverse events of special interest: is defined as event status of 
recovered/resolved or recovered/resolved with sequelae; or return to baseline or lower severity as 
of the latest assessment for pre-existing events.
Time to onset of treatment-emergent AE (TEAE) of interest(weeks): is defined as the (start 
date of the AE - first dose date (of any) +1)/7.
Time to onset of Treatment-Emergent Adverse Event of Interest (cycles): is defined as Cycle
= x where x:
Day 1 date of cycle x < AE start date <=(min (day 1 of cycle X+1, EOT date, end of study (EOS)
date).
6. ANALYSIS SETS
6.1
INTENT-TO-TREAT
The intent-to-treat (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.  Stratified analyses will be based on the stratification factor as recorded at 
randomization. 
6.2
SAFETY ANALYSIS SET
The safety analysis set will include all patients from Parts A and B who receive any amount of 
denintuzumab mafodotin or any component of RCHOP or RCHP.  Treatment group will be 
determined using the actual treatment received, regardless of the randomization treatment 
assignment.  In Part B, patients who received any amount of denintuzumab mafodotin will be 
assigned to the denintuzumab mafodotin in combination with either RCHOP or RCHP actual 
treatment arm.
                   
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7. INTERIM ANALYSES
No formal interim analysis is planned for this study.  
An SMC will monitor the trial for safety and will convene regularly during both parts of the 
study. Members of the SMC will include the study investigators, medical monitor, and 
biostatistician and Sponsor’s medical expert.  The primary role of this SMC will be to monitor 
safety data during Part A. 
Formal safety evaluations of cumulative data from both treatment groups will be conducted at 
predefined interim safety evaluations (for complete details see Section 3.1.1 for Part A)   
During the treatment period, the SMC may also recommend conducting additional safety 
analyses or temporarily halting enrolment until an appropriate evaluation of the cumulative 
safety data, including review of unanticipated safety issues, has been completed.
An ongoing real-time review of serious adverse events (SAEs) in both parts of the study will be 
conducted by the Seattle Genetics Program Safety Monitoring Team.  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 Haematology.
8. DATA REVIEW
8.1
DATA HANDLING AND TRANSFER
Data handling and transfer specifications will be stated and conducted according to the Data 
Management Plan.  
AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA, Version 19.1 
or higher).
Laboratory values will be graded according to the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE, version 4.03 or higher).
Concomitant medications will be coded using World Health Organization (WHO) Drug
Dictionary (version June 2016 or more recent).
8.2
DATA SCREENING
Beyond the data review and cleaning built into the PRA Data Management Plan, the PRA 
programming of analysis datasets, tables, figures, and listings (TFLs) provides additional data 
review.
Review of a TFL dry run on the nearly finalized database will allow for further data review prior 
to finalization. The dry run TFLs will be discussed with the sponsor in a data review meeting to 
                   
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identify any final data issues and seek corrections prior to database lock. The PRA statistician 
and Seattle Genetics must approve database lock.
9. STATISTICAL METHODS
All data collected during this study for all subjects will be displayed in data listings, unless 
otherwise specified. Data listings will be sorted by treatment and subject identifier. Screen 
failures will be excluded from all tables, with the exception of the Analysis Sets summary table,  
but will be included in listings.  In addition, listings will include all relevant derived variables.
Summary statistics for continuous variables, unless otherwise specified, will include the number 
of subjects, mean, standard deviation, median, minimum, and maximum values. Continuous 
variables will generally be presented with the mean, median, Q1, and Q3 to 1 decimal more than 
individual data, and standard deviation to 2 decimals more than individual data. Data with > 3 
decimal places (if any) may not follow this rule. Frequencies and percentages will be used to 
summarize categorical variables.
Unless specified otherwise, the tables, figures and listings will be presented by treatment groups 
and overall.
All data summaries and tabulations will be prepared with SASVersion 9.4 or higher.
9.1
SUBJECT DISPOSITION  
The number of subjects who were screened, enrolled, and/or, randomized in the study and the 
number and percentage of subjects who were treated with any amount of denintuzumab 
mafodotin or any component of RCHOP or RCHP, and the number of subjects in each analysis 
set will be summarized.
Disposition of subjects will be summarized by treatment group and overall for the ITT analysis 
set. The number and percentage of subjects who are on treatment, off treatment, who complete 
treatment, who discontinue treatment early, the reasons for discontinuation from the treatment 
and who are in follow up will be tabulated. All percentages will be based on the number of 
subjects randomized to the respective treatment group and overall. 
9.2
DEMOGRAPHIC AND BASELINE CHARACTERISTICS  
Demographic and baseline characteristics will be summarized and listed by treatment group and 
overall for the ITT and Safety analysis set. Demographic and baseline summaries will include
age, age group, sex, race, ethnicity, Eastern Cooperative Oncology Group (ECOG) performance 
status, weight, height, BMI, and BSA. Disease characteristics include diagnosis, time since 
diagnosis, disease stage, serum lactate dehydrogenase (LDH) levels, extranodal disease 
involvement, disease transformed from prior Non-Hodgkin lymphoma (NHL) diagnosis, IPI 
score, aaIPI score, COO, and B-symptoms. CD30 expression will be listed.
Comorbid inflammatory conditions will be listed. 
Medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA), version 19.1 and listed.
                   
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9.3
PROTOCOL DEVIATIONS AND VIOLATIONS
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.    A by-patient listing of important 
protocol deviations will be presented.  
9.4
TREATMENTS  
9.4.1 Extent of Study Drug Exposure
Exposure to study drugs denintuzumab mafodotin, RCHOP, or RCHP will be provided 
separately for each treatment group. Summaries will include the duration of treatment, number of 
doses received, number of doses eliminated, number of cycles received, number of subjects with 
at least 1 dose interruption, number of doses interrupted, the reasons for dose interruption, the 
number of subjects with at least 1 dose decreased for toxicity, the number of doses decreased for 
toxicity, the number of subjects with at least 1 dose delay, the number of dose delays, the 
cumulative dose, the relative dose intensity, the number of patients with infusion related or 
delayed hypersensitivity reaction.  
9.4.2 Prior and Concomitant Medications
Verbatim prior and concomitant medications will be coded to preferred name using the World 
Health Organization Drug Dictionary (WHODRUG, 2016JUNE01 DDE (Enhanced)).
Prior and concomitant medications will be listed by patient, displaying verbatim name and 
preferred name, indication, and start and stop dates.
Prior cancer related therapies will be listed. 
9.5
EFFICACY ANALYSES
Response at the end of treatment visit as assessed using Lugano 2014 will be summarized. 
Disease response assessments will be listed by patient. Secondary efficacy analyses and variables 
will not be calculated, as they pertain to part B.
9.6
PHARMACOKINETIC, ANTITHERAPEUTIC ANTIBODY 
MEASUREMENTS AND BIOMARKERS
The individual plasma concentrations of denintuzumab mafodotin ADC, TAb, and unconjugated 
drug (cys-mcMMAF) and serum concentrations of rituximab will be summarized with 
descriptive statistics at each PK sampling time point. Individual PK parameters will be estimated 
using noncompartmental analysis methods (where data allow), and summarized with descriptive 
statistics for each dose cohort. Additional PK and PK/PD/biomarker analyses may be conducted 
and presented in a separate analysis plan and report.  
                   
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ATA incidence will be summarized by treatment group and overall and ATA results will be 
listed. 
9.7
HANDLING OF DROPOUTS AND MISSING DATA
With the exception of time-related endpoints, missing observations will generally be treated as 
missing at random and will not be imputed, unless otherwise noted.
For missing or partial start and stop adverse event dates, see Appendix 2 for imputation rules.
Note that the actual value for date (not imputed) will be presented in all data listings and imputed 
dates will be used for derivations only.
9.8
SAFETY ANALYSES
All safety analyses will be based on the Safety analysis set unless otherwise specified.
9.8.1 Adverse Events and Serious Adverse Events
All adverse events will be coded into system organ class (SOC) and preferred term (PT) using 
the MedDRA version 19.1 or higher classification scheme, and severity grade using NCI
CTCAE Version 4.03.
A treatment-emergent AE (TEAE) is defined as a newly occurring or worsening AE after the 
first dose of study drug and is defined in Appendix 3.  Unless documented as a pre-existing 
condition, adverse events with unknown start date will be counted as treatment-emergent.  
Treatment-emergent AEs may or may not have a causal relationship with the study drug being 
studied. All summaries will include all AEs, unless otherwise specified. 
Summary of AEs will be tabulated by treatment group and overall for Part A and B, respectively, 
and sorted by the highest frequency in the overall group by descending preferred term unless 
otherwise specified.   
Any treatment-related AE summary will include any AE that is deemed related to denintuzumab 
mafodotin or any component of RCHOP or RCHP. AEs with missing relationship will be 
considered as related. 
Dose modifications include dose elimination, dose reduction, dose delay, and any unplanned 
dose adjustment. 
Summary of AEs include the following:  

Pre-existing AEs

All TEAEs

All Adverse Events

Treatment-related AEs

Denintuzumab mafodotin-related AEs

RCHOP/RCHP-related AEs
                   
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
Serious AEs

Serious treatment-related AEs

Serious DM-related AEs

Serious RCHOP/RCHP-related AEs

AEs leading to dose modifications of DM

AEs leading to dose modifications of any component of RCHOP/RCHP

AEs leading to dose eliminations of DM

AEs leading to dose eliminations of any component of RCHOP/RCHP

AEs leading to dose delays

AEs leading to dose delays of DM

AEs leading to dose delays of any component of RCHOP/RCHP

Denintuzumab mafodotin-related AEs leading to dose delays of DM

AEs leading to dose reductions of DM

AEs leading to dose reductions of any component of RCHOP/RCHP

AEs leading to dose interruption or dose being stopped early of DM

AEs leading to dose interruption or dose being stopped early of any component of 
RCHOP/RCHP

AEs leading to treatment discontinuation

Dose-delaying toxicities AEs

Infusion-related reaction AEs

Delayed hypersensitivity reactions AEs

AEs with outcome of death

Grade 3-5 TEAEs

TEAEs by SOC and PT

TEAEs by SOC, PT, and maximum CTCAE grade
When AEs are counted by subject, subjects will be counted only once within each SOC or PT. 
When AEs are summarized by subject and CTCAE grade, a subject will be summarized based on 
the most severe AE for that SOC or PT. If CTCAE grade is missing, it will remain and be 
displayed as missing.
All AEs recorded on the CRF and captured in the database will be presented data listings. Dose-
delaying toxicities, SAEs, and AEs leading to treatment discontinuation will be listed separately. 
                   
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9.8.2 Adverse Events of Special Interest
Adverse Events of Interest include PN and ocular toxicity events. Neuropathy events will be 
identified by the broad search MedDRA SMQ (Standardized Medical Dictionary for Regulatory 
Activities Queries, sensory and motor). Ocular AEs (corneal, eye symptom, and blurry vision
AEs) will be identified using three sponsor specified queries (SSQ) defined in Appendix 4. All 
outputs defined for ocular AEs of interest will be presented separately for each SSQ. For 
definitions of resolutions and improvement, see Section 5. 
Peripheral Neuropathy (PN) and Ocular AEs will be summarized separately by descending 
preferred term (unless otherwise specified) as follows:

Pre-existing AEs of interest 

Treatment-Emergent AEs of interest

Treatment-Related AEs of interest

DM Related AEs of interest

RCHP/RCHOP Related AEs of interest
AEs of special interest will also be presented by maximum severity. 
Time to onset (weeks and cycles), as well as resolution and improvement of AE events will be 
summarized.
Maximum severity relationship between the 3 Ocular SSQs  will be summarized. Duration from 
Grade 3 or 4 corneal AEs to Grade 2 or better, duration from Grade 2 or 3 eye symptom AEs to 
Grade 2 or better, and duration from Grade 2 or 3 blurry vision AEs to Grade 2 or better will be 
summarized using the Kaplan-Meier method. Subjects without improvement to desired grade or 
better will be censored at the date of their last ocular exam. 
AEs of Peripheral Neuropathy and Ocular AEs will be listed separately. 
9.8.3 Deaths 
The total number of deaths, deaths within 30 days of last dose, deaths after 30 days of last dose, 
as well as relationship to disease, will be summarized by treatment arm and total. Cause of death 
will be summarized by preferred term. Deaths and AEs with outcome of deaths will be listed. 
  
9.8.4 Laboratory Data
All safety laboratory data will be converted to standard units by conversion programming.
                   
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The worst observed post-baseline value in CTCAE 4.03 will be summarized. Subjects with at 
least 1 on-study measurement for each laboratory parameter will be included, regardless of 
whether or not a baseline assessment is present.
All lab results will be listed. 
9.8.5 Vital Signs  
All vital sign results will be listed.
9.8.6 Physical Examinations, ECGs, ECOG, and Other Observations 
Related to Safety
Clinically significant findings observed during physical examinations will be recorded on the AE 
and pre-existing condition CRFs. No presentation for physical examinations will be performed. 
Electrocardiogram (ECG) and ECOG assessments will be listed.
9.8.7 Ocular Examinations and Visual Function Survey
Ocular exams and visual function survey results will be listed. 
Additionally, the visual function survey will be scored according to the VFQ-25 scoring manual, 
and scores will be summarized by visit and treatment arm. 
10. VALIDATION
PRA's goal is to ensure that each TFL delivery is submitted to the highest level of quality. Our 
quality control procedures will be documented separately in the study specific quality control 
plan. 
11. REFERENCES
Cheson BD, Fisher RI, Barrington SF, et al.  Recommendations for Initial Evaluation, Staging, 
and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano 
Classification.  J Clin Oncol. 32(27): 3059-67, 2014.
Collett D (1994). Interval-censored survival data. Modelling survival data in medical research. 
Boca Raton, Fla., Chapman & Hall/CRC: 237-251.
                   
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APPENDIX 1 GLOSSARY OF ABBREVIATIONS
Term
Definition
aaIPI
age-adjusted International Prognostic Index
ADC
antibody-drug conjugate
ADI
absolute dose intensity
AE
adverse event
ATA
antitherapeutic antibody
BMI
body mass index
BSA
body surface area
BMI
body mass index
BSA
body surface area
CI
confidence interval
CMR
complete metabolic response
COO
cell of origin
CR
complete response
CRF
case report form
CRO
Clinical Research Organization
CSR
clinical study report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
cys-mcMMAF
cysteine maleimidocaproyl monomethyl auristatin F
DDT
dose-delaying toxicity
DLBCL
diffuse large B-cell lymphoma
DM
denintuzumab mafodotin
DMP
Data Management Plan
DOCR
duration of complete response
DOR
duration of objective response
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EFS
event-free survival
                   
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EOS
end of study
EOT
end of treatment 
FcγR
Fc-gamma receptor
FL
follicular lymphoma
GCB
germinal center B cell
IDI
Intended dose intensity
IHC
immunohistochemistry
IPI
International Prognostic Index
ITT
intent-to-treat 
MedDRA
Medical Dictionary for Regulatory Activities
MRD
minimal residual disease
NCI
National Cancer Institute 
NHL
Non-Hodgkin lymphoma
ORR
objective response rate
OS
overall survival
PD
pharmacodynamic 
PET
positron emission tomography
PK
pharmacokinetics 
PFS
progression-free survival
PMR
partial metabolic response
PN
peripheral neuropathy
PT
preferred term
RCHOP
rituximab, cyclophosphamide, doxorubicin, vincristine, and 
prednisone 
RCHP
rituximab, cyclophosphamide, doxorubicin, and prednisone
RDI
relative dose intensity
SAE
serious adverse event
SAP
statistical analysis plan
sCD19
soluble CD19
SGN-CD19A
denintuzumab mafodotin
SMC
Safety Monitoring Committee 
SMQ
Standardized Medical Dictionary for Regulatory Activities 
                   
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QueriesMedDRA Query
SOC
system organ class
SSQ
sponsor derived query
TEAE
treatment-emergent adverse event
TFLTFLs
tables, figures, and listings
US
United States
WHO
World Health Organization
                   
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APPENDIX 2 IMPUTATION OF PARTIALLY UNKNOWN ADVERSE 
EVENT DATES
The algorithm below should be used to impute pre-existing condition and adverse event (AE) 
start dates for which only partial information is known. For ease of reading, both pre-existing 
conditions and AEs will be referred to as AE for the remainder of this document. The algorithm 
should be applied to every AE record on a record by record basis. AE start dates should be 
imputed before imputation of AE condition end date in all cases. The AE condition end date 
should only be used in the imputation of the AE start date if it a full known date. 
                   
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1. AE day and month are missing:
a.
If the year is the same as the year of first dose of any study treatment (for 
combination studies this implies any component of the regimen) and the onset 
period indicates that the start of the AE was pre-dose:
i. AE start date will be imputed as the minimum of (AE condition end date*, 
day prior to first dose of any study treatment)
b. If the year is the same as the year of first dose of any study treatment and the 
onset period indicates that the start of the AE was post-dose:
i. AE start date will be imputed as the minimum of (AE condition end date*, 
first dose date of any study treatment)
c.
If the year is before the year of first dose of any study treatment:
i. AE start date will be imputed as the minimum of (AE condition end date*, 
December 31st) - see example 2 below
d. If the year is after the year of first dose of any study treatment:
i. AE start date will be imputed as the minimum of (AE condition end date*, 
January 31st) - see example 2 below
2. AE month only is missing:
a.
Treat day as missing and replace both month and day according to the above 
procedure
3. AE day only is missing:
a.
If the month/year is the same as the month/year of first dose of any study 
treatment and the onset period indicates that the start of the AE was pre-dose:
i. AE start date will be imputed as the minimum of (AE condition end date*, 
day prior to first dose of any study treatment)
b. If the month/year is the same as the month/year of first dose of any study 
treatment and the onset period indicates that the start of the AE was post-dose:
i. AE start date will be imputed as the minimum of (AE condition end date*, 
first dose date of any study treatment)
c.
If the month/year is before the month/year of first dose of any study treatment:
i. AE start date will be imputed as the minimum of (AE condition end date*, 
last day of the month)
d. If the month/year is after the month/year of first dose of any study treatment:
i. AE start date will be imputed as the minimum of (AE condition end date*, 
last day of the month)
* Only use condition end date if known and full end date is available.
The following algorithm should be used to impute AE condition end dates:
1. The AE records for a condition/event should be sorted by the imputed start dates then 
record position (order of entry into the eCRF). 
a.
After sorting, if any condition end date month/year is greater than any subsequent 
record end date month/year, then change the imputed start day only to end of 
month.  
                   
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b. Repeat step 1. 
2.
After sorting the AE records, apply the following rules to partial or missing AE 
condition end dates:
a.
For all records excluding the last chronological record for a condition/event:
i. AE condition end date will be imputed as the start date of the subsequent 
record
b. For the last chronological record for a condition/event:
ii. If outcome is “recovered/resolved”, ”recovered/resolved with sequelae”, 
or “fatal”:
1. AE condition end date will be imputed as the minimum of (last 
dose date + 30, death date, data extraction date, or last day of 
month if month and year known, or last day of year if only year is 
known)
iii. If outcome is “recovering/resolving”, “not recovered/resolved”, 
“unknown”, or blank:
1. AE condition end date will not be imputed.
Example 1:
AESPID 1: Condition/Event HEADACHE
First dose date 01JAN2012
Prior to imputation:
Start date
Condition end date
Severity
Outcome
Onset
UNUNK2011
15APR2012
1
not recovered/resolved
pre-ICF
15APR2012
UNMAY2012
2
recovering/resolving
post 1st dose
UNMAY2012
UNJUN2012
1
not recovered/resolved
post 1st dose
UNJUN2012
UNJUN2012
3
recovering/resolving
post 1st dose
UNJUN2012
10JUL2012
2
recovering/resolving
post 1st dose
10JUL2012
--
1
not recovered/resolved
post 1st dose
Post imputation:
Start date
Condition end date
Severity
Outcome
31DEC2011
15APR2012
1
not recovered/resolved
15APR2012
31MAY2012
2
recovering/resolving
31MAY2012
30JUN2012
1
not recovered/resolved
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
                   
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15JAN2013
UNUNK2013
2
recovering/resolving
post 1st dose
UNUNK2013
UNFEB2013
2
not 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
15JAN2013
31JAN2013
2
recovering/resolving
31JAN2013
UNFEB2013
2
not recovered/resolved
Example 2a:
Prior to imputation:
Start date
Condition end date
Severity
Outcome
Onset
15FEB2013
UNUNK2013
2
recovering/resolving
post 1st dose
UNUNK2013
UNFEB2013
2
not recovered/resolved
post 1st dose
Post imputation:
Start date
Condition end date
Severity
Outcome
15FEB2013
UNUNK2013
2
recovering/resolving
31JAN2013*
15FEB2013
2
not recovered/resolved
*Note: This AE would now precede the other AE with the same year after sorting.
                   
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APPENDIX 4 OCULAR AES OF INTEREST SSQ DEFINITION
Preferred Terms for SSQ Corneal Adverse Events
Acquired corneal dystrophy
Corneal epithelium defect
Keratitis interstitial
Allergic keratitis
Corneal erosion
Keratitis sclerosing
Atopic keratoconjunctivitis
Corneal exfoliation
Keratoconus
Bowman’s membrane disorder
Corneal hypertrophy
Keratopathy
Corneal abrasion
Corneal infiltrates
Keratorhexis
Corneal abscess
Corneal irritation
Limbal hyperaemia
Corneal bleeding
Corneal lesion
Limbal stem cell deficiency
Corneal cyst
Corneal oedema
Limbal swelling
Corneal decompensation
Corneal opacity
Macrocornea
Corneal defect
Corneal perforation
Microcornea
Corneal degeneration
Corneal pigmentation
Neurotrophic keratopathy
Corneal deposits
Corneal scar
Photokeratitis
Corneal diameter decreased
Corneal striae
Punctate keratitis
Corneal diameter increased
Corneal thickening
Terrien’s marginal 
degeneration
Corneal disorder
Corneal thinning
Topography corneal abnormal
Corneal dystrophy
Dellen
Ulcerative keratitis
Corneal endothelial cell loss
Detached Descemet’s 
membrane
Vital dye staining cornea 
present
Corneal endotheliitis
Iridocorneal endothelial 
syndrome
Deposit eyea
Corneal epithelial microcysts
Keratic precipitates
Ocular toxicitya
Dry eyeb
Keratitis
Slit-lamp tests abnormala
a Broad Terms                                                            b only if LLT is “Keratoconjunctivitis sicca”
Preferred Terms for SSQ Eye Symptom Adverse Events
(Preferred Terms for Blurry Vision Adverse Events are labeled with *)
Abnormal sensation eye
Excessive eye blinking
Oscillopsia
*Acute Myopia
Eye disorder
Photalgia
Amaurosis
Eye irritation
Photophobia
                   
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Amaurosis fugax
Eye pain
Photopsia
Asthenopia
Eye pruritis
Presbyopia
*Blindness
Eyelid pain
Saccadic eye monement
*Blindness day
Foreign body sensation in eyes
Scintillating scotoma
*Blindness transient
Halo vision
Tunnel vision
*Blindness unilateral
Hypoaesthesia eye
*Vision blurred
Chloropsia
Lacrimal disorder
*Visual acuity reduced
Colour blindness
Lacrimation decreased
*Visual acuity reduced 
transiently
Colour blindness acquired
Lacrimation increased
Visual brightness
Contact lens intolerance
Loss of visual contrast 
sensitivity
*Visual impairment
Cyanopsia
Meibomian gland discharge
Vitreous floaters
*Diplopia
Meibomian gland dysfunction
Xanthopsia
Dry eyea
*Myopia
Xerophthalmia
Dysmetropsia
*Night blindness
Erythropsia
Ocular discomfort
a  if the LLT is “Keratoconjunctivitis sicca”, the event will be categorized as corneal SSQ
                   
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