Conditions: Acute Myeloid Leukemia
Keywords: Antibodies, monoclonal Antibody drug conjugate Antigens, cluster of differentiation 33 (CD33) Drug therapy Immunotherapy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 240
Healthy volunteers: no

Brief summary:
The purpose of this study in AML patients is to test whether vadastuximab talirine (SGN-CD33A; 33A) combined with either azacitidine or decitabine improves remission rates and extends overall survival as compared to placebo combined with either azacitidine or decitabine.

Detailed description:
Hypomethylating agents (HMAs), such as decitabine or azacitidine, are considered a standard treatment for older patients with AML. The primary goals of this study are to test whether patients treated with an HMA (either decitabine or azacitidine) in combination with 33A will have better anti-tumor activity and/or survive longer than patients treated with an HMA in combination with placebo.

Patients who meet eligibility criteria will be randomly assigned to one of two treatment groups: 1) 33A plus HMA (Experimental Arm); or 2) placebo plus HMA (Comparator Arm). In addition to evaluating survival and remission rates, the minimal residual disease (MRD)-negative remission rate, duration of remission, event free- and leukemia-free survival, and safety and tolerability will be compared between arms.

Arms:
arm 1: 33A plus azacitidine or decitabine arm 2: placebo plus azacitidine or decitabine

Interventions: intervention 1: 33A intervention 2: placebo intervention 3: azacitidine intervention 4: decitabine
Intervention descriptions: intervention 1: 33A, 10 mcg/kg, every 4 weeks via intravenous (IV) push intervention 2: Volume equivalent to 10 mcg/kg, every 4 weeks via IV push intervention 3: 75 mg/m2 given subcutaneously (SC) or IV x 7 days, every 4 weeks intervention 4: 20 mg/m2 given IV x 5 days, every 4 weeks

Protocol document:
Prot_001.pdf: 


Study SGN33A-005 
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PROTOCOL SYNOPSIS 
Protocol Number 
SGN33A-005 
Version 
Amendment 3; 27-March-2017 
Phase 
Phase 3 
Product Name 
vadastuximab talirine 
Sponsor 
Seattle Genetics, Inc. 
21823 30th Drive SE 
Bothell, WA 98021, USA 
 
Protocol Title 
A randomized, double-blind phase 3 study of vadastuximab talirine (SGN-CD33A) versus placebo in 
combination with azacitidine or decitabine in the treatment of older patients with newly diagnosed acute 
myeloid leukemia (AML) 
Study Objectives 
Primary 
● 
To compare the composite complete remission (CRc) rate (morphologic complete remission [CR] and 
morphologic CR with incomplete hematologic recovery [CRi]) between treatment arms 
● 
To compare overall survival (OS) between treatment arms 
Secondary 
● 
To compare the minimal residual disease-negative remission (MRD-negative CRc) rate between treatment 
arms 
● 
To evaluate the duration of remission in the 2 treatment arms 
● 
To evaluate event-free survival (EFS) in the 2 treatment arms 
● 
To evaluate leukemia-free survival (LFS) in the 2 treatment arms 
● 
To evaluate the safety profiles in the 2 treatment arms 
● 
To evaluate the time to response in the 2 treatment arms 
● 
To evaluate the 30- and 60-day mortality rates in the 2 treatment arms 
Additional 
● 
To evaluate the treatment effect of vadastuximab talirine compared to the control group on the change in 
patient reported outcomes (PRO) and medical resource utilization (MRU) 
● 
To assess the incidence of antitherapeutic antibodies (ATA) 
● 
To assess exploratory markers of clinical outcome and the pharmacodynamics of vadastuximab talirine in 
combination with a hypomethylating agent (HMA) 
Study Population 
The population to be studied includes patients with newly diagnosed, previously untreated, cytologically or 
histologically confirmed de novo or secondary acute myeloid leukemia (AML), with intermediate or adverse 
cytogenetic risk (per revised UK Medical Research Council [MRC] classification, (Grimwade 2010), who are 
not considered candidates for allogeneic stem cell transplant. Eligible patients must be ≥18 years of age and 
have a life expectancy of at least 12 weeks. In addition, patients must be eligible for therapy with either 
decitabine or azacitidine, have an Eastern Cooperative Oncology Group (ECOG) performance status of ≤2 
(patients age ≥80 years must have an ECOG performance status of 0 or 1), and have adequate baseline hepatic 
and renal function. 
Patients must not have a history of essential thrombocythemia, polycythemia vera, or primary myelofibrosis, 
must not have received prior treatment with an HMA or chemotherapy for antecedent myelodysplastic 


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syndrome (MDS), or have a history of allogeneic stem cell transplant. In addition, patients must not have 
concurrent active malignancy other than nonmelanoma skin cancer or carcinoma in situ of the following: 
bladder, stomach, colon, cervix, endometrium, melanoma, or breast. Patients with previous malignancies are 
eligible if the malignancy has been confined and surgically resected (or treated with other modalities) with 
curative intent. Any active systemic therapy must have been completed >1 year from enrollment (except for 
hormonal/anti-hormonal treatment, e.g. breast cancer). Patients are also excluded if they have central nervous 
system leukemia based on imaging or documented positive cytology in cerebral spinal fluid, or if they have had 
any uncontrolled Grade 3 or higher viral, bacterial, or fungal infection within 14 days prior to the first dose of 
study treatment. 
Number of Planned Patients 
Approximately 540 patients will be randomized in this trial. 
Study Design 
This is a randomized, double-blind, placebo-controlled phase 3 study designed to compare the CRc rate and OS 
between patients treated with HMA plus vadastuximab talirine (experimental arm) versus patients treated with 
HMA plus placebo (comparator arm). Patients will be randomized in a 1:1 manner to one of the study arms. 
Investigators may select either HMA (azacitidine or decitabine). 
Response will be assessed by bone marrow examination and complete blood counts (CBC) between Day 22 to 
28 of even numbered cycles until CR or CRi. The response assessment window may be up to Day 42 in the 
event of a delay in the start of the next cycle of treatment. After CR or CRi, response assessment will continue 
to be performed by CBC surveillance. In addition, bone marrow examination will be conducted according to the 
following schedule: 
● 
2 cycles after initial confirmation of CR or CRi 
● 
At the time of conversion from CRi to CR 
● 
At the time of suspected relapse 
● 
End of treatment (EOT), if not performed within the previous 4 weeks 
Patients may continue on study treatment until progression, leukemic recurrence, or unacceptable toxicity, 
whichever comes first. Patients who achieve stable disease or better should receive a minimum of 4 cycles of 
study treatment. Progression is defined after 4 or more cycles of treatment as either a >25% absolute rise in the 
percent of bone marrow blasts from baseline (or a proportional increase of >25% in patients with baseline bone 
marrow blasts >75%), or appearance of new extramedullary disease. Patients who fulfill the criteria for 
progression but who are still deriving clinical benefit in the opinion of the investigator may continue on study 
treatment. 
After discontinuation of study treatment, patients will be followed for survival status every 2 months (or more 
frequently as needed to support analysis of the study endpoints) after EOT until death or study closure, 
whichever comes first. Patients who have not experienced progression or leukemic recurrence will continue to 
be assessed for response by CBC surveillance every 2 months through 24 months after EOT, and every 
4 months thereafter, until initiation of another anticancer treatment (excluding stem cell transplant and 
maintenance therapy in the absence of relapse), progression, or leukemic recurrence, whichever comes first. 
Two interim analyses for OS are planned: the first interim analysis is to evaluate futility and the second interim 
analysis is to evaluate the superiority of vadastuximab talirine. 
Safety will be monitored over the course of the study by an Independent Data Monitoring Committee (IDMC). 


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Test Product, Dose, and Mode of Administration 
Both Arms 
HMA, either: 
● 
Azacitidine 75 mg/m2 given subcutaneously (SC) or intravenously (IV) x 7 (7 consecutive days or 5 days 
on/2 days off/2 days on), every 4 weeks, or 
● 
Decitabine 20 mg/m2 given IV daily x 5, every 4 weeks 
Experimental Arm 
Blinded study treatment: vadastuximab talirine, 10 mcg/kg, every 4 weeks (on the last day of HMA 
administration) via IV push 
Comparator Arm 
Blinded study treatment: placebo, volume equivalent to 10 mcg/kg, every 4 weeks (on the last day of HMA 
administration) via IV push 
Duration of Treatment 
Patients may continue on study treatment until progression, leukemic recurrence, or unacceptable toxicity, 
whichever comes first. Patients who achieve stable disease or better should receive a minimum of 4 cycles of 
study treatment. 
Efficacy Assessments 
Anti-leukemic activity will be assessed by routine laboratory tests and bone marrow examinations. Response 
will be determined according to a modification of the response categorization in the Revised Recommendations 
of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, 
and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia (Cheson 2003). 
Safety Assessments 
Safety assessments will include the surveillance and recording of adverse events (AEs), physical examination 
findings, and laboratory tests. 
Quality of Life Assessments 
Patient-reported outcome (PRO) assessments will be used to obtain quality of life information at 
protocol-specified timepoints. Two validated tools will be used: the EORTC Quality of Life Questionnaire, 
QLQ-C30, and the EuroQol 5-dimensions (EQ-5D). 
Pharmacokinetic, ATA, and Biomarker Assessments 
Validated enzyme-linked immunosorbent assays (ELISA) and liquid chromatography-tandem mass 
spectrometry (LC-MS/MS) assays will be used to measure vadastuximab talirine and its associated drug, 
SGD-1882, respectively. A qualified electrochemiluminescence assay will be used to measure concentrations of 
ATA in serum. Biomarker assessments may include central assessment of CD33 expression, profiling for 
somatic mutations or alterations in genes or RNAs commonly altered in hematologic malignancies, and other 
genes or RNAs potentially associated with disease relapse or resistance to vadastuximab talirine. MRD will be 
measured. Additional assessments may include measurement of soluble factors such as sCD33 that may be 
associated with clinical outcome. 
Statistical Methods 
Stratification 
Patients will be stratified based on the following variables: 
● 
Cytogenetic risk per revised MRC classification 
● 
ECOG performance status 
● 
HMA 
● 
Age 


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Sample Size Considerations 
There are 2 primary endpoints for this study, CRc rate and OS. To maintain strong control of type I error rate at 
0.05, a fallback procedure proposed by Wiens will be used in the testing of the primary endpoints, with an alpha 
of 0.01 pre-assigned to CRc rate and an alpha of 0.04 pre-assigned to OS. 
The sample size was calculated based on maintaining 90% power to test both primary endpoints and to account 
for 2 planned interim analyses for OS using the O’Brien-Fleming method. 
For the primary endpoint of CRc rate, at least 308 patients are required to provide 90% power to detect an 
improvement in CRc rate from 20% to 40% using a chi-squared test at a significance level of 0.01. 
For the primary endpoint of OS, approximately 354 OS events are required with 90% power to detect a hazard 
ratio of 0.70 (12.9 months median OS in the experimental arm [vadastuximab talirine plus HMA] versus 
9 months for the comparator arm [placebo plus HMA]) using a 2-sided log-rank test at an alpha of 0.04. 
To provide adequate power for both primary endpoints, a total of 540 patients will be randomized in a 1:1 ratio 
to either the experimental arm or the comparator arm, assuming an accrual period of approximately 26 months 
with a slower rate of accrual for the first 6 months, a 12 month follow-up, and a 5% yearly drop-out rate. 
Timing of Analyses 
The primary analysis of CRc rate is planned when the following 2 conditions are met: 1) 6 months after 
308 patients have been randomized, and 2) approximately 212 OS events have occurred. The estimated duration 
of the study through the primary analysis of CRc rate is approximately 2 years from randomization of the first 
patient based on the design assumptions. Only the first 308 patients randomized will be included in the primary 
analysis of CRc rate. CRc rate will also be analyzed for all randomized patients at the time of the final analysis. 
The estimated duration of the study through the final analysis for OS is approximately 3 years from 
randomization of the first patient based on design assumptions. 
Two formal interim analyses for OS are planned in this study. The first interim analysis will take place when 
approximately 106 OS events have occurred (~30% of the targeted number of events) and will assess the futility 
of vadastuximab talirine in combination with azacitidine or decitabine. 
The second interim analysis for OS will occur in conjunction with the primary analysis of CRc rate. The 
analysis will be conducted when the following 2 conditions are met: 1) 6 months after 308 patients have been 
randomized, and 2) approximately 212 OS events have occurred (~60% of the targeted number of events). The 
interim OS results will be assessed for early stopping for efficacy. 
The IDMC will provide recommendations to the sponsor's Data Review Board as to appropriate study direction 
at the interim analyses. 
Analysis Methods 
CRc rate and OS will be analyzed based on the intent-to-treat (ITT) population. 
The CRc rate between the experimental and comparator arms will be compared using the Cochran-Mantel-
Haenszel test. OS will be analyzed using the Kaplan-Meier method. A stratified log-rank test without 
adjustments for covariates will be used in the primary evaluation of OS differences between the 2 treatment 
arms. The hazard ratio along with its confidence intervals will be estimated using an unadjusted stratified Cox 
model. 


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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ....................................................................................................................................... 2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ......................................................................... 9 
1 
INTRODUCTION ......................................................................................................................................... 11 
1.1 
Acute Myeloid Leukemia ................................................................................................................... 11 
1.2 
Therapy for AML Patients Unfit for Intensive Induction Chemotherapy ........................................... 11 
1.3 
CD33 .................................................................................................................................................. 12 
1.4 
Vadastuximab Talirine ....................................................................................................................... 12 
1.5 
Rationale for Vadastuximab Talirine in Combination with Hypomethylating Agents ....................... 13 
2 
OBJECTIVES ............................................................................................................................................... 14 
2.1 
Primary Objectives ............................................................................................................................. 14 
2.2 
Secondary Objectives ......................................................................................................................... 14 
2.3 
Additional Objectives ......................................................................................................................... 14 
2.4 
Endpoints ............................................................................................................................................ 14 
2.4.1 
Primary Efficacy Endpoints.................................................................................................... 14 
2.4.2 
Secondary Endpoints .............................................................................................................. 14 
2.4.3 
Additional Endpoints .............................................................................................................. 15 
3 
INVESTIGATIONAL PLAN ....................................................................................................................... 15 
3.1 
Summary of Study Design .................................................................................................................. 15 
3.1.1 
Study Stopping Criteria .......................................................................................................... 17 
3.2 
Discussion and Rationale for Study Design........................................................................................ 17 
3.2.1 
Method of Assigning Patients to Treatment Groups .............................................................. 18 
3.2.2 
Rationale for Selection of Doses ............................................................................................ 18 
3.2.3 
Blinding .................................................................................................................................. 19 
4 
STUDY POPULATION................................................................................................................................ 19 
4.1 
Inclusion Criteria ................................................................................................................................ 19 
4.2 
Exclusion Criteria ............................................................................................................................... 20 
4.3 
Childbearing Potential ........................................................................................................................ 22 
4.4 
Removal of Patients From Therapy or Assessment ............................................................................ 22 
4.4.1 
Discontinuation of Study Drug ............................................................................................... 22 
4.4.2 
Patient Withdrawal From Study ............................................................................................. 22 
5 
TREATMENTS ............................................................................................................................................ 23 
5.1 
Treatments Administered.................................................................................................................... 23 
5.2 
Investigational Study Drug ................................................................................................................. 23 
5.2.1 
Description ............................................................................................................................. 23 
5.2.2 
Dose and Administration ........................................................................................................ 24 
5.2.3 
Dose Modifications ................................................................................................................ 24 
5.2.4 
Storage and Handling ............................................................................................................. 25 
5.2.5 
Packaging and Labeling ......................................................................................................... 26 
5.2.6 
Preparation.............................................................................................................................. 26 
5.3 
Azacitidine and Decitabine ................................................................................................................. 26 
5.3.1 
Description ............................................................................................................................. 26 
5.3.2 
Method of Procurement .......................................................................................................... 26 
5.3.3 
Dose and Administration ........................................................................................................ 27 
5.3.4 
Storage and Handling ............................................................................................................. 27 
5.3.5 
Packaging and Labeling ......................................................................................................... 27 
5.3.6 
Preparation.............................................................................................................................. 27 
5.4 
Required Premedication and Postmedication ..................................................................................... 27 
5.5 
Concomitant Therapy ......................................................................................................................... 27 
5.5.1 
Required Concomitant Therapy.............................................................................................. 27 
5.5.2 
Allowed Concomitant Therapy .............................................................................................. 27 
5.5.3 
Prohibited Concomitant Therapy ............................................................................................ 28 


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5.6 
Management of Adverse Reactions .................................................................................................... 28 
5.6.1 
Management of Infusion Reactions ........................................................................................ 28 
5.6.2 
Overdose ................................................................................................................................. 29 
5.7 
Treatment Compliance ....................................................................................................................... 29 
6 
STUDY ACTIVITIES ................................................................................................................................... 29 
6.1 
Schedule of Events ............................................................................................................................. 29 
6.2 
Screening Visit (Days −28 to 1) ......................................................................................................... 29 
6.2.1 
Baseline Visit (Days −7 to Day 1) .......................................................................................... 29 
6.3 
Treatment Period (Day 1 to Day 28) .................................................................................................. 30 
6.3.1 
Day 1 (±1 day) of Each Cycle ................................................................................................ 30 
6.3.2 
Day 2 to 4 of Each Cycle ........................................................................................................ 30 
6.3.3 
Day 5 of Each Cycle ............................................................................................................... 31 
6.3.4 
Day 6 of Each Cycle (only for patients receiving azacitidine; Day 8 if alternative azacitidine 
dosing schedule used) ............................................................................................................. 31 
6.3.5 
Day 7 of Each Cycle (only for patients receiving azacitidine; Day 9 if alternative azacitidine 
dosing schedule used) ............................................................................................................. 31 
6.3.6 
Day 15 (±2 days) of Cycles 1−4 only ..................................................................................... 31 
6.3.7 
Day 21 (±2 days) of Cycles 1 and 2 only ............................................................................... 32 
6.3.8 
Day 28 (–6 day window) of Each Even Numbered Cycle ...................................................... 32 
6.4 
End of Treatment Visit (30 to 37 days after last dose of study drug) ................................................. 32 
6.5 
Follow-up ........................................................................................................................................... 33 
6.6 
End of Study/End of Follow-up .......................................................................................................... 33 
7 
STUDY ASSESSMENTS ............................................................................................................................. 34 
7.1 
Screening/Baseline Assessments ........................................................................................................ 34 
7.2 
Response/Efficacy Assessments ......................................................................................................... 34 
7.3 
Pharmacokinetic, ATA, and Biomarker Assessments ........................................................................ 34 
7.4 
Biospecimen Repository ..................................................................................................................... 35 
7.5 
Patient Reported Outcome Assessments ............................................................................................. 35 
7.5.1 
EORTC Core Quality of Life Questionnaire, QLQ-C30 ........................................................ 35 
7.5.2 
EuroQol-5 Dimensions ........................................................................................................... 35 
7.6 
Medical Resource Utilization ............................................................................................................. 36 
7.7 
Safety Assessments............................................................................................................................. 36 
7.7.1 
Adverse Events ....................................................................................................................... 36 
7.7.2 
Clinical Laboratory Tests ....................................................................................................... 41 
7.7.3 
Physical Examination ............................................................................................................. 41 
7.7.4 
Cardiac Monitoring ................................................................................................................ 42 
7.7.5 
ECOG Performance Status ..................................................................................................... 42 
7.7.6 
Vital Signs .............................................................................................................................. 42 
7.8 
Appropriateness of Measurements...................................................................................................... 42 
8 
DATA QUALITY CONTROL AND QUALITY ASSURANCE ................................................................ 42 
8.1 
Site Training and Monitoring Procedures ........................................................................................... 42 
8.2 
Data Management Procedures ............................................................................................................ 43 
8.3 
Access to Source Data ........................................................................................................................ 43 
8.4 
Accuracy and Reliability of Data........................................................................................................ 44 
8.5 
Quality Assurance Procedures ............................................................................................................ 44 
8.6 
Data Handling and Record Keeping ................................................................................................... 44 
8.6.1 
Data Handling ......................................................................................................................... 44 
8.6.2 
Investigator Record Retention ................................................................................................ 44 
9 
DATA ANALYSIS METHODS ................................................................................................................... 45 
9.1 
Determination of Sample Size ............................................................................................................ 45 
9.2 
Study Endpoint Definitions ................................................................................................................ 45 
9.2.1 
Primary Endpoints .................................................................................................................. 45 
9.2.2 
Secondary Efficacy Endpoints................................................................................................ 46 
9.3 
Statistical and Analytical Plans .......................................................................................................... 47 


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9.3.1 
General Considerations .......................................................................................................... 47 
9.3.2 
Patient Disposition ................................................................................................................. 50 
9.3.3 
Patient Characteristics ............................................................................................................ 50 
9.3.4 
Treatment Compliance ........................................................................................................... 50 
9.3.5 
Efficacy Analyses ................................................................................................................... 50 
9.3.6 
Pharmacokinetic, ATA, and Biomarker Analyses .................................................................. 51 
9.3.7 
Patient Reported Outcomes Analyses ..................................................................................... 52 
9.3.8 
MRU Analyses ....................................................................................................................... 52 
9.3.9 
Safety Analyses ...................................................................................................................... 52 
9.3.10 Interim Analyses ..................................................................................................................... 53 
10 INFORMED CONSENT, ETHICAL REVIEW, AND REGULATORY CONSIDERATIONS ................. 54 
10.1 Informed Consent ............................................................................................................................... 54 
10.2 Ethical Review .................................................................................................................................... 54 
10.3 Regulatory Considerations.................................................................................................................. 54 
10.3.1 Investigator Information ......................................................................................................... 54 
10.3.2 Protocol Amendments and Study Termination ....................................................................... 55 
10.4 Study Documentation, Privacy and Records Retention ...................................................................... 55 
10.5 Clinical Trial Agreement .................................................................................................................... 55 
11 REFERENCES .............................................................................................................................................. 56 
APPENDIX A-1: 
SCHEDULE OF EVENTS – AZACITIDINE .................................................................. 60 
APPENDIX A-2: 
SCHEDULE OF EVENTS – DECITABINE ................................................................... 61 
APPENDIX B: 
PHARMACOKINETIC, ATA, AND BIOMARKER SAMPLING TIMEPOINTS ........ 62 
APPENDIX C: 
ECOG AND KARNOFSKY PERFORMANCE STATUS .............................................. 63 
APPENDIX D: 
REVISED MRC PROGNOSTIC CLASSIFICATION BASED ON  
MULTIVARIABLE ANALYSES .................................................................................... 64 
APPENDIX E: 
RESPONSE CATEGORIES ............................................................................................. 65 
APPENDIX F: 
NEW YORK HEART ASSOCIATION (NYHA) CLASSIFICATION ........................... 66 
APPENDIX G 
GUIDANCE ON CONTRACEPTION ............................................................................. 67 
APPENDIX H: 
INVESTIGATOR SIGNATURE PAGE .......................................................................... 68 
APPENDIX I: 
DOCUMENT HISTORY ................................................................................................. 69 
 
LIST OF IN-TEXT TABLES 
Table 1: 
Dose modifications for blinded study treatment-associated toxicity ............................................. 25 
LIST OF IN-TEXT FIGURES 
Figure 1: 
Study Design ................................................................................................................................. 16 
Figure 2: 
Study Treatments ........................................................................................................................... 23 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ADC 
antibody-drug conjugate 
AE 
adverse event 
Allo-SCT 
allogeneic stem cell transplant 
ALT 
alanine aminotransferase 
AML 
acute myeloid leukemia 
APL 
acute promyelocytic leukemia  
AST 
aspartate aminotransferase 
ATA 
antitherapeutic antibodies 
CBC 
complete blood count 
CCI 
Charlson Comorbidity Index 
CR 
morphologic complete remission  
CRc 
composite complete remission (CR+CRi) 
CRF 
case report form 
CRi 
morphologic complete remission with incomplete blood count recovery 
CRi(n) 
morphologic complete remission with incomplete neutrophil recovery 
CRi(p)/CRp 
morphologic complete remission with incomplete platelet recovery 
CTFG 
Clinical Trial Facilitation Group 
DLT 
dose-limiting toxicity 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EFS 
event-free survival 
ELISA 
enzyme-linked immunosorbent assays  
EOT 
end of treatment 
EQ-5D 
EuroQuol 5-dimensions 
GCP 
good clinical practice 
HCT-CI 
Hematopoietic Cell Transplantation-Specific Comorbidity Index 
HIV 
human immunodeficiency virus 
HMA 
hypomethylating agents 
HNSTD 
highest non-severely toxic dose  
ICH 
International Conference on Harmonisation  
IDMC 
independent data monitoring committee 
IEC 
independent ethics committee 
IND 
Investigational New Drug 
IRB 
institutional review board 
ITT 
intent-to-treat 
IV 
intravenous(ly) 
LC-MS/MS 
liquid chromatography-tandem mass spectrometry 
LFS 
leukemia-free survival 
LTFU 
long-term follow up 
MCV 
mean corpuscular volume 
MDR 
multidrug resistant 
MDS 
myelodysplastic syndrome 
MedDRA 
Medical Dictionary for Regulatory Activities 
mLFS 
morphologic leukemia-free state  
MRC 
Medical Research Council 


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MRD 
minimal residual disease 
MRU 
medical resource utilization 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NOAEL 
no observed adverse effect level  
OS 
overall survival 
PBD 
pyrrolobenzodiazepine 
PCR 
polymerase chain reaction 
PD 
progressive disease 
PICC 
peripherally inserted central catheter  
PR 
partial remission 
PRO 
patient reported outcome 
RBC 
red blood cell 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous(ly) 
SCT 
stem cell transplant 
SD 
stable disease 
Siglec 
sialic acid binding sialoadhesin receptor  
SmPC 
summary of product characteristics 
SOS 
sinusoidal obstructive syndrome 
TTCR 
time to complete remission  
TLS 
tumor lysis syndrome  
ULN 
upper limit of normal 
VOD 
veno-occlusive disease 
WBC 
white blood cell  
 


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1 
INTRODUCTION 
1.1 Acute Myeloid Leukemia 
Acute myeloid leukemia (AML) is a bone marrow malignancy defined by the dysregulation 
of differentiation and proliferation of hematopoietic progenitor cells. This results in the 
uncontrolled proliferation of immature malignant cell blasts and a deficiency in normal blood 
cells. If untreated, AML generally causes death in weeks to months due to infection, 
bleeding, or complications related to a large volume of abnormal cells in the vasculature 
(e.g., disseminated intravascular coagulopathy, endothelial damage). There are 
approximately 37,000 cases of AML per year across the EU and US (Visser 2012; Siegel 
2014). The prognosis for AML heavily depends on factors such as patient age, cytogenetic 
and molecular abnormalities, and underlying myelodysplasia. 
1.2 Therapy for AML Patients Unfit for Intensive Induction Chemotherapy 
AML is associated with poor survival rates in patients who are not eligible for intensive 
chemotherapy due to advanced age, medical comorbidities, and/or disease risk factors. Low 
intensity therapies, such as low dose cytarabine (Burnett 2007), and hypomethylating agents 
(HMAs), such as decitabine or azacitidine, are frequently employed for this population. 
Randomized trials in older patients with AML have demonstrated a trend toward 
improvement in overall survival (OS) for patients treated with either azacitidine or decitabine 
versus low-dose cytarabine (Fenaux 2010; Kantarjian 2012; Dombret 2015). Outcomes with 
either of these low-intensity therapies remain suboptimal in this population with very few 
long-term survivors. The DACO-016 study of decitabine versus treatment choice (low dose 
cytarabine or best supportive care) in patients ≥65 years old with newly diagnosed AML 
(blasts ≥20%) and poor or intermediate risk cytogenetics, demonstrated an improvement in 
the remission rate (complete remission [CR] + complete remission with incomplete platelet 
recovery [CRp]) of 17.8% vs. 7.8% (p=0.001) and a nonsignificant increase in median OS of 
7.7 months vs. 5 months (p=0.108) (Kantarjian 2012). The AML-001 trial of azacitidine 
compared to conventional care regimens (including supportive care, low dose cytarabine, or 
intensive chemotherapy) in patients ≥65 years old with newly diagnosed AML (blasts ≥30%) 
and poor or intermediate risk cytogenetics, demonstrated a CR+ complete remission with 
incomplete blood count recovery (CRi) rate of 27.8% vs. 25.1% (p=0.5384) and a median OS 
of 10.4 month vs. 6.5 month (p=0.1009) (Dombret 2015). 
Although intensive chemotherapy-based therapies are available, these approaches in older, 
unfit patients with AML are associated with increased treatment-related mortality and 
inferior outcomes compared to younger, fit patients (Juliusson 2009; Kantarjian 2010). 
Deaths during initial treatment with intensive regimens have been reported in as many as 
20 to 30% of patients (Klepin 2013), treatments require prolonged hospitalizations (Roboz 
2012), and the 5-year OS is approximately 10%. The AML-001 trial of azacitidine in this 
patient population has demonstrated that the overall survival rate with azacitidine was 
equivalent, if not superior, to intensive chemotherapy (Dombret 2015). Retrospective 
observational studies have also demonstrated that survival rates are equivalent in older 


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patients when treated with HMA compared to standard anthracycline/cytarabine-based 
regimens studies (Quintas-Cardama 2012; Gupta 2015). 
Given the lack of safe and effective therapeutic options for primarily older adults with AML 
who are not candidates for intensive induction chemotherapy, there continues to be a 
significant unmet medical need for improved treatment options in this patient population. 
1.3 CD33 
CD33, also known as Siglec-3 or gp67, is a 67 kilodalton glycosylated transmembrane 
protein of the sialic acid binding sialoadhesin receptor (Siglec) family (von Gunten 2008; 
Jandus 2011). Signaling through CD33 has been reported to mediate inhibitory signals that 
regulate intracellular calcium mobilization (Ulyanova 1999), cell adhesion (Taylor 1999), 
apoptosis of leukemic cells (Vitale 2001), myeloid cell maturation (Ferlazzo 2000), as well 
as production of cytokines (Sutherland 2009). 
The CD33 antigen is present on the surface of malignant cells in the majority of patients with 
AML. As described in detail in the vadastuximab talirine Investigator’s Brochure, 
CD33-targeted agents have been investigated as treatments for AML with modest success. 
For example, efforts to integrate the CD33-targeted antibody drug conjugate (ADC) 
gemtuzumab ozogamicin as part of frontline AML therapy have demonstrated improvement 
in event-free and/or overall survival in subsets of patients (Burnett 2011; Delaunay 2011; 
Burnett 2012; Castaigne 2012). Taken together, these previous data help confirm the validity 
of CD33 as a drug target, but suggest that an improved ADC with a favorable safety and 
toxicity profile is desirable (Jurcic 2012). 
1.4 Vadastuximab Talirine 
Vadastuximab talirine (also referred to as SGN-CD33A) is an ADC consisting of 
3 functional subunits: 1) an anti-CD33 antibody with an engineered cysteine residue in 
position 239 of each heavy chain (h2H12ec), 2) a DNA cross-linking pyrrolobenzodiazepine 
(PBD) dimer drug (SGD-1882), and 3) a protease-cleavable linker that covalently attaches 
SGD-1882 to h2H12ec.
 
 
 
 
 
 


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1.5 Rationale for Vadastuximab Talirine in Combination with 
Hypomethylating Agents 
Hypomethylating agents (HMAs) reduce the methylation of genes through covalent 
interactions with DNA methyltransferase enzymes (Lyko 2005), resulting in the increased 
expression of epigenetically silenced genes. Gene demethylation and disruption of the 
genetic machinery by azacitidine or decitabine have been reported to promote cell 
differentiation and to exert cytotoxic effects on tumor cells (Flotho 2009; Hollenbach 2010). 
Epigenetic priming with HMAs has also been shown to sensitize resistant tumor cells to 
cytotoxic drugs (Plumb 2000; Niitsu 2006; Qin 2007). 
In preclinical studies combining vadastuximab talirine with HMAs (azacitidine and 
decitabine), enhanced activity was demonstrated in multidrug resistant (MDR)-positive AML 
models (Sutherland 2014). Enhanced tumor cell killing in these models was associated with 
synergism in the activation of the DNA damage sensory and apoptosis pathways. 
Furthermore, increased exposure of AML cells to HMAs appeared to modestly upregulate 
cell surface expression of CD33 and increase incorporation of PBD dimer into DNA 
(Sutherland 2015). The combination of HMAs with vadastuximab talirine may exact a 
greater burden on the DNA repair pathway in leukemic cells, enhancing the processes 
leading to apoptosis and cell death. 
The clinical safety and activity of vadastuximab talirine has been evaluated in a phase 1 
first-in-human study (Study SGN33A-001), with 10 mcg/kg identified as the recommended 
dose in combination with decitabine or azacitidine. In the combination cohort of this phase 1 
study (N=24), the regimen was generally well tolerated with a low early mortality rate 
observed. At the time of an interim analysis (July 2015), Grade 3 or higher adverse events 
(AEs) reported in >20% of patients were febrile neutropenia (46%), anemia (25%), 
neutropenia (25%), and thrombocytopenia (21%). Other treatment-emergent AEs regardless 
of relationship to study treatment reported in ˃20% of patients were nausea (29%), decreased 
appetite (25%), and constipation (21%). Fifteen of the 23 efficacy evaluable patients (65%) 
achieved CR (5 patients, 22%) or CRi (10 patients, 43%) (Fathi 2015). Complete remissions 
were observed in patients with adverse risk factors. 
A complete summary of the clinical and nonclinical data relevant to the investigational 
product and its study in human subjects is provided in the Investigator’s Brochure. 


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2 
OBJECTIVES 
2.1 Primary Objectives 
● 
To compare the composite complete remission (CRc) rate (morphologic complete 
remission [CR] and morphologic CR with incomplete hematologic recovery [CRi]) 
between treatment arms 
● 
To compare overall survival (OS) between treatment arms 
2.2 Secondary Objectives 
● 
To compare the minimal residual disease-negative remission (MRD-negative CRc) 
rate between treatment arms 
● 
To evaluate the duration of remission in the 2 treatment arms 
● 
To evaluate event-free survival (EFS) in the 2 treatment arms 
● 
To evaluate leukemia-free survival (LFS) in the 2 treatment arms 
● 
To evaluate the safety profiles in the 2 treatment arms 
● 
To evaluate the time to response in the 2 treatment arms 
● 
To evaluate the 30- and 60-day mortality rates in the 2 treatment arms 
2.3 Additional Objectives 
● 
To evaluate the treatment effect of vadastuximab talirine compared to the control 
group on the change in patient reported outcomes (PRO) and medical resource 
utilization (MRU) 
● 
To assess the incidence of antitherapeutic antibodies (ATA) 
● 
To assess exploratory markers of clinical outcome and the pharmacodynamics of 
vadastuximab talirine in combination with a hypomethylating agent (HMA) 
2.4 Endpoints 
2.4.1 Primary Efficacy Endpoints 
● 
CRc rate 
● 
OS 
2.4.2 Secondary Endpoints 
The secondary endpoints are: 
● 
MRD-negative CRc rate 
● 
Duration of remission 


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● 
EFS 
● 
LFS 
● 
Type, incidence, severity, seriousness, and relatedness of adverse events 
● 
Laboratory abnormalities 
● 
Time to CR or CRi 
● 
Mortality rates at Day 30 and Day 60 post the first study treatment 
2.4.3 Additional Endpoints 
● 
Change from baseline in PRO 
● 
MRU based on the number of medical care encounters 
● 
Incidence of ATA to vadastuximab talirine 
● 
Biomarkers of pharmacodynamic effects 
● 
Exploratory markers of clinical activity 
3 
INVESTIGATIONAL PLAN 
3.1 Summary of Study Design 
This is a randomized, double-blind, placebo-controlled, phase 3 study designed to compare 
the CRc rate and OS between patients treated with HMA plus vadastuximab talirine 
(experimental arm) versus patients treated with HMA plus placebo (comparator arm). 
Approximately 540 patients will be randomized in a 1:1 manner to one of the study arms 
(~270 patients per arm). Investigators may select either HMA (azacitidine or decitabine; see 
Section 5.1 for details). 
Response will be assessed by bone marrow examination and complete blood counts (CBC) 
conducted between Day 22 to 28 of even-numbered cycles until CR or CRi. The response 
assessment window may be up to Day 42 in the event of a delay in the start of the next cycle 
of treatment. After CR/CRi, response assessment will continue to be performed by CBC 
surveillance. In addition, bone marrow examination will be conducted according to the 
following schedule: 
● 
2 cycles after initial confirmation of CR or CRi 
● 
At the time of conversion from CRi to CR 
● 
At the time of suspected relapse 
● 
EOT (if not performed within the previous 4 weeks) 
Patients may continue on study treatment until progression, leukemic recurrence, or 
unacceptable toxicity, whichever comes first. Patients who achieve stable disease or better 


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should receive a minimum of 4 cycles of study treatment. Progression is defined after 4 or 
more cycles of treatment as either a >25% absolute rise in the percent of bone marrow blast 
from baseline (or a proportional increase of >25% in patients with baseline bone marrow 
blasts >75%) or appearance of new extramedullary disease. Patients who fulfill the criteria 
for progression but who are still deriving clinical benefit in the opinion of the investigator 
may continue on study treatment. 
After discontinuation of study treatment, patients who have not experienced progression or 
leukemic recurrence will continue to be assessed for response by CBC surveillance every 
2 months through 24 months after the end-of-treatment (EOT), and every 4 months 
thereafter, until initiation of another anticancer treatment (excluding SCT and maintenance 
therapy in the absence of relapse), progression, or leukemic recurrence, whichever comes 
first. For all patients, survival status follow up will take place every 2 months (or more 
frequently as needed to support analysis of the study endpoints) after EOT until death or 
study closure, whichever comes first. 
Two interim analyses for OS are planned: the first interim analysis is to evaluate futility and 
the second interim analysis is to evaluate the superiority of vadastuximab talirine (see 
Section 9.3.10). 
Safety, including SAEs and early mortality, will be monitored over the course of the study by 
an Independent Data Monitoring Committee (IDMC). 
A study schema is presented in Figure 1. 
Figure 1: 
Study Design 
Experimental Arm:
 Vadastuximab talirine + 
HMA in 4-week cyclesa, b
Comparator Arm:
Placebo + HMA in 
4-week cyclesa, b
Randomization
End-of-treatment
Follow-up:
  
For patients who discontinue 
treatment prior to progression or 
leukemic recurrence – response 
assessments continuec 
For all patients, survival status 
follow upd
Stratification Factors
for Randomization
- Cytogenetic risk
- ECOG
- HMA
       - Age
 
a 
Open-label treatment with HMA administered in combination with blinded vadastuximab talirine or placebo.  
HMA = either azacitidine 75 mg/m2 SC or IV x 7, every 4 weeks or decitabine 20 mg/m2 IV x 5, every 4 weeks. 
b 
Treatment until progression or leukemic recurrence. Response assessments between Day 22−28 of 
even-numbered cycles until CR or CRi. After CR or CRi, response will continue to be evaluated by CBC every cycle; 
bone marrow examinations will be performed as described in Section 6. 
c 
Response assessed by CBC every 2 months through 24 months after EOT, and every 4 months thereafter, until 
initiation of another anticancer treatment (excluding stem cell transplant and maintenance therapy in the absence of 
relapse), progression, or leukemic recurrence, whichever comes first. 
d 
Every 2 months after EOT (or more frequently as needed to support analysis of the study endpoints) until death or 
study closure, whichever comes first. 
 


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3.1.1 Study Stopping Criteria 
The Sponsor will pause enrollment and notify the FDA, and other global health authorities as 
applicable, if the stopping criteria are met. The IDMC will provide recommendations to the 
Sponsor if either of the following criteria are met: 
● 
 
 
 
 
 
 
 
 
 
3.2 Discussion and Rationale for Study Design 
Non-intensive therapies, such as the HMAs decitabine and azacitidine, are frequently 
employed for patients with AML who are not candidates for intensive induction 
chemotherapy or allogeneic SCT, although response rates and median survival remain 
suboptimal in this population. HMAs are considered a standard of care option in patients for 
whom a low intensity therapy is deemed appropriate. Clinical practice guidelines support 
their use in this setting, and randomized phase 3 trials have shown these agents to have 
similar efficacy compared to other recommended low intensity therapies such as 
subcutaneous low dose cytarabine (Dohner 2010; Kantarjian 2012; Dombret 2015). 
Patients with intermediate and adverse risk AML who are not considered candidates for 
allogeneic transplant define a population in which low response rates and high mortality rates 
have been observed with intensive chemotherapy regimens. Less than 10% of older patients 
are cured with traditional chemotherapeutic regimens (Appelbaum 2006; Buchner 2009). 
Retrospective observational studies have demonstrated that survival rates are equivalent in 
these older patients when treated with HMAs compared to standard anthracycline/cytarabine-
based regimens (Quintas-Cardama 2012; Gupta 2015). In addition, a large prospective 
randomized study demonstrated that in the proposed patient population, the overall survival 
with azacitidine was equivalent, if not superior, to intensive chemotherapy (Dombret 2015). 
Patients with favorable risk AML who have potentially chemotherapy-sensitive karyotypes 
will be excluded from this trial. It is intended that the study population will primarily be 
older patients who have been shown to benefit from low-intensity therapies such as HMAs, 
but are medically unfit and/or unwilling to receive standard intensive induction 
chemotherapy. Historical data show that within the older AML population, outcomes are 
worse in the subset of patients who are age 80 years and older with poor performance status 
(Kantarjian 2010; Oran 2012). Age ≥80 years and a high degree of comorbidity were 
associated with an increased risk of early death and shorter median overall survival 


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regardless of therapy received, including HMAs. Therefore, patients age 80 and older will be 
required to have an ECOG performance status of 0 or 1. 
The randomized trial design of the current study includes the opportunity for the investigator 
to select from either HMA (decitabine or azacitidine) prior to patient randomization. Both 
decitabine and azacitidine have very similar mechanisms of action, whereby they are 
incorporated into DNA leading to DNA methyl-transferase inhibition, DNA 
hypomethylation, and induction of DNA damage. 
CD33 is expressed on leukemic blasts in approximately 90% of patients with AML 
(Pollard 2012; Ehninger 2014; Krupka 2014). Because all patients enrolled on this study will 
receive an HMA, which is standard of care for AML regardless of CD33 expression, 
documentation of CD33 expression will not be required to enroll on this trial. 
Remission will be evaluated by investigator assessment with local pathology according to a 
modification of the response categorization in the Revised Recommendations of the 
International Working Group for Diagnosis, Standardization of Response Criteria, Treatment 
Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia 
(Cheson 2003); see Appendix E. The blinded, randomized design of this study ensures the 
robustness of investigator-assessed remission status. 
3.2.1 Method of Assigning Patients to Treatment Groups 
Following informed consent and screening assessments, patients will be randomly assigned 
to study treatment in a 1:1 ratio. Randomization procedures are detailed in the Study Manual. 
Stratified block randomization will be performed centrally. Patients will be stratified by the 
following factors: 
● 
Cytogenetic risk per revised UK Medical Research Council (MRC) classification 
(intermediate versus adverse; see Appendix D). Local assessment of cytogenetic risk 
will be used for eligibility and stratification. 
● 
Eastern Cooperative Oncology Group (ECOG) performance status (0−1 versus 2) 
● 
HMA (azacitidine versus decitabine) 
● 
Age (<75 years versus ≥75 years) 
3.2.2 Rationale for Selection of Doses 
In the first-in-human study (Study SGN33A-001), a 10 mcg/kg dose of vadastuximab talirine 
was selected for evaluation in combination with HMAs because it was the highest dose 
where no dose-limiting toxicities (DLTs) were observed in the monotherapy cohorts. It also 
represented the no observed adverse effect level (NOAEL) and 1/6th of the highest 
non-severely toxic dose (HNSTD) in the single-dose monkey toxicology study. In the cohort 
of 24 AML patients who received combination therapy in Study SGN33A-001, tolerable 
myelosuppression was observed, no DLTs were noted, and there has been no 
clinically-significant off-target toxicity. At the time of an interim analysis (July 2015), the 
30- and 60-day mortality rates were 0% and 4%, respectively, with no treatment-related 


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deaths reported. The observed remission rate of 65% was more than double the historical rate 
associated with HMA monotherapy in this patient population (Fathi 2015). 
The clinical safety data observed in the phase 1 dose-escalation study of vadastuximab 
talirine support 10 mcg/kg every 4 weeks as the dose and schedule in combination with an 
HMA. Dose reductions of blinded study treatment to 5 mcg/kg are permitted (see 
Section 5.2.3). The primary rationale for selection of the combination dose level is the 
observed activity balanced with the acceptable safety and tolerability profile. 
3.2.3 Blinding 
Maintaining the blind of the study is crucial for achieving the study objectives. Investigators, 
patients, and the sponsor will be blinded to treatment assignments, unless otherwise specified 
in the Study Manual. 
Prior to study closure, unblinding a patient’s treatment assignment must be limited to 
emergency circumstances where knowledge of the treatment assignment would affect 
decisions regarding the management of the patient. In the event of such an emergency 
circumstance, a formal unblinding procedure, carried out by a third party organization, will 
be followed to allow the investigator to immediately access a patient’s treatment assignment 
(see Study Manual). Information on study treatment assignment should not be distributed to 
any other personnel involved in the clinical trial. In the event of any emergency unblinding, 
Seattle Genetics is to be notified within 24 hours of the occurrence. 
4 
STUDY POPULATION 
Patients must meet all of the enrollment criteria to be eligible for this study. Eligibility 
criteria may not be waived by the investigator and are subject to review in the event of Good 
Clinical Practice (GCP) audit and/or health regulatory authority inspection. 
4.1 Inclusion Criteria 
1. Patients with newly diagnosed, previously untreated, cytologically or histologically 
confirmed de novo or secondary AML according to WHO classification (except for acute 
promyelocytic leukemia [APL]). 
2. Age ≥18 years. 
3. Life expectancy of at least 12 weeks. 
4. Patient is eligible for therapy with either decitabine or azacitidine. 
5. For patients <80 years, an ECOG performance status ≤2 (Appendix C). Patients 
≥80 years must have an ECOG performance status of 0 or 1. 
6. The following baseline laboratory data: 
● 
White blood cell (WBC) count <30,000/µL; use of hydroxyurea to control WBC is 
acceptable. 


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● 
Serum bilirubin ≤1.5 x upper limit of normal (ULN) or ≤3 x ULN for patients with 
Gilbert’s disease, or direct bilirubin ≤ 2 x ULN if total bilirubin is abnormal. 
● 
Serum creatinine ≤2.5 x ULN and estimated creatinine clearance ≥30 mL/min. 
● 
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3 x ULN. 
7. Female patients (for those of childbearing potential as defined in Section 4.3), the 
following stipulations apply: 
a. Must have a negative serum or urine pregnancy test (minimum sensitivity 25 mIU/mL 
or equivalent units of beta human chorionic gonadotropin [β-hCG]) result within 
7 days prior to the first dose of study treatment. Females with false positive results 
and documented verification that the patient is not pregnant are eligible for 
participation. 
b. Must agree not to try to become pregnant during the study and for at least 6 months 
after the final dose of study drug administration. 
c. Must agree not to breastfeed or donate ova, starting at time of informed consent and 
continuing through 6 months after the final dose of study drug administration. 
d. If heterosexually active, must consistently use 2 highly effective methods of birth 
control (as defined in Appendix G) starting at time of informed consent and 
continuing throughout the study and for at least 6 months after the final dose of study 
drug administration. 
8. Male patients under the following conditions: 
a. Must agree not to donate sperm starting at time of informed consent and continuing 
throughout the study period and for at least 6 months after the final study drug 
administration. 
b. If heterosexually active with non-pregnant, pregnant, or breastfeeding partner, must 
consistently use 2 highly effective methods of birth control (as defined in 
Appendix G) starting at time of informed consent and continuing throughout the 
study and for at least 6 months after the final dose of study drug administration. 
9. Patients must provide written informed consent. 
4.2 Exclusion Criteria 
1. AML associated with favorable risk karyotypes including inv(16), t(8;21), t(16;16), or 
t(15;17). 
2. Patients who are medically fit and willing to receive standard intensive induction 
chemotherapy. 


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3. Patients who are candidates for allogeneic stem cell transplant at the time of 
enrollment. 
4. Patients with a history of one of the following myeloproliferative neoplasms: essential 
thrombocythemia, polycythemia vera, and primary myelofibrosis. 
5. Received prior treatment with HMA or chemotherapy for antecedent MDS. Prior 
hydroxyurea or 6-mercaptopurine is permitted, as is prior lenalidomide treatment for 
MDS. 
6. History of allogeneic stem cell transplant. 
7. History of clinically significant chronic liver disease (e.g. liver cirrhosis) and/or 
ongoing alcohol abuse. 
8.  Patients with supplemental oxygen requirement or resting oxygen saturation of <90%. 
9. Concurrent active malignancy other than nonmelanoma skin cancer or carcinoma in situ 
of the following: bladder, stomach, colon, cervix, endometrium, melanoma, or breast. 
Patients with previous malignancies are eligible if the malignancy has been confined 
and surgically resected (or treated with other modalities) with curative intent. Any 
active systemic therapy must have been completed >1 year from enrollment (except for 
hormonal/anti-hormonal treatment, e.g. breast cancer). 
10. Central nervous system leukemia based on imaging or documented positive cytology in 
cerebral spinal fluid. 
11. Any uncontrolled Grade 3 or higher (per NCI CTCAE, Version 4.03) viral, bacterial, or 
fungal infection within 14 days prior to the first dose of study treatment. Antimicrobial 
prophylaxis or ongoing treatment of resolving/controlled infection is permitted. 
12. Patients with any of the following: 
● 
Known positive hepatitis B polymerase chain reaction (PCR) assay who have also 
tested positive for hepatitis B surface antigen and/or anti-hepatitis B core antibody; 
patients with a negative PCR assay are permitted with appropriate antiviral 
prophylaxis. 
● 
Known or suspected active hepatitis C infection (positive by PCR or on antiviral 
therapy within the last 6 months). 
● 
Known human immunodeficiency virus (HIV) infection. 
13. Documented history of a cerebral vascular event (stroke or transient ischemic attack), 
unstable angina, or myocardial infarction within 6 months prior to their first dose of 
study drug, or cardiac symptoms consistent with New York Heart Association (NYHA) 
Class III-IV within 6 months prior to the first dose of study treatment (see Appendix F). 
14. Current therapy with other systemic anti-neoplastic or investigational agents, with the 
exception of hydroxyurea. 


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15. Females who are breastfeeding. 
16. Known hypersensitivity to any excipient contained in the drug formulation of any study 
treatment. 
17. Significant history of pulmonary, renal, neurologic, psychiatric, endocrine, metabolic, 
immunologic, hepatic, cardiovascular disease, or any other condition which, in the 
opinion of the investigator, would adversely affect participation in this study, 
compromise patient safety or interfere with data interpretation. 
4.3 Childbearing Potential 
A woman of childbearing potential is any female who has experienced menarche and who 
has not undergone surgical sterilization (e.g., hysterectomy, bilateral salpingectomy, bilateral 
oophorectomy) or has not completed menopause. Menopause is defined clinically as 
12 months of amenorrhea in a woman over age 45 in the absence of other biological, 
physiological, or pharmacological causes. 
4.4 Removal of Patients From Therapy or Assessment 
Seattle Genetics or their designee must be notified if a patient is withdrawn from study 
treatment or from the study. The reason(s) for withdrawal must be documented in the 
patient’s medical records and case report form (CRF). 
4.4.1 Discontinuation of Study Drug 
A patient’s treatment with study drug may be discontinued for any of the following reasons: 
● 
Progressive disease (including leukemic relapse/recurrence) 
● 
Adverse event (AE) 
● 
Investigator decision 
● 
Patient decision, Non-AE 
● 
Study termination by sponsor 
● 
Other, Non-AE 
Patients who discontinue from study treatment will remain on study for follow-up unless they 
withdraw consent. 
4.4.2 Patient Withdrawal From Study 
Any patient may be discontinued from the study for any of the following reasons: 
● 
Patient withdrawal of consent 
● 
Study termination by sponsor 
● 
Lost to follow-up 
● 
Death 
● 
Other 


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5 
TREATMENTS 
5.1 Treatments Administered 
Patients in this study will be treated with HMA (azacitidine or decitabine) administered in 
combination with either vadastuximab talirine (experimental arm) or placebo (comparator 
arm); see Figure 2. 
Investigators may choose either HMA for the majority of the study. However, to ensure 
balanced proportions of patients receive either decitabine or azacitidine for analysis of the 
primary endpoint, there may be certain periods during which the specific HMA will be 
assigned. 
Figure 2: 
Study Treatments 
Open-label treatment with one of the following HMAs:  
       - azacitidine 75 mg/m2 SC or IV x 7, every 4 wks
- decitabine 20 mg/m2 IV x 5, every 4 wks
Experimental Arm
Vadastuximab talirine 10 mcg/kg every 4 wks 
(after HMA on the last day of HMA 
administration) via IV push, until leukemic 
recurrence or progression
Comparator Arm
Placebo volume equivalent to 10 mcg/kg every
4 wks (after HMA on the last day of HMA 
administration) via IV push, until leukemic 
recurrence or progression
In combination with blinded 
study treatmenta 
 
a 
Randomized in a 1:1 ratio (vadastuximab talirine: placebo) 
5.2 Investigational Study Drug 
Investigational study drug (vadastuximab talirine or placebo) will be supplied in a blinded 
manner. Detailed information describing the preparation, administration, and storage of study 
treatment is located in the Pharmacy Binder. 
5.2.1 Description 
Vadastuximab talirine and placebo are supplied as a sterile, preservative-free, lyophilized 
cake or powder for reconstitution for IV administration and are supplied by Seattle Genetics 


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in single-use amber glass vials. Each vial of vadastuximab talirine contains vadastuximab 
talirine,
 
5.2.2 Dose and Administration 
The patient will be randomized to either the experimental arm or the comparator arm within 
1 business day prior to the first dose of HMA. 
Dosing is based on patient actual body weight (to the nearest tenth of a kilogram) obtained 
according to the institutional standard; however, doses must be adjusted for patients who 
experience a ≥10% change in weight from baseline. An exception to weight-based dosing is 
made for patients weighing greater than 100 kg; doses will be based on 100 kg for these 
individuals (the maximum dose for this study is 1000 mcg per single 10 mcg/kg dose). 
The dose of study treatment is 10 mcg/kg every 4 weeks (after HMA on the last day of HMA 
administration) via IV push. It is recommended that study treatment is administered via 
central venous access port (e.g., peripherally inserted central catheter [PICC], Hickman line, 
or similar according to institutional standard). However, if study treatment is not 
administered via central venous access port, a secure and free-flowing peripheral line must be 
used. Due to potential for severe tissue damage, monitor the injection site closely for redness, 
swelling, pain, infection during and at any time after administration. Advise patients to report 
redness or discomfort promptly at the time of administration or after infusion. Follow 
institutional guidelines for the administration of chemotherapy and take precautions to 
prevent extravasation per institutional standards and as described in “Preventing and 
Managing Vesicant Chemotherapy Extravasations” (Schulmeister 2010). 
Depending on the lot of study treatment supplied, a sterile 0.2 µm filter may be required for 
administration; see the Pharmacy Binder for details. After the infusion, the IV infusion line 
(including the filter and any associated tubing or closed-delivery injection devices) must be 
flushed with at least 20 mL of saline. 
5.2.3 Dose Modifications 
Dose modifications (delays, reductions, or eliminations) of blinded study treatment are at the 
discretion of the investigator; see Table 1 for required dose modifications. Cycles of blinded 
study treatment may be delayed for hematologic toxicity in the absence of leukemia. A dose 
reduction of blinded study treatment to 5 mcg/kg is permitted if a second dose delay is 
required. After dose reduction, a delay of up to 56 days is permitted before resuming blinded 
study treatment. Consider bone marrow evaluation in the setting of prolonged cytopenias. 


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Table 1: 
Dose modifications for blinded study treatment-associated toxicity 
Category 
Event 
Action 
Hematologic toxicity in 
the absence of leukemia 
(CR, CRi, morphologic 
leukemia-free state 
[mLFS]; see Appendix E) 
≥ Grade 3 neutropenia or 
thrombocytopenia 
Cycles of blinded study treatment must be delayed up 
to 28 daysb until hematologic recovery is observed. 
Adequate hematologic recovery is defined as ANC 
< Grade 3, and rising and/or platelets < Grade 3 
(unsupported). 
Dose reduction of blinded study treatment to 5 mcg/kg 
is permitted after any dose delay, and is required if a 
second dose delay occurs. Treatment must be 
discontinued for delays of >56 days after dose 
reduction, unless approved by the medical monitor.  
Hematologic toxicity with 
persistent leukemiaa 
≥ Grade 3 neutropenia or 
thrombocytopenia  
Blinded study treatment may continue without dose 
modification. 
Non−hematologic toxicity 
or non-hematologic 
laboratory abnormality 
(with the exception of 
hepatic toxicity) 
≥ Grade 3 event  
Treatment delay of up to 14 days is requiredb until 
resolution of toxicity to < Grade 3. 
Laboratory evidence of 
hepatic toxicity (elevation 
in ALT, AST, or total 
bilirubin) 
≥ Grade 3 event 
Treatment delay of up to 14 days is required until 
resolution of toxicity to ≤ Grade 1 or baseline. If 
toxicity has not resolved within 14 days, must 
permanently discontinue blinded study treatment. 
a 
Blasts are at least 5% in bone marrow by morphology, circulating blasts are present, or there is evidence of 
extramedullary leukemia 
b 
Delays of >14 days may be permitted with approval of the medical monitor 
 
HMA dose modifications are at the discretion of the treating physician and should adhere to 
the HMA package insert or Summary of Product Characteristics (SmPC) or institutional 
guidelines/standards. If dosing is delayed for either blinded study treatment or HMA, both 
should be held and resumed together on the same schedule. 
Blinded study treatment or HMA treatment may be permanently discontinued in the event of 
unacceptable treatment-related toxicity. Patients will not be considered off treatment until 
both blinded study treatment and HMA have been discontinued. 
5.2.4 Storage and Handling 
Single-use amber vials containing study treatment must be stored under refrigeration at 
2−8°C, protected from light (both sunlight and artificial light), 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 2−8°C, protected from light. However, the drug product does not contain 
preservatives; therefore, from a microbiological standpoint, opened and reconstituted vials 
should be used immediately. If not used immediately, the in-use storage of the reconstituted 
product should not be longer than 24 hours under refrigeration at 2−8°C. If dilution is 
needed, the reconstituted drug product should be diluted in 0.9% Sodium Chloride Injection, 
USP, or equivalent standard, at the time of use. The prepared dosing solution (reconstituted 


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drug product or drug product dilution) may be kept for up to 4 hours at room temperature in 
the amber vial. 
It is recommended that the drug product vials and solutions be protected from light (both 
sunlight and artificial light) until the time of use. 
Do not shake reconstituted or diluted study treatment. 
Any partially used vials or prepared dosing solutions should be discarded by the site 
according to institutional drug disposal procedures. Unused vials should not be discarded by 
the site prior to authorization by the Sponsor. 
Drug accountability instructions are provided in the Pharmacy Binder. 
5.2.5 Packaging and Labeling 
Refer to the Pharmacy Binder for information regarding packaging and labeling. 
5.2.6 Preparation 
Recommended safety measures for handling and preparation include masks, protective 
clothing, gloves (double glove with nitrile gloves), and vertical laminar airflow safety 
cabinets. 
Study treatment must be reconstituted before administration. The reconstituted drug product 
may be further diluted depending on the dose level. Detailed drug preparation instructions are 
provided in the Pharmacy Binder. 
5.3 Azacitidine and Decitabine 
5.3.1 Description 
Azacitidine is a pyrimidine nucleoside analog of cytidine. It is a white to off-white solid. 
Branded or generic equivalent may be used. It is recommended that azacitidine is 
administered subcutaneously (SC) unless contraindicated, in which case intravenous (IV) 
administration is permitted. Azacitidine is supplied in a sterile form for reconstitution for 
subcutaneous injection or reconstitution as a solution with further dilution for IV infusion. 
Vials contain 100 mg of azacitidine and 100 mg mannitol as a sterile lyophilized powder. 
Decitabine is an analogue of the natural nucleoside 2'-deoxycytidine. Decitabine is a fine, 
white to almost white powder with the molecular formula of C8H12N4O4 and a molecular 
weight of 228.21. Branded or generic equivalent may be used. Decitabine for injection is a 
white to almost white sterile lyophilized powder supplied in a clear colorless glass vial. Each 
20 mL, single dose, glass vial contains 50 mg decitabine, 68 mg monobasic potassium 
phosphate (potassium dihydrogen phosphate) and 11.6 mg sodium hydroxide. 
5.3.2 Method of Procurement 
In the US, azacitidine and decitabine will be supplied by the study site and billed to patients 
and/or their third-party payer (insurance, a healthcare provider, or applicable government 


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program). In countries outside of the US, supplies will be re-labeled to meet country-specific 
regulatory requirements and supplied by the sponsor. 
5.3.3 Dose and Administration 
Refer to the azacitidine and decitabine package inserts or SmPC for complete instructions for 
dosing and administration. The dose of azacitidine is 75 mg/m2 SC or IV x 7 (7 consecutive 
days or 5 days on/2 days off/2 days on), every 4 weeks. The dose of decitabine is 20 mg/m2 
IV daily x 5, every 4 weeks. Dose modifications for HMAs are discussed in Section 5.2.3. 
5.3.4 Storage and Handling 
Refer to the azacitidine and decitabine package inserts for appropriate storage and handling 
instructions. 
5.3.5 Packaging and Labeling 
Refer to the azacitidine and decitabine package inserts for packaging and labeling 
information. 
5.3.6 Preparation 
Preparation of azacitidine and decitabine should be according to the appropriate package 
inserts and in adherence to institutional standards. 
5.4 Required Premedication and Postmedication 
There are no required pre- or postmedications for any component of study treatment. 
5.5 Concomitant Therapy 
All concomitant medications, blood products, and radiotherapy administered will be recorded 
from Day 1 (predose) through the safety reporting period. Any concomitant medication given 
for a study protocol-related adverse event should be recorded from the time of informed 
consent. 
5.5.1 Required Concomitant Therapy 
None. 
5.5.2 Allowed Concomitant Therapy 
Antimicrobial prophylaxis measures are strongly recommended, per institutional standard of 
care; decisions regarding use and choice of antibiotics should be made by the individual 
institutions based on the prevailing organisms and their drug resistance patterns (de Naurois 
2010; Freifeld 2011; Flowers 2013). The use of myeloid growth factors are considered 
appropriate supportive care per the American Society of Clinical Oncology (ASCO) and the 
European Society for Medical Oncology (ESMO) Clinical Practice Guidelines (Smith 2006; 
Fey 2013) and are strongly recommended as primary and/or secondary prophylaxis and as 
support of clinically significant neutropenia during treatment. 


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The use of anti-emetics is permitted. Premedications for HMAs are allowed per institutional 
standard of care. 
Routine premedication for infusion reactions should not be administered prior to the first 
dose of blinded study treatment. However, patients who experience an infusion-related 
reaction (with the exception of anaphylaxis) may receive subsequent treatment with 
premedication as described in Section 5.6.1. 
Prophylactic treatment/measures are strongly recommended for patients at risk for tumor 
lysis syndrome (TLS), per the institutional or community standard (e.g., treatment with 
allopurinol or rasburicase, as well as adequate hydration (Coiffier 2008). 
Hydroxyurea (up to 14 days of therapy) and/or leukapheresis are permitted in the setting of 
uncontrolled leukocytosis. 
The use of red blood cell (RBC) and platelet transfusions, and/or colony-stimulating factors 
per institutional practice is permitted. Intrathecal prophylactic treatment for 
cerebral/meningeal disease is permitted at the discretion of the investigator. 
Concomitant palliative focal external beam radiation may be given for symptomatic control 
of pain. 
5.5.3 Prohibited Concomitant Therapy 
Patients may not receive other investigational drugs, immunosuppressive medications (with 
the exception of the medications listed in Section 5.5.2), non-study systemic anti-neoplastic 
therapy, or allo-SCT during the treatment period. 
If patients become candidates for allo-SCT after enrollment, blinded study treatment must be 
discontinued at least 30 days prior to initiation of the preparative regimen for allo-SCT. 
5.6 Management of Adverse Reactions 
5.6.1 Management of Infusion Reactions 
Infusion-related reactions may occur during the infusion of blinded study treatment. The 
infusion should be administered at a site properly equipped and staffed to manage 
anaphylaxis should it occur. All supportive measures consistent with optimal patient care 
should be given throughout the study according to institutional standards. Supportive 
measures may include administering medications for infusion-related reactions. 
Patients who have experienced an infusion-related reaction may be premedicated for 
subsequent infusions. Premedication may include pain medication (e.g., acetaminophen), an 
antihistamine, and a corticosteroid administered 30–60 minutes prior to each infusion or 
according to institutional standards. Should a patient experience infusion-related reactions in 
the setting of premedication, continued treatment with blinded study treatment must be 
discussed with the medical monitor prior to the next planned dose. 


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If anaphylaxis occurs, study treatment administration should be immediately and 
permanently discontinued. 
5.6.2 Overdose 
In the event of an overdose ≥10%, the site should notify the sponsor as soon as they are 
aware of the overdose. 
5.7 Treatment Compliance 
Study drug administration will be performed by study site staff and documented in source 
documents and the CRF. 
6 
STUDY ACTIVITIES 
6.1 Schedule of Events 
Adverse events and concomitant medications will be recorded from Day 1 (predose) through 
the safety reporting period (see Section 7.7.1.3). Day 1 is the first dose of HMA. Any study 
protocol-related AE should be recorded from the time of informed consent as well as any 
concomitant medications given for treatment of the AE. Medical resource utilization (MRU) 
data will be collected from Day 1 (predose) through EOT. 
Separate schedule of events tables are provided for patients treated with azacitidine and those 
treated with decitabine (see Appendix A). Details of PK, ATA, and biomarker sampling 
timepoints are provided in Appendix B. Study activities are listed by visit in this section and 
descriptions of all study assessments are presented in Section 7. 
6.2 Screening Visit (Days −28 to 1) 
● 
Informed consent 
● 
Study eligibility per inclusion/exclusion criteria 
● 
Medical history 
● 
Diagnostic bone marrow examination for local baseline disease assessment and 
cytogenetics (bone marrow aspirate is sufficient; however, if marrow cannot be 
aspirated, a biopsy may be conducted). A bone marrow assessment performed prior to 
informed consent and up to 60 days prior to first dose of study treatment may be used. 
● 
Bone marrow sample for central assessment of cytogenetic risk, minimal residual 
disease (MRD), CD33 expression, profiling for disease-associated somatic mutations 
or alterations in genes or RNAs commonly altered in hematologic malignancies and 
other genes or RNAs potentially associated with disease relapse or resistance to 
vadastuximab talirine 
● 
Serum and plasma sample for central assessment of soluble factors potentially 
associated with clinical outcome, e.g., sCD33 
6.2.1 Baseline Visit (Days −7 to Day 1) 
● 
Physical exam 


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● 
Height and weight 
● 
Electrocardiogram (ECG) 
● 
Pulse oximetry testing for oxygen saturation level at room air 
● 
Pregnancy test for females of childbearing potential 
● 
ECOG performance status (Appendix C) 
● 
Collection of data to calculate the Charlson Comorbidity Index (CCI), the 
Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI), and 
Wheatley Risk group 
● 
Serum chemistry panel 
● 
Complete blood count (CBC) with differential 
● 
EQ-5D 
● 
EORTC-QLQ-C30 
● 
Randomization (to occur within 1 business day of planned first dose of HMA). 
6.3 Treatment Period (Day 1 to Day 28) 
6.3.1 Day 1 (±1 day) of Each Cycle 
● 
Physical exam 
● 
Pregnancy test for females of childbearing potential 
● 
Weight 
● 
ECOG performance status (Appendix C) 
● 
Serum chemistry panel 
● 
CBC with differential 
● 
HMA (azacitidine or decitabine) administration 
● 
EQ-5D 
● 
EORTC-QLQ-C30 
● 
Blood sample for ATA (Cycles 1 to 4 and every 4th cycle thereafter) 
● 
Serum and plasma sample for central assessment of soluble factors potentially 
associated with clinical outcome, e.g., sCD33 (Cycles 1 and 2 only; pre-HMA 
administration, see Appendix B) 
 
If Baseline Visit activities occur within 1 business day prior to Cycle 1 Day 1, the following 
assessments do not need to be repeated at the Cycle 1 Day 1 visit: physical exam, ECOG 
performance status, serum chemistry panel, CBC with differential, and EQ-5D and EORTC-
QLQ-C30. 
If dosing is delayed due to laboratory abnormalities, CBC with differential and serum 
chemistry panel should still be sent to the central lab. 
6.3.2 Day 2 to 4 of Each Cycle 
● 
HMA (azacitidine or decitabine) administration 


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6.3.3 Day 5 of Each Cycle 
Only for patients receiving azacitidine: 
● 
Azacitidine administration 
Only for patients receiving decitabine: 
● 
Physical exam (Cycles 1 and 2 only) 
● 
Serum chemistry panel (Cycles 1 and 2 only) 
● 
CBC with differential (Cycles 1 and 2 only) 
● 
Decitabine administration 
● 
Vital signs (pre- and within 30 minutes post-blinded study treatment administration) 
● 
Blinded study treatment given after decitabine 
● 
Blood sample for PK (predose Cycles 1 and 2 only; postdose all cycles; see 
Appendix B) 
● 
Serum and plasma sample for central assessment of soluble factors potentially 
associated with clinical outcome, e.g., sCD33 (Cycles 1 and 2 only; sample taken 
pre-blinded study treatment administration [see Appendix B]) 
6.3.4 Day 6 of Each Cycle (only for patients receiving azacitidine; Day 8 if 
alternative azacitidine dosing schedule used) 
● 
Azacitidine administration 
6.3.5 Day 7 of Each Cycle (only for patients receiving azacitidine; Day 9 if 
alternative azacitidine dosing schedule used) 
● 
Physical exam (Cycles 1 and 2 only) 
● 
Serum chemistry panel (Cycles 1 and 2 only) 
● 
CBC with differential (Cycles 1 and 2 only) 
● 
Azacitidine administration 
● 
Vital signs (pre- and within 30 minutes post-blinded study treatment administration) 
● 
Blinded study treatment administration (given after HMA) 
● 
Blood sample for PK (predose Cycles 1 and 2 only; postdose all cycles; see 
Appendix B) 
● 
Serum and plasma sample for central assessment of soluble factors potentially 
associated with clinical outcome, e.g., sCD33 (Cycles 1 and 2 only; pre-blinded study 
treatment administration; see Appendix B) 
6.3.6 Day 15 (±2 days) of Cycles 1−4 only 
● 
Physical exam 
● 
Serum chemistry panel 
● 
CBC with differential 


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6.3.7 Day 21 (±2 days) of Cycles 1 and 2 only 
● 
Physical exam 
● 
Serum chemistry panel 
● 
CBC with differential 
6.3.8 Day 28 (–6 day window) of Each Even Numbered Cycle 
The assessments listed below will be done until CR/CRi. The window may be up to Day 42 
in the event of a delay in the start of the next cycle of treatment. 
● 
CBC with differential 
● 
Bone marrow examination for response assessment (bone marrow aspirate is 
sufficient; however, if marrow cannot be aspirated, a biopsy may be conducted). 
Cytogenetics are also required if abnormal at baseline. 
● 
Bone marrow sample for central assessment of MRD, CD33 expression, profiling for 
disease-associated somatic mutations or alterations in genes or RNAs commonly 
altered in hematologic malignancies and other genes or RNAs potentially associated 
with disease relapse or resistance to vadastuximab talirine 
● 
Serum and plasma sample for central assessment of soluble factors potentially 
associated with clinical outcome, e.g., sCD33 
After CR/CRi, the above samples and assessments will be conducted according to the 
following schedule: 
● 
2 cycles after initial confirmation of CR or CRi 
● 
At the time of conversion from CRi to CR 
● 
At the time of suspected relapse 
6.4 End of Treatment Visit (30 to 37 days after last dose of study drug) 
End of Treatment (EOT) visits should occur 30 to 37 days after the last dose of any study 
drug treatment unless delayed due to an AE. However, EOT evaluations must be performed 
before initiation of a new therapy. If EOT evaluations are completed before 30 days after the 
last study treatment, the patient will be contacted 30 to 37 days following the last treatment 
to assess for adverse events. The following assessments will be done: 
● 
Physical examination 
● 
Pregnancy test for females of childbearing potential 
● 
ECOG performance status (Appendix C) 
● 
Serum chemistry panel 
● 
CBC with differential 
● 
EQ-5D 
● 
EORTC-QLQ-C30 
● 
Blood sample for ATA 


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The following assessments will also be required if not conducted within 4 weeks of EOT: 
● 
Bone marrow examination for response assessment (bone marrow aspirate is 
sufficient; however, if marrow cannot be aspirated, a biopsy may be conducted). 
Cytogenetics are also required if abnormal at baseline. 
● 
Bone marrow sample for central assessment of MRD, CD33 expression, profiling for 
disease-associated somatic mutations or alterations in genes or RNAs commonly 
altered in hematologic malignancies or potentially associated with disease relapse or 
resistance to vadastuximab talirine 
● 
Serum and plasma sample for central assessment of soluble factors potentially 
associated with clinical outcome, e.g., sCD33 
6.5 Follow-up 
All patients will be contacted every 2 months (or more frequently as needed to support 
analysis of the study endpoints) after EOT until death or study closure for survival status and 
collection of subsequent anticancer treatment information. 
Events of sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) that occur 
within 180 days of the last dose of blinded study drug will be reported to the sponsor, 
regardless of causality. Patients who undergo subsequent allo-SCT within 180 days of the 
last dose of blinded study drug in the absence of relapse and additional therapy will be 
followed for SOS/VOD for 100 days post-transplant (refer to Section 7.7.1.4). 
Patients who discontinue study treatment prior to leukemic relapse or progression will have a 
CBC with differential done every 2 months through 24 months after EOT, and every 
4 months thereafter until initiation of another anticancer treatment, progression or leukemic 
relapse. 
At time of either suspected relapse or conversion from mLFS to CRi/CR or CRi to CR, the 
following assessments must be done: 
● 
Bone marrow examination for response assessment (bone marrow aspirate is 
sufficient; however, if marrow cannot be aspirated, a biopsy may be conducted). 
Cytogenetics are also required if abnormal at baseline. 
● 
Bone marrow sample for central assessment of MRD, CD33 expression, profiling for 
disease-associated somatic mutations or alterations in genes or RNAs commonly 
altered in hematologic malignancies and other genes or RNAs potentially associated 
with disease relapse or resistance to vadastuximab talirine. 
6.6 End of Study/End of Follow-up 
The date the patient met criteria for study discontinuation and the reason for study 
discontinuation will be recorded. 


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7 
STUDY ASSESSMENTS 
7.1 Screening/Baseline Assessments 
Only patients who meet all inclusion and exclusion criteria specified in Section 4 will be 
enrolled in this study. 
Patient medical history includes a thorough review of significant past medical history with 
baseline comorbidities, current conditions, any treatment for prior malignancies and response 
to prior treatment, and any concomitant medications. 
7.2 Response/Efficacy Assessments 
Treatment response will be assessed locally per investigator by pathology review of bone 
marrow aspirate/biopsy and flow cytometry analysis of the number of blasts in bone marrow 
at protocol-specified timepoints (see Section 6 and Appendix A). 
CBC and differential will also be used to assess the presence of blasts in peripheral blood as 
well as the extent of hematopoietic recovery of platelets, erythrocytes, and leukocytes, 
including neutrophils. 
Clinical response will be determined at each assessment according to a modification of the 
response categorization in the Revised Recommendations of the International Working 
Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and 
Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia (Cheson 2003); see 
Appendix E. The category of CR with incomplete platelet recovery (CRp, also referred to as 
CRi[p]), which has been reported in prior AML trials, will be included as CRi. 
Patients’ clinical data must be available for CRF source verification. Copies of bone marrow 
reports including flow cytometry reports must be made available for review by the sponsor 
(or its designee), upon request. Bone marrow slides will be made available for central 
pathology review if requested. 
7.3 Pharmacokinetic, ATA, and Biomarker Assessments 
Blood samples for PK and ATA assessment will be collected at the timepoints outlined in 
Appendix B. Sensitive, qualified assays will be used to measure concentrations of ADC 
(vadastuximab talirine) and SGD-1882 in plasma and ATA in serum. Remaining PK samples 
will be archived for possible analysis of vadastuximab talirine-related species. The assays 
will include validated enzyme-linked immunosorbent assays (ELISA) and LC-MS/MS 
assays, as well as other assays if further characterization is required. A qualified 
electrochemiluminescence assay will be used to assess ATA. 
Peripheral blood and bone marrow aspirates will be collected for biomarker studies at the 
timepoints outlined in Appendix B. 
Biomarker assessments may include central assessment of CD33 expression, profiling for 
disease-associated somatic mutations or alterations in genes or RNAs commonly altered in 
hematologic malignancies or potentially associated with disease relapse or resistance to 


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vadastuximab talirine. Additional assessments may include measurement of soluble factors 
potentially associated with clinical outcome, e.g., sCD33. 
MRD will be assessed by a central laboratory in bone marrow samples (see the Research 
Specimen Manual for details). 
7.4 Biospecimen Repository 
In the US only, for patients who provide additional consent, remaining de-identified unused 
blood and/or tissue will be retained by the sponsor and used for future research, including but 
not limited to the evaluation of targets for novel therapeutic agents, the biology of ADC 
sensitivity and resistance mechanisms, and to identify predictive pharmacodynamic 
biomarkers of ADCs. Blood and tissue samples donated for future research will be retained 
for a period of up to 25 years. If additional consent is not provided, any remaining biological 
samples will be destroyed following study completion. 
7.5 Patient Reported Outcome Assessments 
Two validated tools will be used: the EORTC Quality of Life Questionnaire, QLQ-C30, and 
the EuroQol 5-dimensions (EQ-5D). 
PRO assessments should be completed before any other procedures at the study visits noted 
in the schedule of events (Appendix A). 
7.5.1 EORTC Core Quality of Life Questionnaire, QLQ-C30 
The EORTC Quality of Life Questionnaire was developed to measure aspects of quality of 
life pertinent to patients with a broad range of cancers who are participating in clinical trials 
(Aaronson 1993; Sneeuw 1998). The current version of the core instrument (QLQ-C30, 
version 3) is a 30-item questionnaire consisting of the following: 
● 
5 functional domains (physical, role, cognitive, emotional, social); 
● 
3 symptom scales (fatigue, pain, nausea & vomiting); 
● 
Single items for symptoms (shortness of breath, loss of appetite, sleep disturbance, 
constipation, diarrhea) and financial impact of the disease; and 
● 
2 global items (health, overall quality of life). 
7.5.2 EuroQol-5 Dimensions 
The EQ-5D is a standardized instrument developed by the EuroQol Group for use as a 
generic, preference-based measure of health outcome. It is applicable to a wide range of 
health conditions and treatments and provides a simple descriptive profile and a single index 
value for health status. The EQ-5D is a 5-item self-reported measure of functioning and well-
being, which assesses 5 dimensions of health, including mobility, self-care, usual activities, 
pain/discomfort and anxiety/depression. Each dimension comprises 3 levels (no problems, 
some/moderate problems, extreme problems). A unique EQ-5D health state is defined by 
combining 1 level from each of the 5 dimensions. This questionnaire also records the 


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respondent’s self-rated health status on a vertical graduated (0 to 100) visual analogue scale. 
Responses to the 5 items will also be converted to a weighted health state index (utility score) 
based on values derived from general population samples. The EQ-5D is recommended for 
use in cost-effectiveness analyses commonly employed in health technology assessments by 
the Washington Panel on Cost Effectiveness in Health and Medicine (Gold 1996). 
7.6 Medical Resource Utilization 
During the study, all medical care encounters that occur from Day 1 (predose) through EOT 
will be collected for all patients. MRU data will not be collected for per-protocol study visits 
and procedures. Examples of data to be collected are transfusion requirements, number of 
medical care encounters, such as hospital admissions, outpatient and home visits, and 
emergency room visits, and major diagnostic procedures. 
7.7 Safety Assessments 
The assessment of safety during the course of this study will consist of the surveillance and 
recording of adverse events (AEs) including serious adverse events (SAEs), recording of 
concomitant medication and measurements of protocol-specified physical examination 
findings and laboratory tests. 
Safety will be monitored over the course of the study by an IDMC as described in 
Section 9.3.10. 
7.7.1 Adverse Events 
7.7.1.1 Definitions 
Adverse Event 
According to the International Conference on Harmonization (ICH) E2A guideline 
Definitions and Standards for Expedited Reporting, and 21 CFR 312.32, IND Safety 
Reporting, an AE is any untoward medical occurrence in a patient or clinical investigational 
subject administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment. 
The following information should be considered when determining whether or not to record a 
test result, medical condition, or other incident on the Adverse Events and Pre-existing 
Conditions case report form (CRF): 
● 
From the time of informed consent through the day prior to study Day 1, only study 
protocol-related AEs should be recorded. A protocol-related AE is defined as an 
untoward medical event occurring as a result of a protocol mandated procedure. 
● 
All medical conditions present or ongoing predose on study Day 1 should be 
recorded. 
● 
All AEs (regardless of relationship to study drug) should be recorded from study 
Day 1 (during and post-dose) through the end of the safety reporting period (see 


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Section 7.7.1.3). Complications that occur in association with any procedure 
(e.g., biopsy) should be recorded as AEs whether or not the procedure was protocol 
mandated. 
● 
Changes in medical conditions and AEs, including changes in severity, frequency, or 
character, during the safety reporting period should be recorded. 
● 
In general, an abnormal laboratory value should not be recorded as an AE unless it is 
associated with clinical signs or symptoms, requires an intervention, results in a 
serious adverse event (SAE), or results in study termination or 
interruption/discontinuation of study treatment. When recording an AE resulting from 
a laboratory abnormality, the resulting medical condition rather than the abnormality 
itself should be recorded (e.g., record “anemia” rather than “low hemoglobin”). 
Serious Adverse Events 
An AE should be classified as an SAE if it meets one of the following criteria: 
Fatal: 
AE resulted in death 
 
Life threatening: 
The AEs placed the patient at immediate risk of death. This classification does not 
apply to an AE that hypothetically might cause death if it were more severe. 
 
Hospitalization: 
The AE required or prolonged an existing inpatient hospitalization. Hospitalizations 
for elective medical or surgical procedures or treatments planned before the signing 
of informed consent in the study or routine check-ups are not SAEs by this criterion. 
Admission to a palliative unit or hospice care facility is not considered to be a 
hospitalization. Hospitalizations or prolonged hospitalizations for scheduled therapy 
of the underlying cancer or study target disease need not be captured as SAEs. 
 
Disabling/ 
incapacitating: 
Resulted in a persistent or significant incapacity or substantial disruption of the 
patient’s ability to conduct normal life functions. 
 
Congenital anomaly or 
birth defect: 
An adverse outcome in a child or fetus of a patient exposed to the molecule or study 
treatment regimen before conception or during pregnancy. 
 
Medically significant: 
The AE did not meet any of the above criteria, but could have jeopardized the patient 
and might have required medical or surgical intervention to prevent one of the 
outcomes listed above or involves suspected transmission via a medicinal product of 
an infectious agent. 
Adverse Event Severity 
AE severity should be graded using the National Cancer Institute’s Common Terminology 
Criteria for Adverse Events (NCI CTCAE), version 4.03. These criteria are provided in the 
study manual. 
AE severity and seriousness are assessed independently. ‘Severity’ characterizes the intensity 
of an AE. ‘Serious’ is a regulatory definition and serves as a guide to the sponsor for defining 
regulatory reporting obligations (see definition for Serious Adverse Events). 


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Relationship of the Adverse Event to Study Treatment 
The relationship of each AE to each study treatment should be evaluated by the investigator 
using the following criteria: 
Related: 
There is evidence to suggest a causal relationship between the drug and the AE, such 
as: 
● 
an event that is uncommon and known to be strongly associated with drug 
exposure (e.g., angioedema, hepatic injury, Stevens-Johnson Syndrome) 
● 
an event that is not commonly associated with drug exposure, but is otherwise 
uncommon in the population exposed to the drug (e.g., tendon rupture) 
Unrelated: 
Another cause of the AE is more plausible (e.g., due to underlying disease or occurs 
commonly in the study population), or a temporal sequence cannot be established 
with the onset of the AE and administration of the study treatment, or a causal 
relationship is considered biologically implausible 
 
7.7.1.2 Procedures for Eliciting and Recording Adverse Events 
Investigator and study personnel will report all AEs and SAEs whether elicited during patient 
questioning, discovered during physical examination, laboratory testing and/or other means 
by recording them on the CRF and/or SAE form, as appropriate. 
Eliciting Adverse Events 
An open-ended or non-directed method of questioning should be used at each study visit to 
elicit the reporting of AEs. 
Recording Adverse Events 
The following information should be recorded on the Adverse Events and Pre-existing 
Conditions CRF: 
● 
Description including onset and resolution dates 
● 
Whether it met serious criteria 
● 
Severity 
● 
Relationship to study treatment or other causality 
● 
Outcome 
Diagnosis vs. Signs or Symptoms 
In general, the use of a unifying diagnosis is preferred to the listing out of individual 
symptoms. Grouping of symptoms into a diagnosis should only be done if each component 
sign and/or symptom is a medically confirmed component of a diagnosis as evidenced by 
standard medical textbooks. If any aspect of a sign or symptom does not fit into a classic 
pattern of the diagnosis, report the individual symptom as a separate 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.’  


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Instead, record each sign or symptom as an individual AE. If multiple signs or symptoms 
occur with a given infusion-related event, each sign or symptom should be recorded 
separately with its level of severity. 
Recording Serious Adverse Events 
For SAEs, record the event(s) on both the CRF and an SAE form. 
The following should be considered when recording SAEs: 
● 
Death is an outcome of an event. The event that resulted in the death should be 
recorded and reported on both an SAE form and CRF. 
● 
For hospitalizations, surgical, or diagnostic procedures, the illness leading to the 
surgical or diagnostic procedure should be recorded as the SAE, not the procedure 
itself. The procedure should be captured in the narrative as part of the action taken in 
response to the illness. 
Progression of the Underlying Cancer 
Do not use the term ‘disease progression’ alone when reporting AEs, including SAEs, 
because it is too nonspecific. Symptoms of disease progression that meet the criteria for an 
SAE must be reported. When possible, report the specific disease (clinical) manifestation of 
the progression (e.g., ‘malignant pleural effusion’, ‘spinal bone metastases’, 
‘lymphadenopathy’, ‘brain metastases’). Otherwise, it is acceptable to report the specific 
disease (e.g., non-Hodgkin lymphoma) as an SAE. 
Pregnancy 
Notification to Drug Safety: Complete a Pregnancy Report Form for all pregnancies that 
occur from the time of first study drug dose until 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. Email or fax to the sponsor’s Drug Safety 
Department within 48 hours of becoming aware of a pregnancy. All pregnancies will be 
monitored for the full duration; all perinatal and neonatal outcomes should be reported. 
Infants should be followed for a minimum of 8 weeks. 
Collection of data on the CRF: All pregnancies (as described above) that occur within 
30 days of the last dose of study drug(s) will also be recorded on the Adverse Events and Pre-
Existing Conditions CRF. 
Abortion, whether accidental, therapeutic, or spontaneous, should be reported as an SAE. 
Congenital anomalies or birth defects, as defined by the ‘serious’ criterion above (see 
definitions Section 7.7.1.1) should be reported as SAEs. 


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7.7.1.3 Reporting Periods for Adverse Events and Serious Adverse Events 
The safety reporting period for all AEs and SAEs is from study Day 1 (predose) through the 
EOT visit or 30 days after the last study treatment, whichever is later. However, all study 
protocol-related AEs are to be recorded from the time of informed consent. All SAEs that 
occur after the safety reporting period and are considered study treatment-related in the 
opinion of the investigator should also be reported to the sponsor. 
SAEs will be followed until significant changes return to baseline, the event stabilizes 
(recovering/resolving) or is no longer considered clinically significant by the investigator, or 
the patient dies or withdraws consent. All non-serious AEs will be followed through the 
safety reporting period. Certain non-serious AEs of interest may be followed until resolution, 
return to baseline, or study closure. 
7.7.1.4 Adverse Events of Special Interest 
Hepatobiliary serious adverse events, including cases of sinusoidal obstruction 
syndrome/veno-occlusive disease (SOS/VOD), are considered adverse events of special 
interest, regardless of causality. Investigators must complete a detailed “Liver Disease 
Adverse Event Information Form” for all of these events. All reported adverse events of 
special interest will be subject to expedited reporting according to safety reporting 
requirements. Events of SOS/VOD that occur within 180 days of the last dose of blinded 
study treatment will be reported to the sponsor. Patients who undergo subsequent allo-SCT in 
the absence of relapse and additional therapy will be followed for SOS/VOD to 100 days 
post-transplant. 
7.7.1.5 Serious Adverse Events Require Immediate Reporting 
Within 24 hours of observing or learning of an SAE, investigators are to report the event to 
the sponsor, regardless of the relationship of the event to the study treatment regimen. 
For initial SAE reports, available case details are to be recorded on an SAE form. At a 
minimum, the following should be included: 
● 
Patient number 
● 
Date of event onset 
● 
Description of the event 
● 
Study treatment, if known 
 
The completed SAE form and SAE Fax Cover Sheet are to be emailed or faxed to the 
sponsor’s Drug Safety Department at 1 (425) 527-4308 or Drug.Safety@Seagen.com within 
24 hours. 
Relevant follow-up information is to be submitted to the sponsor as soon as it becomes 
available. 


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7.7.1.6 Sponsor Safety Reporting to Regulatory Authorities 
Investigators are required to report all SAEs, including anticipated SAEs, to the sponsor (see 
Section 7.7.1.5). 
The sponsor will report all SAEs to regulatory authorities as required per local regulatory 
reporting requirements. In the United States, endpoints that assess disease-related mortality 
or major morbidity as well other SAEs that are not study endpoints, but are known 
consequences of the underlying disease or condition that are anticipated to occur in the study 
population should not be reported to the Food and Drug Administration (FDA) as individual 
IND safety reports per the final rule amending the IND safety reporting requirements under 
21 CFR 312.32 and the FDA’s guidance Safety Reporting Requirements for INDs and 
BA/BE Studies (December 2012) and FDA’s guidance Safety Assessment for IND Safety 
Reporting (December 2015). 
In this study, the SAEs that do not require individual IND safety reports to the FDA are 
leukemic relapse. Events of febrile neutropenia are anticipated in this population and 
individual IND safety reports will not be submitted to FDA. However, the sponsor will report 
all SAEs, including anticipated events, to international authorities as required per local 
reporting requirements. 
All SAEs will be reviewed periodically by an IDMC. 
7.7.2 Clinical Laboratory Tests 
Samples will be drawn for central and local labs. Local laboratory testing will include 
institutional standard tests for evaluating safety and making clinical decisions. 
The following laboratory assessments will be performed by the central laboratory to evaluate 
safety at scheduled timepoints (see Appendix A) during the course of the study: 
● 
The chemistry panel is to include the following tests: albumin, alkaline phosphatase, 
ALT, AST, blood urea nitrogen, calcium, creatinine, chloride, glucose, lactate 
dehydrogenase (LDH), phosphorus, potassium, sodium, total bilirubin, lipase, 
magnesium, amylase, 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, blasts, RBC count, mean corpuscular volume (MCV), 
hemoglobin and hematocrit. 
7.7.3 Physical Examination 
Physical examinations should include assessments of the following body parts/systems: 
abdomen, extremities, head, heart, lungs, neck, and neurological. Measurements of height 
obtained within the prior 12 months may be utilized. 


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7.7.4 Cardiac Monitoring 
ECGs will be conducted at baseline. Paper copies of the tracings will be used for data entry 
into the CRF. Additional ECGs should be conducted if clinically indicated. 
7.7.5 ECOG Performance Status 
ECOG performance status (Appendix C) will be evaluated at protocol-specified time points. 
7.7.6 Vital Signs 
Vital signs: temperature, heart rate, respiratory rate, and blood pressure, will be evaluated at 
protocol-specified time points.  
7.8 Appropriateness of Measurements 
The safety measures that will be used in this trial are considered standard procedures for 
evaluating the potential adverse effects of study medications. Adverse events and, when 
applicable, clinical laboratory data will be graded using NCI CTCAE, Version 4.03. 
Clinical response will be determined according to a modification of the response 
categorization in the Revised Recommendations of the International Working Group for 
Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting 
Standards for Therapeutic Trials in Acute Myeloid Leukemia (Cheson 2003) (see 
Appendix E). These criteria are considered standard in oncological practice, and the intervals 
of evaluation in this protocol are appropriate for disease management. 
Immunogenicity is commonly assessed for biologics; therefore, standard tests will be 
performed to detect the possible presence of specific antibodies to vadastuximab talirine. 
Pharmacokinetic assessments for drug activity are also common in clinical studies. 
Molecular characterization of disease is common in oncological practice. Biomarker samples 
will be collected at intervals coincident with pharmacokinetic sampling or clinical 
assessments appropriate for disease management. 
8 
DATA QUALITY CONTROL AND QUALITY ASSURANCE 
8.1 Site Training and Monitoring Procedures 
A study manual with instructions for study compliance and CRF completion will be 
provided. Prior to the enrollment of patients at the site, Seattle Genetics or its designated 
clinical and medical personnel will review the following items with the investigator and 
clinic staff: 
● 
The protocol, study objectives, eligibility requirements, study procedures, registration 
and withdrawal processes 
● 
Current Investigator’s Brochure/ package insert 
● 
Recording and reporting AE and SAE 


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● 
Enrollment goals and study timelines 
● 
The CRF completion process and source documentation requirements 
● 
Monitoring requirements 
● 
Institutional Review Board/Independent Ethics Committee (IRB/IEC) review and 
approval process 
● 
Informed consent process 
● 
Good Clinical Practice guidelines and related regulatory documentation requirements 
● 
Key study team roles and responsibilities 
● 
Investigational product storage, accountability, labeling, dispensing and record 
keeping 
● 
Patient coding and randomization (if applicable) 
● 
Study samples/specimen collection, handling and shipping 
● 
Protocol compliance 
● 
Clinical study record keeping, document retention, and administrative requirements 
Monitoring visits will occur periodically, with frequency dependent on the rate of enrollment 
and workload at each site. During monitoring visits, the Seattle Genetics representative will 
review regulatory documentation, CRFs, source documentation, and investigational product 
storage, preparation, and accountability. The CRFs will be reviewed for completeness, 
adherence to the provided guidelines, and accuracy compared to the source documents. The 
investigators must ensure that the monitor is allowed to inspect all source documents 
pertinent to study patients, and must cooperate with the monitor to ensure that any problems 
noted in the course of the trial are resolved. The investigator must maintain a comprehensive 
and centralized filing system of all study-related documentation that is suitable for inspection 
by Seattle Genetics or its designated monitors and by quality assurance auditors, or 
representatives of regulatory authorities. 
8.2 Data Management Procedures 
Seattle Genetics will provide CRF Completion Guidelines for electronic CRF (eCRF) data 
entry. Study specific data management procedures will be maintained in the data 
management plan. Queries resulting from edit checks and/or data verification procedures will 
be posted electronically in the eCRF. 
8.3 Access to Source Data 
The investigator will permit the sponsor’s representatives to monitor the study as frequently 
as the sponsor deems necessary to determine that protocol adherence and data recording are 
satisfactory. Appropriate measures to protect patient confidentiality are to be employed 


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during monitoring. The CRFs and related source documents will be reviewed in detail by the 
monitor at each site visit. Original source documents or certified copies are needed for 
review. This review includes inspection of data acquired as a requirement for participation in 
this study and other medical records as required to confirm that the information contained in 
the CRFs, such as disease assessments, AEs, and concomitant medications, is complete and 
correct. Other study records, such as correspondence with the sponsor and the IRB/IEC and 
screening and drug accountability logs will also be inspected. All source data and study 
records must also be available for inspection by representatives of regulatory authorities. 
8.4 Accuracy and Reliability of Data 
Steps to be taken to assure the accuracy and reliability of data include: 
● 
The selection of qualified investigators and appropriate study centers. 
● 
Review of protocol procedures with the investigators and associated personnel prior 
to the study. 
● 
Periodic monitoring visits by the designated monitor(s). 
● 
CRFs will be reviewed for accuracy and completeness by the designated monitor(s) 
during monitoring visits to the study centers. Any discrepancies will be resolved with 
the investigator or designees as appropriate. 
8.5 Quality Assurance Procedures 
The Clinical Quality Assurance group or its designee may conduct audits at the clinical site 
or other study-related facilities and organizations. Audit reports will be retained by the 
Clinical Quality Assurance group of Seattle Genetics as part of the written record. 
8.6 Data Handling and Record Keeping 
8.6.1 Data Handling 
It is the investigator’s responsibility to ensure the accuracy, completeness, legibility, and 
timeliness of the data reported to the sponsor in the CRFs and in all required reports. Data 
reported on the CRF that is derived from source documents should be consistent with the 
source documents or the discrepancies should be explained. 
Any change or correction to a CRF will be maintained in an audit trail within the electronic 
data capture system. Data changes may only be made by those individuals so authorized. The 
investigator should retain records of the changes and corrections, written and/or electronic. 
8.6.2 Investigator Record Retention 
The investigator shall retain study drug disposition records and all source documentation 
(such as original ECG tracings, laboratory reports, inpatient or office patient records) for the 
maximum period required by the country and Institution in which the study will be 
conducted, or for the period specified by Seattle Genetics, whichever is longer. The 
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study. If the investigator withdraws from the study (due to relocation, retirement, etc.), the 
records shall be transferred to a mutually agreed upon designee, such as another investigator 
or IRB/IEC. Notice of such transfer will be provided in writing to Seattle Genetics. 
9 
DATA ANALYSIS METHODS 
9.1 Determination of Sample Size 
There are 2 primary endpoints for this study: CRc rate and OS. To maintain strong control of 
the type I error rate at 0.05, a fallback procedure proposed by Wiens will be used in the 
testing of the primary endpoints, with an alpha of 0.01 pre-assigned to CRc rate and an alpha 
of 0.04 pre-assigned to OS (Wiens 2005). 
The sample size was calculated based on maintaining 90% power to test both primary 
endpoints and to account for 2 planned interim analyses for OS, one futility analysis at 30% 
and one interim efficacy analysis at 60% of the targeted number of OS events, using the 
O’Brien-Fleming method. 
For the primary endpoint of CRc rate, at least 308 patients are required to provide 90% 
power to detect an improvement in CRc rate from 20% to 40% using a chi-squared test at a 
significance level of 0.01. 
For the primary endpoint of OS, approximately 354 OS events are required with 90% power 
to detect a hazard ratio of 0.70 (12.9 months median OS in the experimental arm 
[vadastuximab talirine plus HMA] versus 9 months for the comparator arm [placebo plus 
HMA]) using a 2-sided log-rank test at an alpha of 0.04. 
To provide adequate power for both primary endpoints, a total of 540 patients will be 
randomized in a 1:1 ratio to either the experimental arm or the comparator arm, assuming an 
accrual period of 26 months with a slower rate of accrual for the first 6 months, a 12-month 
follow up, and a 5% yearly drop-out rate. 
EAST (Version 6.3) was used to calculate and validate the sample size. 
9.2 Study Endpoint Definitions 
9.2.1 Primary Endpoints 
9.2.1.1 Composite Complete Remission (CRc) Rate 
CRc rate is defined as the proportion of patients who achieve CR or CRi according to the 
modified response criteria for AML (Cheson 2003) defined in Appendix E. Patients whose 
disease response cannot be assessed will be considered non-responders for calculating the 
CRc rate. 


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9.2.1.2 Overall Survival (OS) 
Overall survival (OS) is defined as the time from randomization to death due to any cause. 
Specifically, 
 
OS = Date of death – Date of randomization + 1. 
For a patient who is not known to have died by the end of study follow up, observation of OS 
is censored on the date the patient was last known to be alive (i.e., date of last contact). 
Patients lacking data beyond the day of randomization will have their survival time censored 
on the date of randomization (i.e., OS duration of 1 day). 
9.2.2 Secondary Efficacy Endpoints 
9.2.2.1 MRD-negative CRc Rate 
MRD-negative CRc rate is defined as the proportion of patients who achieve both 
morphologic remission (CR or CRi) and MRD-negative status. Patients whose morphologic 
response or MRD status cannot be assessed will be considered non-responders for calculating 
the MRD-negative CRc rate. 
9.2.2.2 Duration of Remission 
Duration of remission is defined as the time from the first documentation of CR or CRi to the 
first documentation of disease relapse or to death due to any cause, whichever comes first. 
Patients who have started a new antitumor therapy (excluding maintenance therapy during 
remission in the absence of relapse, or consolidative allogeneic or autologous stem cell 
transplant after study treatment) prior to documentation of disease relapse will be censored at 
the date of the last response assessment on or prior to start of new therapy. 
Duration of remission will be calculated only for the subgroup of patients achieving a CR or 
CRi. 
9.2.2.3 Event-Free Survival (EFS) 
EFS is defined as the time from randomization to the first documentation of progression, 
disease relapse (see Appendix E) or to death due to any cause, whichever comes first. 
Patients who have started an antitumor therapy (excluding maintenance therapy during 
remission in the absence of relapse, or consolidative allogeneic or autologous stem cell 
transplant after study treatment) other than the study treatment prior to documentation of 
progression or disease relapse will be censored at the date of the last response assessment on 
or prior to start of new therapy. 
9.2.2.4 Leukemia-Free Survival (LFS) 
LFS is defined as the time from the first documentation of blast clearance (morphologic 
leukemia-free state [mLFS], CR or CRi) to the first documentation of disease relapse or to 
death due to any cause, whichever comes first (see Appendix E). Patients who have started 
an antitumor therapy (excluding maintenance therapy during remission in the absence of 


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relapse, or consolidative allogeneic or autologous stem cell transplant after study treatment) 
other than the study treatment prior to documentation of progression or disease relapse will 
be censored at the date of the last response assessment on or prior to start of new therapy. 
LFS will be calculated only for the subgroup of patients achieving a CR or CRi. 
9.2.2.5 Time to Complete Remission 
Time to complete remission (TTCR) is defined as the time from randomization to the first 
documentation of CR or CRi. TTCR will be calculated only for the subgroup of patients 
achieving a CR or CRi. 
9.2.2.6 Mortality Rates 
The 30-day mortality rate is defined as the proportion of patients who die within 30 days of 
randomization. The 60-day mortality rate is defined as the proportion of patients who die 
within 60 days of randomization. 
9.3 Statistical and Analytical Plans 
The statistical and analytical plans presented below summarize the more complete plans to be 
detailed in the statistical analysis plan (SAP). A change to the data analysis methods 
described in the protocol will require a protocol amendment only if it alters site conduct (e.g., 
adding baseline assessments to define a subgroup). The SAP will be finalized prior to the 
first interim analysis. Any changes to the methods described in the final SAP will be 
described and justified in the clinical study report. 
9.3.1 General Considerations 
9.3.1.1 Randomization and Blinding 
This is a randomized study that will enroll approximately 540 patients. Patients will be 
randomized in a 1:1 manner to receive either vadastuximab talirine plus HMA or placebo 
plus HMA. 
Patients will be stratified based on the following variables to ensure that patient-specific risk 
factors are appropriately balanced between treatment arms: 
● 
Cytogenetic risk per revised UK MRC classification (intermediate versus adverse; see 
Appendix D) 
● 
ECOG performance status (0−1 versus 2) 
● 
HMA (azacitidine versus decitabine) 
● 
Age (<75 years versus ≥75 years) 
After stratification, patients will be randomized into 1 of 2 treatment arms, for a total of 
approximately 270 patients per arm. 


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Randomization will be performed centrally using a system that will assign a unique patient 
randomization number. The actual treatment assignment will remain blinded. Randomization 
procedures are detailed in the Study Manual. 
9.3.1.2 Adjustments for Covariates 
Stratified analyses will include adjustment for the stratification factor as recorded at 
randomization (described in Section 9.3.1.1). Other covariates may be considered for 
adjustment in exploratory analyses. 
9.3.1.3 Handling of Dropouts and Missing Data 
Missing data will not be imputed, with the exception of AE dates while calculating duration 
of events and treatment-emergent status. Patients with missing values of a variable other than 
response endpoints (CRc rate, MRD-negative CRc rate) and time-to-event endpoints (OS, 
LFS, and EFS) will be excluded from the analysis of that endpoint. Patients whose disease 
response cannot be assessed will be scored as non-responders for calculating the CRc rate 
and MRD-negative CRc rate. Censoring rules will be applied to the estimation of the 
distribution of the time-to-event endpoints, details will be provided in the SAP. 
9.3.1.4 Multicenter Studies 
There are multiple centers in this study, however it is not anticipated that any center will 
accrue enough patients to warrant an analysis by center. 
9.3.1.5 Multiple Comparisons and Multiplicity 
To maintain strong control of the Type I error rate at 0.05, the fallback procedure proposed 
by Wiens will be used in the testing of the primary endpoints, with an alpha of 0.01 pre-
assigned to CRc rate and an alpha of 0.04 pre-assigned to OS. (Wiens 2005). If the test for 
the CRc rate is statistically significant, then the alpha of 0.01 will be re-allocated to OS, and 
the test for OS will be performed at a 2-sided alpha of 0.05. If the test for the CRc rate is not 
statistically significant, then the test for OS will be performed at a 2-sided alpha of 0.04. 
The parallel gatekeeping principle will be used to control the overall type I error rate of 0.05 
(Dmitrienko 2011). The primary endpoints, CRc rate and OS (family 1), will be the 
gatekeepers for testing the secondary endpoint of MRD-negative CRc rate (family 2). If at 
least one of the primary endpoints is statistically significant, then a statistical test will be 
performed for the MRD-negative CRc rate. If both CRc rate and OS are statistically 
significant, then MRD-negative CRc rate will be tested at an overall alpha of 0.05. If only 
one of the 2 primary endpoints is statistically significant, then MRD-negative CRc rate will 
be tested at the corresponding alpha level of the significant primary endpoint. If the tests for 
both CRc rate and OS are not statistically significant, then the p-value of the test for MRD-
negative CRc rate will still be calculated but will be considered descriptive. 
Two formal interim analyses for OS are planned. The test significance level for OS at the 
interim analysis will be adjusted based on the actual number of OS events observed at each 
interim analysis according to the O’Brien-Fleming spending function. 


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9.3.1.6 Data Transformations and Derivations 
For efficacy assessments, the date of response will be the latest of all applicable dates for the 
given assessment (e.g., bone marrow date, CBC date). The date of relapse/progression will be 
the earliest of all applicable dates for the given assessment. Detailed methodology will be 
provided in the SAP. 
9.3.1.7 Analysis Sets 
The intent-to-treat (ITT) analysis set will include all randomized patients. Patients will be 
included in the treatment group assigned at randomization regardless of any actual treatment 
received. 
The modified intent-to-treat (mITT) analysis set will include all patients from the ITT 
analysis set who receive any dose of blinded study treatment (vadastuximab talirine or 
placebo) or HMA. Patients will be included in the treatment group assigned at randomization 
regardless of the actual treatment received. 
The safety analysis set will include all patients who receive any dose of blinded study 
treatment (vadastuximab talirine or placebo) or HMA. Treatment group will be determined 
using the actual treatment received, regardless of the randomization treatment assignment. 
Patients receiving any dose of vadastuximab talirine will be grouped into the experimental 
arm. Patients who do not receive vadastuximab talirine but receive any dose of HMA will be 
grouped into the comparator arm. 
9.3.1.8 Examination of Subgroups 
As exploratory analyses, subgroup analyses may be conducted for selected endpoints, 
including, but not limited to gender, race, AML subtype, and randomization strata 
(cytogenetic risk, ECOG performance status, HMA, and age). Detailed methodology will be 
provided in the SAP. 
9.3.1.9 Timing of Analyses 
The primary analysis of CRc rate is planned when the following 2 conditions are met: 
1) 6 months after 308 patients have been randomized, and 2) approximately 212 OS events 
have occurred. The estimated duration of the study through the primary analysis of CRc rate 
is approximately 2 years from randomization of the first patient based on design assumptions. 
Only the first 308 patients randomized will be included in the primary analysis of CRc rate. 
CRc rate will also be analyzed for all randomized patients at the time of the final analysis. 
The estimated duration of the study through the final analysis for OS is approximately 
3 years from randomization of the first patient based on design assumptions. 
There are 2 planned interim analyses of OS. The first interim analysis will take place when 
approximately 106 OS events have occurred (~30% of the targeted number of events) and 
will assess the futility of vadastuximab talirine in combination with azacitidine or decitabine. 


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The second interim analysis for OS will occur in conjunction with the primary analysis of 
CRc rate. The analysis will be conducted when the following 2 conditions are met: 
1) 6 months after 308 patients have been randomized, and 2) approximately 212 OS events 
have occurred (~60% of the targeted number of events). The interim OS results will be 
assessed for early stopping for efficacy. 
The IDMC will provide recommendations to the sponsor's Data Review Board as to 
appropriate study direction at the interim analysis. 
End-of-trial is defined as the point at which all patients have died or discontinued the study, 
or have been followed for a maximum of 3 years after the last patient enrolled, whichever 
comes first. An end-of-trial analysis will be performed after study closure. 
9.3.2 Patient Disposition 
An accounting of study patients by disposition will be tabulated and the number of patients in 
each analysis set will be summarized. Patients who discontinue study treatment and patients 
who withdraw from the study will be summarized with reason for discontinuation or 
withdrawal. 
9.3.3 Patient Characteristics 
Demographics and other baseline characteristics will be summarized. Details will be 
provided in the SAP. 
9.3.4 Treatment Compliance 
The dose administered at each cycle for each treatment agent will be assessed and dose 
intensity may be summarized. Details will be provided in the SAP. 
9.3.5 Efficacy Analyses 
All efficacy endpoints will be analyzed using the ITT analysis set. Supplemental analyses 
will be performed using the mITT analysis set. 
9.3.5.1 Primary Efficacy Analysis 
CRc rate will be analyzed based on the ITT analysis set. The CRc rate between the 
2 treatment arms will be compared using a Cochran-Mantel-Haenszel test stratified by the 
randomization strata. The CRc rate and its 2-sided 99% confidence interval (CI) will be 
summarized by treatment arm. At the time of the primary analysis of CRc rate, only the first 
308 patients randomized will be included in the population for the analysis of CRc rate. CRc 
rate will also be analyzed for all randomized patients at the time of the final analysis. 
Overall survival will be assessed using Kaplan-Meier methods. A stratified log-rank test 
without adjustments for covariates will be used in the primary evaluation of OS differences 
between the 2 treatment arms based on the ITT population. The hazard ratio will be estimated 
using the unadjusted stratified Cox model. The 2-sided 95% CI and the CI corresponds to the 
significance level of the test following the multiplicity adjustment (see Section 9.3.1.5) will 
be presented. The proportional hazard assumptions will be examined and sensitivity analyses 


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will be conducted if appropriate. All events entered in the database at the time of the analysis 
and source-data verified will be included in the analysis of OS, even if there is more than the 
pre-specified number of events. 
Kaplan-Meier curves depicting OS in the 2 treatment arms will be generated. Additionally, 
the median OS and the probability of OS from 1 month to the end of the follow-up period 
will be reported at pre-specified intervals. The associated 2-sided 95% CIs will be calculated 
using the complementary log-log transformation method (Collett 1994). Detailed 
methodology will be provided in the SAP. 
9.3.5.2 Secondary Efficacy Analyses 
MRD-negative CRc rate: MRD-negative CRc rate will be analyzed based on the ITT 
analysis set. The MRD-negative CRc rate between the 2 treatment arms will be compared 
using a Cochran-Mantel-Haenszel test stratified by the randomization strata. The MRD-
negative CRc rate and its 2-sided 95% CI will be summarized by treatment arm. 
Duration of remission: Duration of remission will be analyzed using Kaplan-Meier 
methodology and Kaplan-Meier plots will be provided by treatment arm using the ITT 
analysis set. The median remission duration and its 2-sided 95% CI using the complementary 
log-log transformation method (Collett 1994) will be calculated by treatment arm. 
Event-free survival: EFS will be analyzed using Kaplan-Meier methodology and 
Kaplan-Meier plots will be provided by treatment arm using the ITT analysis set. The median 
EFS and its 2-sided 95% CI using the complementary log-log transformation method 
(Collett 1994) will be calculated by treatment arm. 
Leukemia-free survival: LFS will be analyzed using Kaplan-Meier methodology and 
Kaplan-Meier plots will be provided by treatment arm using the ITT analysis set. The median 
LFS and its 2-sided 95% CI using the complementary log-log transformation method 
(Collett 1994) will be calculated by treatment arm. 
Time to complete remission: TTCR will be summarized by treatment arm using descriptive 
statistics. 
9.3.6 Pharmacokinetic, ATA, and Biomarker Analyses 
Observed plasma vadastuximab talirine ADC and SGD-1882 (if measurable) will be 
summarized with descriptive statistics at each PK sampling timepoint. These data may be 
combined with data from previous studies for population PK and PK/PD analyses. The 
relationship between vadastuximab talirine PK and PD endpoints, safety, or efficacy may be 
explored; these analyses, if conducted, will be descriptive. 
The incidence of ATA will be summarized by descriptive statistics. 
Biomarker assessments will also be summarized using descriptive statistics. 


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9.3.7 Patient Reported Outcomes Analyses 
PRO analyses will be conducted using the ITT analysis set and will assess the change from 
baseline to the end of treatment in PRO assessments. QLQ-C30 scores will be determined per 
patient self-report. Change from baseline to end of treatment in QLQ-C30 scores will be 
summarized using descriptive statistics. 
EQ-5D Health Index Scores will be determined by patient self-report. The EQ-5D health 
state index and visual analog scale will be summarized descriptively by visit. 
9.3.8 MRU Analyses 
MRU data will be summarized using descriptive statistics. Details will be provided in the 
SAP. 
9.3.9 Safety Analyses 
All safety analyses will be performed using the safety analysis set unless otherwise specified. 
9.3.9.1 Extent of Exposure 
Duration of treatment, number of cycles, total dose and dose intensity may be summarized by 
treatment agent and arm. Dose modifications will also be summarized. Details will be 
provided in the SAP. 
9.3.9.2 Adverse Events 
Adverse events will be defined as treatment emergent if they are newly occurring or worsen 
following study treatment. The incidence of all AEs, treatment-emergent AEs, and treatment-
related AEs will be tabulated. AEs will be classified by system organ class and preferred 
term using the Medical Dictionary for Regulatory Activities (MedDRA). 
AEs will be listed and summarized by treatment arm, MedDRA preferred term, severity, and 
relationship to study drug. In the event of multiple occurrences of the same AE with the same 
preferred term in one patient, the AE will be counted once as the occurrence. The incidence 
of AEs will be tabulated by preferred term and treatment group. AEs leading to premature 
discontinuation of study drug will be summarized and listed in the same manner. 
9.3.9.3 Deaths and Serious Adverse Events 
Serious adverse events will be listed and summarized in the same manner as all AEs. Events 
with a fatal outcome will be listed. 
9.3.9.4 Clinical Laboratory Results 
Summary statistics for actual values and for change from baseline may be tabulated as 
appropriate for selected laboratory results by treatment arm and scheduled visit. Patients with 
laboratory values outside of the normal reference range at any postbaseline assessment will 
be listed. 


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9.3.9.5 Other Safety Analyses 
ECOG Status 
ECOG status may be summarized for each visit. Shifts from baseline to the best and worst 
postbaseline score may be tabulated. 
Vital Signs 
Vital signs will be summarized.  Changes in vital sign measurements from pre-dose to post-
dose of blinded study treatment may be tabulated. 
Hospitalizations 
Hospitalization data will be summarized. Details will be provided in the SAP. 
Transfusions 
RBC and platelet transfusion independence will be summarized. Details will be provided in 
the SAP. 
9.3.10 Interim Analyses 
An IDMC will periodically monitor the trial for safety, including SAEs and early mortality, 
during the treatment period. During the periodical safety review, the IDMC will evaluate the 
60-day mortality rates in the 2 treatment arms. The independent statistician will assist the 
IDMC to evaluate whether there is an increased risk of early death in the experimental arm 
and make appropriate recommendations to the sponsor. 
Two formal interim analyses for OS are planned for the study. The first interim analysis is 
for the purpose of futility testing and will be conducted when approximately 106 OS events 
have occurred (~30% of the targeted number of events). The second interim analysis is for 
superiority testing and will occur in conjunction with the primary analysis of CRc rate. The 
analysis will be conducted when the following 2 conditions are met: 1) 6 months after 
308 patients have been randomized, and 2) approximately 212 OS events have occurred 
(~60% of the targeted number of events). The stopping boundaries will be determined using 
Lan-DeMets spending functions to simulate O’Brien-Fleming boundaries. Details will be 
provided in the SAP. 
The IDMC will provide recommendations to the sponsor's Data Review Board as to 
appropriate study direction. The sponsor will remain blinded to treatment assignment. See the 
IDMC Charter for details. 


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10 INFORMED CONSENT, ETHICAL REVIEW, AND REGULATORY 
CONSIDERATIONS 
This study will be conducted in accordance with the Note for Guidance on GCP (ICH 
Harmonized Tripartite Guideline E6 (R1); FDA CFR [21 CFR § 50, 56, 312]), Declaration of 
Helsinki (Brazil 2013), and all applicable regulatory requirements. 
10.1 Informed Consent 
The investigator is responsible for presenting the risks and benefits of study participation to 
the subject in simple terms using the IRB/IEC approved informed consent document and for 
ensuring patients are re-consented when the informed consent document is updated during 
the study, if required. The investigator will ensure that written informed consent is obtained 
from each patient by obtaining the signature and date on the informed consent document 
prior to the performance of protocol evaluations or procedures. 
10.2 Ethical Review 
The investigator will provide the sponsor or its designee with documentation of the IRB/IEC 
approval of the protocol and the informed consent document before the study may begin at 
the investigative site(s). The name and address of the reviewing ethics committee are 
provided in the investigator file. 
The investigator will supply the following to the investigative site’s IRB/IEC: 
● 
Protocol and amendments 
● 
Informed consent document and updates 
● 
Clinical Investigator’s Brochure and updates 
● 
Relevant curricula vitae, if required 
● 
Required safety and SAE reports 
● 
Any additional submissions required by the site’s IRB/IEC 
The investigator must provide the following documentation to the sponsor or its designee: 
● 
The IRB/IEC periodic (e.g., quarterly, annual) re-approval of the protocol. 
● 
The IRB/IEC approvals of any amendments to the protocol or revisions to the 
informed consent document. 
● 
The IRB/IEC receipt of safety and SAE reports, as appropriate. 
10.3 Regulatory Considerations 
This study will be conducted in accordance with the protocol and ethical principles stated in 
the applicable guidelines on good clinical practice, and all applicable local and/or regional 
laws, rules, and regulations. 
10.3.1 Investigator Information 
The contact information and qualifications of the principal investigator and subinvestigators 
and name and address of the research facilities are included in the investigator file. 


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


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Sutherland MSK, Yu C, Anderson M, Emmerton K, Zeng W, O'Meara MM, Kennedy DA, Ryan MC and 
Benjamin DR (2014). SGN-CD33A in Combination with Cytarabine or Hypomethylating Agents Demonstrates 
Enhanced Anti-Leukemic Activity in Preclinical Models of AML. Blood 124: Abstract 3739. 
Sutherland MSK, Yu C, O'Day C, Alley S, Anderson M, Emmerton K, Zeng W, O'Meara MM, Feldman EJ, 
Kennedy DA, Ryan MC and Benjamin D (2015). SGN-CD33A in Combination with Hypomethylating Agents 
Is Highly Efficacious in Preclinical Models of AML. Blood 126: Abstract 3785. 
Taylor VC, Buckley CD, Douglas M, Cody AJ, Simmons DL and Freeman SD (1999). The myeloid-specific 
sialic acid-binding receptor, CD33, associates with the protein-tyrosine phosphatases, SHP-1 and SHP-2. J Biol 
Chem 274: 11505-12. 
Ulyanova T, Blasioli J, Woodford-Thomas TA and Thomas ML (1999). The sialoadhesin CD33 is a myeloid-
specific inhibitory receptor. Eur J Immunol 29: 3440-9. 
Visser O, Trama A, Maynadie M, Stiller C, Marcos-Gragera R, De Angelis R, Mallone S, Tereanu C, Allemani 
C, Ricardi U, Schouten HC and Group RW (2012). Incidence, survival and prevalence of myeloid malignancies 
in Europe. Eur J Cancer 48: 3257-66. 
Vitale C, Romagnani C, Puccetti A, Olive D, Costello R, Chiossone L, Pitto A, Bacigalupo A, Moretta L and 
Mingari MC (2001). Surface expression and function of p75/AIRM-1 or CD33 in acute myeloid leukemias: 
engagement of CD33 induces apoptosis of leukemic cells. Proc Natl Acad Sci U S A 98: 5764-9. 
von Gunten S and Bochner BS (2008). Basic and clinical immunology of Siglecs. Ann N Y Acad Sci 1143: 61-
82. 
Wiens BL and Dmitrienko A (2005). The fallback procedure for evaluating a single family of hypotheses. J 
Biopharm Stat 15: 929-42. 
 
 


 
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APPENDIX A-1: SCHEDULE OF EVENTS – AZACITIDINE 
 
Visit Window 
Screening 
Baseline 
Enrollment 
 
Each Cycle 
EOTG 
LTFU 
D1 
D2−5 
D6Q 
D7M 
D15 
D21 
D28 
Within 28D 
prior to first 
dose of HMA 
Within 7D prior 
to first dose of 
HMA 
Within 7D prior 
to first dose of 
HMA 
±1D 
 
 
 
±2D 
±2D 
 
30–37 days post last 
dose of HMA/blinded 
study treatment 
±2 wks 
Baseline and 
Safety 
Assessments 
Informed consent 
X 
 
Eligibility documentation  
submitted to sponsor  
prior to study start 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
Diagnostic bone marrow exam, including cytogenetics 
XW 
 
 
 
 
 
 
 
 
 
 
Physical examination 
 
X 
XP 
 
 
XO 
XD 
XO 
 
X 
 
Vital signs 
 
 
 
 
 
XY 
 
 
 
 
 
Weight 
 
XC 
X 
 
 
 
 
 
 
 
 
ECG  
 
X 
 
 
 
 
 
 
 
 
 
Pulse oximetry for oxygen saturation 
 
X 
 
 
 
 
 
 
 
 
 
Pregnancy test (females of childbearing potential) 
 
X 
X 
 
 
 
 
 
 
X 
 
ECOG performance status 
 
X 
XP 
 
 
 
 
 
 
X 
 
Collect data to calculate CCI and HCT-CI and Wheatley Risk 
 
X 
 
 
 
 
 
 
 
 
 
Serum chemistry 
 
X 
XP,U 
 
 
XO 
XD 
XO 
 
X 
 
CBC with differential 
 
X 
XP,U 
 
 
XO 
XD 
XO 
XK,S 
X 
XJ 
Randomization 
 
 
XN 
 
 
 
 
 
 
 
 
 
Con meds & AEs 
Collect any related to study protocol procedures 
Collect pre-Day 1 HMA dose through 30 days post last dose of study treatment or 
EOT visit, whichever is later 
XX 
Treatment 
Administration 
Blinded study treatmentE  
 
 
 
 
 
 
X 
 
 
 
 
 
AzacitidineE 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
QoL/MRU 
EQ-5D and QLQ-C30 
 
X 
 
XP 
 
 
 
 
 
 
X 
 
Medical resource utilization 
 
 
 
Collect from Day 1 to EOT 
 
PK/ATA  
Blood sample for PK 
 
 
 
 
 
 
XF 
 
 
 
 
 
Blood sample for ATA 
 
 
 
XR 
 
 
 
 
 
 
X 
 
Biomarkers 
Bone marrow for cytogenetic risk assessmentA 
X 
 
 
 
 
 
 
 
 
 
 
 
Bone marrow for MRD, CD33 expression & RNA/DNAA 
X 
 
 
 
 
 
 
 
 
XK,S 
XH 
XS,V 
Serum and plasma sample for soluble factorsA 
X 
 
 
XL,O 
 
 
XL,O 
 
 
XK,S 
XH 
 
Response 
Assessments 
Bone marrow examinationB 
 
 
 
 
 
 
 
 
 
XK,S,T 
XH,T 
XS,T,V 
Survival status 
 
 
 
 
 
 
 
 
 
 
 
XI 
 
A 
By central assessment. 
B 
A bone marrow aspirate is sufficient; however, if marrow cannot be aspirated, a biopsy may be conducted. 
C 
Include assessment of height. 
D 
Cycles 1−4 only. 
E 
Alternative schedule of treatment administration permitted: azacitidine daily x 5/2 days off/2 days on and 
vadastuximab talirine or placebo given on Day 9. 
F 
Relative to blinded study drug administration: Cycles 1 and 2, sample obtained predose (within 8 hr prior); all cycles, 
samples obtained within 15 minutes post administration. 
G 
EOT evaluations should be obtained before initiation of non-protocol therapy. If EOT evaluations are completed 
before 30 days following last study treatment, conduct a phone screen 30–37 days after the patient’s last study 
treatment to ensure that no changes in AE profile have occurred. 
H 
Only required if not conducted within 4 weeks prior to EOT. 
I 
Contact patient for survival status and collection of subsequent anticancer treatment information every 2 mos (or more 
frequently as needed to support analysis of the study endpoints) after EOT until death or study closure. 
J 
If study treatment discontinued prior to leukemic relapse or progression, obtain every 2 mos through 24 mos after 
EOT, and every 4 mos thereafter, until initiation of another anticancer treatment, progression, or leukemic recurrence. 
K 
Day 22−28 in even-numbered cycles until CR/CRi. Window may be up to Day 42 in the event of a delay in the start of the 
next cycle of treatment. Additional bone marrow examinations should be performed and submitted as clinically indicated 
to confirm cellular recovery. 
L 
Sample obtained pre-dose HMA on Day 1 and pre-dose blinded study drug on Day 7. 
M 
Day 9 if alternative azacitidine schedule used. 
N 
Randomization to occur after eligibility determined and within 1 business day of planned 1st HMA dose. 
O 
Cycles 1 and 2 only. 
P 
Does not need to be repeated if done within 1 business day of Cycle 1 Day 1. 
Q 
Day 8 if alternative azacitidine schedule used. 
R 
Required in Cycle 1−4 and every fourth cycle thereafter. 
S 
Required 2 mos after confirmation of CR/CRi & at time of conversion from CRi to CR and/or time of suspected relapse. 
T 
If cytogenetics are abnormal at baseline, they are required post-treatment. 
U 
If dosing is delayed due to lab abnormalities, CBC with differential & serum chemistry should still be sent to the central 
lab. 
V 
If patient is not in CR/CRi, should be done every 2 mos through 24 mos after EOT, and then every 4 mos until CR/CRi. 
W 
Can be done up to 60 days prior to first dose of study treatment 
X 
See Sections 6.5 and 7.7 1.4 for details of follow up for adverse events of special interest 
Y 
Pre- and within 30 minutes post-blinded study treatment administration 


 
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APPENDIX A-2: SCHEDULE OF EVENTS – DECITABINE 
 
Visit Window 
Screening 
Baseline 
Enrollment 
 
Each Cycle 
EOTF 
LTFU 
D1 
D2−4 
D5 
D15 
D21 
D28 
Within 28D prior 
to first dose of 
HMA 
Within 7D prior 
to first dose of 
HMA 
Within 7D prior to 
first dose of HMA 
±1D 
 
 
±2D 
±2D 
 
30–37 days post last dose 
of HMA/blinded study 
treatment 
±2 wks 
Baseline and 
Safety 
Assessments 
Informed consent 
X 
 
Eligibility documentation  
submitted to sponsor prior to 
study start 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
Diagnostic bone marrow exam, including cytogenetics 
XT 
 
 
 
 
 
 
 
 
 
Physical examination 
 
X 
XN 
 
XM 
XD 
XM 
 
X 
 
Vital signs 
 
 
 
 
XV 
 
 
 
 
 
Weight 
 
XC 
X 
 
 
 
 
 
 
 
ECG 
 
X 
 
 
 
 
 
 
 
 
Pulse oximetry for oxygen saturation 
 
X 
 
 
 
 
 
 
 
 
Pregnancy test (females of childbearing potential) 
 
X 
X 
 
 
 
 
 
X 
 
ECOG performance status 
 
X 
XN 
 
 
 
 
 
X 
 
Collect data to calculate CCI, HCT-CI, and Wheatley Risk 
 
X 
 
 
 
 
 
 
 
 
Serum chemistry 
 
X 
XN,R 
 
XM 
XD 
XM 
 
X 
 
CBC with differential 
 
X 
XN,R 
 
XM 
XD 
XM 
XJ,P 
X 
XI 
Randomization 
 
 
XL 
 
 
 
 
 
 
 
 
Con meds & AEs 
Collect any related to study protocol procedures 
Collect pre-Day 1 HMA dose through 30 days post last dose of study treatment or 
EOT visit, whichever is later 
XU 
Treatment 
Administration 
Blinded study treatment  
 
 
 
 
 
X 
 
 
 
 
 
Decitabine 
 
 
 
X 
X 
X 
 
 
 
 
 
QoL/MRU 
EQ-5D and QLQ-C30 
 
X 
 
XN 
 
 
 
 
 
X 
 
Medical resource utilization 
 
 
 
Collect from Day 1 to EOT 
 
PK/ATA  
Blood sample for PK 
 
 
 
 
 
XE 
 
 
 
 
 
Blood sample for ATA 
 
 
 
XO 
 
 
 
 
 
X 
 
Biomarkers 
Bone marrow for cytogenetic risk assessmentA 
X 
 
 
 
 
 
 
 
 
 
 
Bone marrow for MRD, CD33 expression & RNA/DNAA 
X 
 
 
 
 
 
 
 
XJ,P 
XG 
XP,S 
Serum and plasma sample for soluble factorsA 
X 
 
 
XK,M 
 
XK,M 
 
 
XJ,P 
XG 
 
Response 
Assessments 
Bone marrow examinationB 
 
 
 
 
 
 
 
 
XJ,P,Q 
XG,Q 
XP,Q,S 
Survival status 
 
 
 
 
 
 
 
 
 
 
XH 
 
A 
By central assessment. 
B 
Bone marrow aspirate is sufficient; however, if marrow cannot be aspirated, a biopsy may be conducted. 
C 
Include assessment of height. 
D 
Cycles 1−4 only. 
E 
Relative to blinded study drug administration: Cycles 1 and 2, sample obtained predose (within 8 hr prior); all cycles, samples 
obtained within 15 minutes post administration. 
F 
EOT evaluations should be obtained before initiation of non-protocol therapy. If EOT evaluations are completed before 30 days 
following last study treatment, conduct a phone screen 30–37 days after the patient’s last study treatment to ensure that no 
changes in AE profile have occurred. 
G 
Only required if not conducted within 4 weeks prior to EOT. 
H 
Contact patient for survival status and collection of subsequent anticancer treatment information every 2 mos after EOT (or more 
frequently as needed to support analysis of the study endpoints) until death or study closure. 
I 
If study treatment discontinued prior to leukemic relapse or progression, obtain every 2 mos through 24 mos after EOT, and every 
4 mos thereafter, until initiation of another anticancer treatment, progression, or leukemic recurrence. 
J 
Day 22−28 in even-numbered cycles until CR/CRi. Window may be up to Day 42 in the event of a delay in the start of the next 
cycle of treatment. Additional bone marrow examinations should be performed and submitted as clinically indicated to confirm 
cellular recovery. 
K 
Sample obtained pre-dose HMA on Day 1 and pre-dose blinded study drug on Day 5. 
L 
Randomization to occur after eligibility determined and within 1 business day of planned 1st HMA dose. 
M 
Cycles 1 and 2 only. 
N 
Does not need to be repeated if done within 1 business day of Cycle 1 Day 1 
O 
Required in Cycle 1−4 and every fourth cycle thereafter. 
P 
Required 2 mos after confirmation of CR/CRi & at time of conversion from CRi to CR or time of 
suspected relapse. 
Q 
If cytogenetics are abnormal at baseline, they are required post-treatment. 
R 
If dosing is delayed due to lab abnormalities, CBC with differential and serum chemistry should still be 
sent to the central lab. 
S 
If patient is not in CR/CRi, should be done every 2 mos through 24 mos after EOT, and then every 4 mos 
until CR/CRi. 
T 
Can be done up to 60 days prior to first dose of study treatment 
U 
See Sections 6.5 and 7.7.1.4 for details of follow-up for adverse events of special interest 
V 
Pre- and within 30 minutes post-blinded study treatment administration 


 
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APPENDIX B: PHARMACOKINETIC, ATA, AND BIOMARKER SAMPLING TIMEPOINTS 
Cycle 
Study Day 
Timing 
Window 
Blood 
Bone Marrow Aspirate 
PK 
ATA 
Serum and 
Plasma Samples 
for Soluble 
Factors 
Cytogenetic 
Risk 
Assessment 
MRD and 
CD33 
Expression 
RNA/DNA 
for Molecular 
Profiling 
Baseline/ 
Screening 
 
Within 28D prior 
to first HMA dose 
 
 
 
X 
X 
X 
X 
All cycles 
D1 
Pre-HMA dose  
Within 24h 
 
XA 
XB 
 
 
 
D5 or 7C 
Pre-blinded study 
treatment dose 
Within 8h 
XB 
 
XB 
 
 
 
Post-blinded study 
treatment dose 
Within 15 min 
X 
 
 
 
 
 
D28 
 
D22–28 
 
 
XD 
 
XD 
XD 
EOT 
D30–37  
Before initiation 
of non-protocol 
therapy 
 
 
X 
XE 
 
XE 
XE 
Long-term 
follow-up 
 
 
 
 
 
 
 
XF 
XF 
 
A 
Required in Cycle 1−4 and every fourth cycle thereafter. 
B 
Cycles 1 and 2 only; sample obtained predose. 
C 
Day 5 for decitabine; Day 7 for azacitidine (or Day 9 if alternative azacitidine dosing schedule used). 
D 
Day 22−28 in even-numbered cycles until CR/CRi. Window may be up to Day 42 in the event of a delay 
in the start of treatment. After CR/CRi, assessed according to the following schedule: 2 cycles after initial 
confirmation of CR or CRi, at the time of conversion from CRi to CR, and at the time of suspected relapse. 
E 
Only required if not conducted within 4 weeks prior to EOT. 
F 
Only required 2 months after confirmation of CR/CRi and at the time of conversion from CRi to CR or 
suspected relapse. 
 
 






 
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APPENDIX E: RESPONSE CATEGORIES 
Term 
 
Definition (all criteria must be met unless otherwise specified)a 
Morphologic complete 
remission (CR) 
 
Absolute neutrophil count (ANC) ≥1000/μL and platelets ≥100,000/μL without transfusions and/or exogenous growth 
factor support (i.e., no transfusion or exogenous growth factor within 7 days of assessment). 
Bone marrow with <5% blasts 
No evidence of extramedullary disease 
Morphologic complete 
remission with 
incomplete blood count 
recovery (CRi) 
CRi(p) 
(morphologic CR with incomplete platelet recovery) 
Bone marrow with <5% blasts 
Platelets <100,000/μL or ≥100,000/μL if patient transfused in last 7 days 
ANC ≥1000/μL without exogenous growth factor support 
No evidence of extramedullary disease 
CRi(n) 
(morphologic CR with incomplete neutrophil recovery) 
Bone marrow with <5% blasts 
ANC <1000/μL or ANC ≥1000/μL with use of exogenous growth factors in last 7 days 
Platelets ≥100,000/μL without transfusions in last 7 days 
No evidence of extramedullary disease  
Morphologic leukemia 
free state (mLFS) 
 
Bone marrow with <5% blasts 
No evidence of extramedullary disease 
Criteria for blood count recovery not met for CR or CRi 
Partial remission (PR) 
 
ANC ≥1000/μL and platelets ≥100,000/μL without transfusions and/or exogenous growth factor support (i.e., no 
transfusion or exogenous growth factor within 7 days of assessment). 
Bone marrow with 5% to 25% blasts and at least a 50% decrease in bone marrow blast percent from baseline 
No evidence of extramedullary disease 
Antileukemic Effect  
 
>25% reduction of bone marrow blasts relative to baseline and criteria for PR not met 
Stable Disease (SD) 
 
Absence of CR, CRi, mLFS, PR, or antileukemic effect. Criteria for progressive disease (PD) not met 
Progressive Disease (PD) 
 
>25% absolute rise in bone marrow blast percent from baseline or appearance of new extramedullary disease after 4 or 
more cycles of treatment. In patients with baseline bone marrow blasts >75%, a 25% proportional (instead of 
absolute) increase in bone marrow blasts is considered PD. 
Relapse from CR/CRi 
 
Reappearance of blasts in the blood (unless consistent with regenerating bone marrow), or bone marrow (>5%), or in 
any extramedullary site after achieving CR or CRi 
a 
Modified from the Revised Recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and 
Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia (Cheson 2003). 
 


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


 
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APPENDIX G: GUIDANCE ON CONTRACEPTION 
 
Acceptable Methods for Highly Effective Birth Control 
Male patients, who are sexually active with a pregnant or breastfeeding woman, choose Option 1 or 2  
Option 1: Male condom with spermicide and cervical cap  
Option 2: Male condom with spermicide and diaphragm  
Female patients who are of childbearing potential AND male patients who are sexually active with women of 
childbearing potentiala, choose any TWO of the following methods: 
● Hormonal methods of contraception (excluding progestin-only pills) 
● Intrauterine device with failure rate <1% 
● Tubal ligation 
● Vasectomy (at least 90 days from the date of surgery with a semen analysis documenting azoospermia) 
● A barrier method (male or female condom with spermicide, cervical cap with spermicide, diaphragm with 
spermicide 
a 
A woman of childbearing potential is defined as any female who has experienced menarche and who has not undergone 
surgical sterilization (e.g., hysterectomy, bilateral salpingectomy, bilateral oophorectomy) or has not completed 
menopause. Menopause is defined clinically as 12 months of amenorrhea in a woman over age 45 in the absence of other 
biological, physiological, or pharmacological causes. 
 
Unacceptable Methods of Contraception 
Abstinence (including periodic abstinence) 
No method 
Withdrawal 
Rhythm 
Any barrier method without spermicide 
Spermicide only 
Progestin-only pills 
Concomitant use of female and male condoms 
 
 


 
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APPENDIX H: INVESTIGATOR SIGNATURE PAGE 
 
Investigator Statement and Signature 
 
I have read the attached protocol entitled “A randomized, double-blind phase 3 study of 
vadastuximab talirine (SGN-CD33A) versus placebo in combination with azacitidine or 
decitabine in the treatment of older patients with newly diagnosed acute myeloid leukemia 
(AML).” 
I understand and agree to the provisions of the protocol, and I accept the responsibilities listed 
above in my role as principal investigator for the study. 
 
 
 
Investigator Signature 
 
Date 
 
 
Investigator Name, Printed 
 
 
 


 
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APPENDIX I: DOCUMENT HISTORY 
Version 
Date 
Original 
20-Jan-2016 
Amendment 1 
22-Mar-2016 
Amendment 2 
20-May-2016 
Amendment 3 
27-Mar-2017 
 


 
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Summary of Changes in Amendment 1 
Section(s) 
Change 
Rationale 
Section 2.2, 2.4.2, 
9.2.2.4, 9.3.5.2, and 
Synopsis 
Duration of remission has been added as a secondary 
objective/endpoint of the study 
To further characterize efficacy in this patient 
population 
Section 3.1 and 9.3.10 
The text has been revised as follows:  
An IDMC will periodically monitor the trial for safety, including 
SAEs and early mortality, during the treatment period. See the IDMC 
Charter for details. 
Clarification 
Section 4.2 
The following new exclusion criterion has been added: 
 
2. Patients who are medically fit and willing to receive standard 
intensive induction chemotherapy 
To clarify the older AML patient population who would 
receive low intensity therapy per standard of care 
Section 4.2 
The following new exclusion criterion has been added: 
 
14. Any other condition which, in the opinion of the investigator, 
would compromise patient safety or interfere with data interpretation. 
To further characterize the patient population who are 
eligible for enrollment  
Section 5.3.3 
The following language has been added: 
 
Refer to the azacitidine and decitabine package inserts or SmPC for 
complete instructions for dosing and administration.  
Clarification 
Section 5.5.2 
The text has been revised as follows: 
 
Antimicrobial prophylaxis measures are strongly recommended, per 
institutional standard of care; decisions regarding use and choice of 
antibiotics should be made by the individual institutions based on the 
prevailing organisms and their drug resistance patterns (de Naurois 
2010; Freifeld 2011; Flowers 2013). The use of myeloid growth 
factors as part of supportive care for clinically significant 
neutropenia is recommended per the American Society of Clinical 
Oncology (ASCO) and the European Society for Medical Oncology 
(ESMO) Clinical Practice Guidelines (Smith 2006; Fey 2013). 
Clarification 


 
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Section(s) 
Change 
Rationale 
Section 7.7.2 
RBC count and MCV have been added to the list of clinical 
laboratory tests 
To further clarify the list of hematology tests to be 
performed 
Section 9.3.1.9 
The definition of the end of trial has been added 
Clarification 
Appendix B 
Footnote f has been removed 
To correct an error 
 


 
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Summary of Changes in Amendment 2 
Section(s) 
Change 
Rationale 
Section 1.2, 3.1.1, 4.1, 
and Synopsis 
The lower age limit for study eligibility has been changed from 
≥65 years to ≥18 years 
To allow enrollment of all adult AML patients who are 
unfit for intensive chemotherapy, regardless of age 
Section 4.1 and 4.2 
The eligibility criteria have been revised to require females of 
childbearing potential to have a negative pregnancy test prior to 
enrollment as well as to use 2 effective contraceptive methods during 
the study. Female patients who are breastfeeding have also been 
excluded from enrollment  
Pregnancy- and contraceptive-related restrictions and 
requirements have been added in accordance with the 
new lower age limit for the study 
Section 5.5.2 
The text has been revised as follows: 
Antimicrobial prophylaxis measures are strongly recommended, per 
institutional standard of care; decisions regarding use and choice of 
antibiotics should be made by the individual institutions based on the 
prevailing organisms and their drug resistance patterns (de Naurois 
2010; Freifeld 2011; Flowers 2013). The use of myeloid growth 
factors are considered appropriate as part of supportive care for 
clinically significant neutropenia is recommended per the American 
Society of Clinical Oncology (ASCO) and the European Society for 
Medical Oncology (ESMO) Clinical Practice Guidelines (Smith 
2006; Fey 2013) and are strongly recommended as primary and/or 
secondary prophylaxis and as support of clinically significant 
neutropenia during treatment. 
To better emphasize the recommendations for 
prophylaxis of neutropenia for patients on the study 
Section 6.2.1, 6.4, 
Appendix A 
To require pregnancy testing at screening and end of treatment for 
females of childbearing potential  
These assessments have been added in accordance with 
the new lower age limit for the study 
Section 6.3.3 and 6.3.5 
The text has been clarified to reflect the sampling schedule for PK on 
Days 5 and 7 
Clarification 
Section 9.3.1.7  
The language has been modified as follows: 
The modified intent-to-treat (mITT) analysis set will include all 
patients from the ITT analysis set who receive any dose of blinded 
study treatment (vadastuximab talirine or placebo) or HMA. Patients 
will be included in the treatment group assigned at randomization 
regardless of the actual treatment received. 
The safety analysis set will include all patients who receive any 
amount dose of blinded study treatment (vadastuximab talirine or 
placebo) or HMA. Treatment group will be determined using the 
actual treatment received, regardless of the randomization treatment 
To clarify the analysis sets for the study 


 
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Section(s) 
Change 
Rationale 
assignment. Patients receiving any dose of vadastuximab talirine will 
be grouped into the experimental arm. Patients who do not receive 
vadastuximab talirine but receive any dose of HMA will be grouped 
into the comparator arm. 
Section 9.3.5 
The following language has been added: 
All efficacy endpoints will be analyzed using the ITT analysis set. 
Supplemental analyses will be performed using the mITT analysis 
set. 
To clarify the analysis sets for the study 
Section 9.3.10 
The language has been modified as follows: 
An IDMC will periodically monitor the trial for safety, including 
SAEs and early mortality, during the treatment period. See the IDMC 
Charter for details. During the periodical safety review, the IDMC 
will evaluate the 60-day mortality rates in the 2 treatment arms. The 
independent statistician will assist the IDMC to evaluate whether 
there is an increased risk of early death in the experimental arm and 
make appropriate recommendations to the sponsor. 
Two formal interim analyses for OS are planned for the study. The 
first interim analysis is for the purpose of futility testing and will be 
conducted when approximately 100 OS events have occurred (~30% 
of the targeted number of events). The second interim analysis is for 
superiority testing and will be conducted when approximately 200 
OS events have occurred (~60% of the targeted number of events). 
The stopping boundaries will be determined using Lan-DeMets 
spending functions to simulate O’Brien-Fleming boundaries. Details 
will be provided in the SAP. 
The IDMC will provide recommendations to the sponsor's Data 
Review Board as to appropriate study direction. The sponsor will 
remain blinded to treatment assignment. See the IDMC Charter for 
details. 
To specify a blinded interim safety analysis to detect 
differences in early mortality between the arms 
 




 
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Section(s) 
Change 
Rationale 
Section 4.2 and Synopsis 
Exclusion Criterion 9 (previously Criterion 7) has been revised as 
follows: 
Second malignancy requiring active systemic therapy within 1 year 
(except for hormonal/anti hormonal treatment, e.g., prostate or breast 
cancer). 
Concurrent active malignancy other than nonmelanoma skin cancer 
or carcinoma in situ of the following: bladder, stomach, colon, 
cervix, endometrium, melanoma, or breast. Patients with previous 
malignancies are eligible if the malignancy has been confined and 
surgically resected (or treated with other modalities) with curative 
intent. Any active systemic therapy must have been completed >1 
year from enrollment (except for hormonal/anti-hormonal treatment, 
e.g. breast cancer). 
Clarification to further enhance trial population 
homogeneity and facilitate interpretation of outcomes. 
Section 4.2 and Synopsis 
Exclusion Criterion 17 (previously Criterion 15) has been revised as 
follows: 
Significant history of pulmonary, renal, neurologic, psychiatric, 
endocrine, metabolic, immunologic, hepatic, cardiovascular disease, 
or Aany other condition which, in the opinion of the investigator, 
would adversely affect participation in this study compromise patient 
safety, or interfere with data interpretation. 
To further enhance trial population homogeneity, ensure 
patient safety, and facilitate interpretation of outcomes. 
Section 4.3 and 
Appendix G 
Section 4.3 has been added to define childbearing potential as it 
pertains to trial eligibility. Appendix G has been added to provide 
guidance on contraception. 
Clarification and to ensure patient safety per the EU 
CTFG “Recommendations Related to Contraception and 
Pregnancy Testing in Clinical Trials.” 


 
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Section(s) 
Change 
Rationale 
Section 5.2.3 
The dose modification section has been revised as follows: 
● 
Rules have been added for dose modifications in the event of 
laboratory evidence of hepatic toxicity (elevated AST, ALT, or 
total bilirubin) 
● 
Instructions have been added to discontinue treatment for 
delays of >56 days after dose reduction unless approved by the 
medical monitor 
● 
The rules for non-hematologic toxicity (with the exception of 
hepatic toxicity) have been revised to change the period of 
required treatment delay for ≥ Grade 3 events from 28 days to 
14 days and to remove the stipulation that ≥ Grade 3 events 
must be clinically significant or symptomatic to invoke 
treatment delay 
To ensure patient safety. 
Section 5.5.3 
The prohibited concomitant medications section has been revised as 
follows: 
Patients may not receive other investigational drugs, 
immunosuppressive medications (with the exception of the 
medications listed in Section 5.5.2), or non-study systemic anti-
neoplastic therapy, or allo-SCT during the treatment period. 
If patients become candidates for allo-SCT after enrollment, blinded 
study treatment must be discontinued at least 30 days prior 
to initiation of the preparative regimen for allo-SCT. 
To clarify that allogeneic stem cell transplantation is 
prohibited during the treatment period and within 
30 days of the last dose of blinded study treatment. 
6.3.1 and Appendix A 
A pregnancy test has been added on Day 1 of each cycle of study 
treatment. 
To ensure patient safety per the EU CTFG 
“Recommendations Related to Contraception and 
Pregnancy Testing in Clinical Trials.” 
6.2.1 and Appendix A 
A pulse oximetry test has been added at baseline to assess oxygen 
saturation level at room air. 
To ensure patient safety. 
6.3.3, 6.3.5, 7.7.6, 
9.3.9.5, Appendix A 
Measurement of vital signs has been added pre- and within 
30 minutes post-blinded study treatment administration. 
To ensure patient safety. 
6.5 
The follow up assessments section has been revised for clarity and to 
provide information regarding follow-up of adverse events of special 
interest. 
To provide clarity and ensure patient safety. 


 
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Section(s) 
Change 
Rationale 
7.7.1.4 
A new section has been added to define hepatobiliary serious adverse 
events, including cases of sinusoidal obstruction syndrome/veno-
occlusive disease (SOS/VOD), as adverse events of special interest 
and to provide instructions on reporting of these events. 
To ensure patient safety. 
Throughout protocol 
Additional minor clarifications/edits and administrative changes have 
been made. 
To improve clarity and ensure consistency throughout 
the protocol as well as to make administrative changes. 
 
 

SAP_000.pdf: 
 
 
 
Part or all of the information in this statistical analysis plan may be unpublished material.  Accordingly, this 
document is to be treated as confidential and restricted to its intended use.  This material is the property of 
Seattle Genetics, Inc. and must not be disclosed or used except as authorized in writing by Seattle Genetics, Inc. 
STATISTICAL ANALYSIS PLAN 
 
Protocol Number: 
SGN33A-005 
Version: 
5   04-Dec-2017 
Protocol Title: 
A randomized, double-blind phase 3 study of vadastuximab 
talirine (SGN-CD33A) versus placebo in combination with 
azacitidine or decitabine in the treatment of older patients with 
newly diagnosed acute myeloid leukemia (AML)  
Sponsor: 
Seattle Genetics, Inc. 
21823 30th Drive SE 
Bothell, WA 98021, USA 




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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ................................................................................................................................ 5 
1 
INTRODUCTION ........................................................................................................................................... 6 
2 
STUDY OBJECTIVES ................................................................................................................................... 6 
2.1 
Primary Objective ................................................................................................................................. 6 
2.2 
Secondary Objectives ............................................................................................................................ 6 
2.3 
Additional Objectives ............................................................................................................................ 7 
3 
STUDY ENDPOINTS .................................................................................................................................... 7 
3.1 
Primary Endpoint .................................................................................................................................. 7 
3.2 
Secondary Endpoints ............................................................................................................................. 7 
3.3 
Additional Endpoints ............................................................................................................................. 7 
4 
STUDY DESIGN ............................................................................................................................................ 8 
5 
ANALYSIS SETS ........................................................................................................................................... 9 
5.1 
Intent-to-Treat Analysis Set .................................................................................................................. 9 
5.2 
Modified Intent-to-Treat Analysis Set ................................................................................................... 9 
5.3 
Safety Analysis Set ................................................................................................................................ 9 
6 
STATISTICAL CONSIDERATIONS ............................................................................................................ 9 
6.1 
General Principles ................................................................................................................................. 9 
6.2 
Determination of Sample Size ............................................................................................................. 10 
6.3 
Randomization and Blinding ............................................................................................................... 10 
6.4 
Data Transformations and Derivations ................................................................................................ 11 
6.5 
Handling of Dropouts and Missing Data ............................................................................................. 11 
6.6 
Multicenter Studies ............................................................................................................................. 12 
6.7 
Multiple Comparison/Multiplicity....................................................................................................... 12 
6.8 
Examination of Subgroups .................................................................................................................. 12 
6.9 
Covariates ............................................................................................................................................ 13 
6.10 Timing of Analyses ............................................................................................................................. 14 
7 
PLANNED ANALYSES .............................................................................................................................. 14 
7.1 
Disposition .......................................................................................................................................... 14 
7.2 
Demographic and Baseline Characteristics ......................................................................................... 14 
7.3 
Protocol Deviations ............................................................................................................................. 14 
7.4 
Treatment Administration ................................................................................................................... 15 
7.5 
Efficacy Analyses ................................................................................................................................ 16 
7.5.1 
Primary Endpoint ................................................................................................................... 16 
7.5.2 
Secondary Endpoints .............................................................................................................. 16 
7.6 
Safety Analyses ................................................................................................................................... 17 
7.6.1 
Adverse Events ....................................................................................................................... 17 
7.6.2 
Clinical Laboratory Parameters .............................................................................................. 19 
7.6.3 
ECOG Performance Status ..................................................................................................... 19 
7.6.4 
Concomitant Medications ....................................................................................................... 19 
7.6.5 
Deaths ..................................................................................................................................... 20 
7.7 
Additional Analyses ............................................................................................................................ 20 
7.7.1 
Stem Cell Transplant .............................................................................................................. 20 
7.7.2 
Pharmacokinetics .................................................................................................................... 20 
7.7.3 
Antitherapeutic Antibody Incidence Rate .............................................................................. 20 
7.7.4 
Biomarker Analyses ............................................................................................................... 20 
8 
INTERIM ANALYSIS.................................................................................................................................. 20 
9 
CHANGES FROM PLANNED ANALYSES .............................................................................................. 20 
9.1 
Changes from the Protocol .................................................................................................................. 20 
9.2 
Changes from the Original SAP .......................................................................................................... 21 
9.2.1 
Version 2 Changes .................................................................................................................. 21 


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9.2.2 
Version 3 Changes .................................................................................................................. 21 
9.2.3 
Version 4 Changes .................................................................................................................. 22 
9.2.4 
Version 5 Changes .................................................................................................................. 22 
10 REFERENCES .............................................................................................................................................. 23 
APPENDIX A: IMPUTATION OF PARTIALLY MISSING ADVERSE EVENT DATES .............................. 24 
APPENDIX B: IMPUTATION OF PARTIALLY MISSING SUBSEQUENT ANTICANCER THERAPY 
START DATE............................................................................................................................................... 27 
APPENDIX C: DEFINITION OF THE TERM “TREATMENT-EMERGENT” WITH RESPECT TO AE 
CLASSIFICATION ...................................................................................................................................... 28 
 


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LIST OF ABBREVIATIONS 
ADI 
absolute dose intensity 
AE 
adverse event 
AML 
acute myeloid leukemia 
ANC 
absolute neutrophil count 
ATA 
antitherapeutic antibodies 
CBC 
complete blood count 
CI 
confidence interval 
CR 
morphologic complete remission 
CRc 
composite complete remission (CR+CRi) 
CRi 
morphologic complete remission with incomplete blood count recovery   
CRF 
case report form 
CSR 
clinical study report 
ECOG 
Eastern Cooperative Oncology Group 
EFS 
event-free survival 
EOT 
end of treatment 
HMA 
hypomethylating agents 
HCT-CI 
hematopoietic cell transplantation-comorbidity index 
IDI 
intended dose intensity  
IDMC 
independent data monitoring committee 
ITT 
intent-to-treat 
LFS 
leukemia-free survival 
MDS 
myelodysplastic syndrome 
MedDRA 
Medical Dictionary for Regulatory Activities 
mLFS 
morphologic leukemia-free state  
MRC 
Medical Research Council 
MRD 
minimal residual disease 
MRU 
medical resource utilization 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
OS 
overall survival 
PRO 
Patient reported outcome 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PT 
preferred term 
RDI 
relative dose intensity  
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SOC 
system organ class 
TRM 
treatment related mortality  
TTCR 
time to complete remission  
 


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1 
INTRODUCTION 
This document outlines the statistical methods to be implemented within the scope of 
Protocol SGN33A-005, entitled “A randomized, double-blind phase 3 study of vadastuximab 
talirine (SGN-CD33A) versus placebo in combination with azacitidine or decitabine in the 
treatment of older patients with newly diagnosed acute myeloid leukemia (AML)”.  Results 
of the proposed analyses will become the basis of the clinical study report (CSR) for this 
protocol. 
The purpose of this plan is to provide specific guidelines from which the analysis will 
proceed.  All planned analyses specified in this document will be performed.  Any changes to 
this plan, in the form of “post hoc” or “data driven” analyses will be identified as such in the 
final CSR.  Any changes will either be reflected in amendments to this plan before the 
database lock or specifically documented in the CSR. 
Due to safety concerns raised by the IDMC, the study was terminated early prior to the 
formal interim analyses planned in the protocol.  Final analysis will be performed based on 
240 patients randomized into the study by the time enrollment was closed.  This SAP reflects 
the proposed analyses for the abbreviated CSR. 
2 
STUDY OBJECTIVES 
2.1 Primary Objective 
● 
To compare the composite complete remission (CRc) rate (morphologic complete 
remission [CR] and morphologic CR with incomplete hematologic recovery [CRi]) 
between treatment arms 
● 
To compare overall survival (OS) between treatment arms 
2.2 Secondary Objectives 
● 
To compare the minimal residual disease-negative remission (MRD-negative CRc) 
rate between treatment arms 
● 
To evaluate the duration of remission in the 2 treatment arms 
● 
To evaluate event-free survival (EFS) in the 2 treatment arms 
● 
To evaluate leukemia-free survival (LFS) in the 2 treatment arms 
● 
To evaluate the safety profiles in the 2 treatment arms  
● 
To evaluate the time to response in the 2 treatment arms 
● 
To evaluate the 30- and 60-day mortality rates in the 2 treatment arms 


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2.3 Additional Objectives 
● 
To evaluate the treatment effect of vadastuximab talirine compared to the control 
group on the change in patient reported outcomes (PRO) and medical resource 
utilization (MRU) 
● 
To assess the incidence of antitherapeutic antibodies (ATA) 
● 
To assess exploratory markers of clinical outcome and the pharmacodynamics (PD) 
of vadastuximab talirine in combination with a hypomethylating agent (HMA) 
3 
STUDY ENDPOINTS 
3.1 Primary Endpoint 
● 
CRc rate 
● 
OS 
3.2 Secondary Endpoints 
The secondary endpoints are: 
● 
MRD-negative CRc rate 
● 
Duration of remission 
● 
EFS 
● 
LFS 
● 
Type, incidence, severity, seriousness, and relatedness of adverse events 
● 
Laboratory abnormalities 
● 
Time to CR or CRi (TTCR) 
● 
Mortality rates at Day 30 and Day 60 post the first study treatment 
3.3 Additional Endpoints 
● 
Change from baseline in PRO 
● 
MRU based on the number of medical care encounters 
● 
Incidence of ATA to vadastuximab talirine 
● 
Biomarkers of pharmacodynamic effects  
● 
Exploratory markers of clinical activity 


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4 
STUDY DESIGN 
This is a randomized, double-blind, placebo-controlled, phase 3 study designed to compare 
the CRc rate and OS between patients treated with HMA plus vadastuximab talirine 
(experimental arm) versus patients treated with HMA plus placebo (comparator arm). 
Patients will be randomized in a 1:1 manner to one of the study arms, stratified by 
cytogenetic risk, Eastern Cooperative Oncology (ECOG) performance status, HMA, and age.  
Investigators may select either HMA (azacitidine or decitabine).  Response will be assessed 
by bone marrow examination and complete blood count (CBC) conducted between Day 22 to 
28 of even-numbered cycles until CR or CRi.  The response assessment window may be up 
to Day 42 in the event of a delay in the start of the next cycle of treatment.  After CR/CRi, 
response assessment will be performed by CBC surveillance.  In addition, bone marrow 
examination will be conducted according to the following schedule: 
• 2 cycles after initial confirmation of CR or CRi 
• At the time of conversion from CRi to CR 
• At the time of suspected relapse  
• End of treatment (EOT), if not performed within the previous 4 weeks 
Patients may continue on study treatment until progression, leukemic recurrence, or 
unacceptable toxicity, whichever comes first.  Patients who achieve stable disease or better 
should receive a minimum of 4 cycles of study treatment.  Progression is defined after 4 or 
more cycles of treatment as either a >25% absolute rise in the percent of bone marrow blast 
from baseline (or a proportional increase of >25% in patients with baseline bone marrow 
blasts >75%) or appearance of new extramedullary disease.  Patients who fulfill the criteria 
for progression but who are still deriving clinical benefit in the opinion of the investigator 
may continue on study treatment. 
After discontinuation of study treatment, patients who have not experienced progression or 
leukemic recurrence will continue to be assessed for response by CBC surveillance every 
2 months through 24 months after EOT, and every 4 months thereafter, until initiation of 
another anticancer treatment (excluding stem cell transplant and maintenance therapy in the 
absence of relapse), progression, or leukemic recurrence, whichever comes first.  For all 
patients, survival status follow up will take place every 2 months (or more frequently as 
needed to support analysis of the study endpoints) after EOT until death or study closure, 
whichever comes first.   
Safety, including SAEs and early mortality, will be monitored over the course of the study by 
an Independent Data Monitoring Committee (IDMC). 


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5 
ANALYSIS SETS 
5.1 Intent-to-Treat Analysis Set 
The intent-to-treat (ITT) analysis set will include all randomized patients.  Patients will be 
included in the treatment group assigned at randomization regardless of the actual treatment 
received. 
5.2 Modified Intent-to-Treat Analysis Set 
The modified intent-to-treat (mITT) analysis set will include all patients from the ITT 
analysis set who receive any dose of blinded study treatment (vadastuximab talirine or 
placebo) or HMA. Patients will be included in the treatment group assigned at randomization 
regardless of the actual treatment received. 
5.3 Safety Analysis Set 
The safety analysis set will include all patients who receive any dose of blinded study 
treatment (vadastuximab talirine or placebo) or HMA.  Treatment group will be determined 
using the actual treatment received, regardless of the randomization treatment assignment.  
Patients receiving any dose of vadastuximab talirine will be grouped into the experimental 
arm.  Patients who do not receive vadastuximab talirine but receive any dose of HMA will be 
grouped into the comparator arm. 
6 
STATISTICAL CONSIDERATIONS 
6.1 General Principles 
Descriptive statistics (mean, median, standard deviation, minimum and maximum) will be 
used to summarize continuous variables.  Frequencies and percentages will be used to 
summarize categorical variables.  The median survival time will be estimated using the 
Kaplan-Meier method; the associated confidence interval (CI) will be calculated based on the 
complementary log-log transformation (Collett 1994). 
Unless otherwise specified, all statistical tests will be performed using a two-sided alpha of 
0.05.  Confidence intervals will be calculated at a two-sided 95% level.  Multiplicity 
adjustment for alpha level is discussed in Section 6.7. 
Any analysis not described in this plan will be considered exploratory, and will be 
documented in the CSR as a post hoc analysis or a change to the planned analysis. 
To comply with regulatory electronic submission guidelines, listings of all clinical data will 
be submitted as electronic data sets.  To facilitate data review for the study report, only 
pertinent data listings will be created and attached to the appendix of the CSR. 
All statistical tables, listings, and figures will be produced using SAS®, version 9.3 or more 
recent.  Other statistical software, if used, will be described in the CSR. 


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6.2 Determination of Sample Size 
There are 2 primary endpoints for this study: CRc rate and OS.  To maintain strong control of 
the type I error rate at 0.05, a fallback procedure proposed by Wiens will be used in the 
testing of the primary endpoints, with an alpha of 0.01 pre-assigned to CRc rate and an alpha 
of 0.04 pre-assigned to OS (Wiens 2005).   
The sample size was calculated based on maintaining 90% power to test both primary 
endpoints and to account for 2 planned interim analyses for OS, one futility analysis at 30% 
and one interim efficacy analysis at 60% of the targeted number of OS events, using the 
O’Brien-Fleming method. 
For the primary endpoint of CRc rate, at least 308 patients are required to provide 90% 
power to detect an improvement in CRc rate from 20% to 40% using a chi-square test at a 
significance level of 0.01. 
For the primary endpoint of OS, approximately 354 OS events are required to provide 90% 
power to detect a hazard ratio of 0.70 (12.9 months median OS in the experimental arm 
[vadastuximab talirine plus HMA] versus 9 months for the comparator arm [placebo plus 
HMA]) using a log-rank test at a 2-sided alpha of 0.04.   
To provide adequate power for both primary endpoints, a total of 540 patients will be 
randomized in a 1:1 ratio to either the experimental arm or the comparator arm, assuming an 
accrual period of 26 months with a slower rate of accrual for the first 6 months, a 12-month 
follow-up from the last patient enrolled to the final analysis of OS (after approximately 354 
OS events have occurred), and a 5% yearly drop-out rate. 
EAST (Version 6.3) was used to calculate and validate the sample size. 
6.3 Randomization and Blinding 
This is a randomized, double-blind, placebo-controlled, comparative study that will enroll 
approximately 540 patients in a 1:1 manner. 
Randomization will be stratified by: 
● 
Cytogenetic risk per revised UK Medical Research Council (MRC) classification 
(intermediate versus adverse) 
● 
ECOG performance status (0–1 versus 2) 
● 
HMA (azacitidine versus decitabine) 
● 
Age (<75 years versus ≥75 years) 
Fixed block randomization will be performed centrally using a system that will assign a 
unique patient randomization number.  The actual treatment assignment will remain blinded.  
Randomization procedures are detailed in the Study Manual.  


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6.4 Data Transformations and Derivations 
Age as entered in the CRF will be used for any calculations and analyses, if available.  If age 
is not available, age in years will be calculated with the SAS INTCK function using consent 
date and birth date.  
Study Day will be calculated as (Date of Visit [or Event] – Date of Randomization + 1) for 
dates on or after randomization.  For dates prior to randomization, Study Day will be 
calculated as (Date of Visit [or Event] – Date of Randomization).   
Other time variables based on two dates (e.g., Start Date and End Date) will be calculated as 
(End Date – Start Date + 1) (in days) unless otherwise specified in the planned analysis 
section. 
The following unit conversion will be implemented unless otherwise specified: 
Months = Days / 30.4375 
Years = Days / 365.25 
Baseline values used in all analyses will be the most recent non-missing measurement prior 
to the first dose of study treatment (HMA or blinded study drug). For patients who did not 
receive any study treatment, baseline is the last non-missing measurement on study. 
At baseline, if both bone marrow biopsy and aspirate results are available, the biopsy result 
will be used as the baseline bone marrow blasts.  The only exception will be if the biopsy 
result is blasts <20% and the patient was qualified for the study based on the aspirate result 
(blasts ≥20%), then the aspirate result will be used as the baseline bone marrow blasts.  
The EOT date will be the date the EOT visit is performed, or 30 days after the last dose of 
any study treatment if an EOT visit is not performed. 
For efficacy analysis, if the response is determined to be progression or disease relapse, the 
earliest date of the bone marrow examination or CBC (within a 14 day window from the 
bone marrow examination) that supports the overall response assessment at a given visit will 
be the response assessment date.  For any other responses (CR, CRi, mLFS, partial response, 
anti-leukemic effect, and stable disease), the latest date of the bone marrow examination or 
CBC (within a 14 day window from the bone marrow examination) that supports the overall 
response assessment at a given visit will be the response assessment date.  
6.5 Handling of Dropouts and Missing Data 
Missing data will not be imputed unless otherwise specified.  Missing AE dates will be 
imputed while calculating duration of events and treatment emergent status.  Missing 
subsequent anticancer therapy start date will be imputed while deriving time-to-event 
endpoints as applicable (see Appendix A and B for imputation details).  Missing data in PRO 
assessment will be handled according to the questionnaire’s standard guidelines.  Patients 
with a missing value for a variable other than response or time-to-event endpoints (e.g., CRc 


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rate and OS) will be excluded from the analysis of that endpoint.  Censoring rules will be 
applied in the analysis of time-to-event endpoints as detailed in Section 7.5.  
6.6 Multicenter Studies 
There are multiple centers in this study, however it is not anticipated that any center will 
accrue enough patients to warrant an analysis by center. 
6.7 Multiple Comparison/Multiplicity 
To maintain strong control of the Type I error rate at 0.05, the fallback procedure proposed 
by Wiens will be used in the testing of primary endpoints, with an alpha of 0.01 pre-assigned 
to CRc rate and an alpha of 0.04 pre-assigned to OS (Wiens 2005).  If the test for the CRc 
rate is statistically significant, then the alpha of 0.01 will be re-allocated to OS, and the test 
for OS will be performed at a 2-sided alpha of 0.05.  If the test for the CRc rate is not 
statistically significant, then the test for OS will be performed at a 2-sided alpha of 0.04. 
The parallel gatekeeping principle will be used to control the overall type I error rate of 0.05 
(Dmitrienko 2011).  The primary endpoints, CRc rate and OS (family 1), will be the 
gatekeepers for testing the secondary endpoint of MRD-negative CRc rate (family 2).  If at 
least one of the primary endpoints is statistically significant, then a statistical test will be 
performed for the MRD-negative CRc rate.  If both CRc rate and OS are statistically 
significant, then MRD-negative CRc rate will be tested at an overall alpha of 0.05.   If only 
one of the 2 primary endpoints is statistically significant, then MRD-negative CRc rate will 
be tested at the corresponding alpha level of the significant primary endpoint.  If the tests for 
both CRc rate and OS are not statistically significant, then the p-value of the test for MRD-
negative CRc rate will still be calculated but considered descriptive.   
Two formal interim analyses for OS are planned.  The test significance level for OS at the 
interim analysis will be adjusted based on the actual number of OS events observed at each 
interim analysis according to the O’Brien-Fleming spending function.   
Due to safety concerns raised by the IDMC, the study was terminated early prior to the first 
interim analysis planned in the protocol.  Final analysis will be performed based on 240 
patients randomized into the study by the time enrollment was closed.  All efficacy analysis 
will be descriptive in nature and no multiple testing procedure will be applied. 
6.8 Examination of Subgroups 
As exploratory analyses, subgroup analyses may be conducted for selected endpoints (see 
Section 7).  Subgroups may include but are not limited to the following: 
● 
ECOG performance status (0–1, 2) 
● 
Cytogenetic risk by MRC (adverse, intermediate/unknown) 
● 
HMA 
● 
Age (<75, ≥75 years old)  


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● 
Age (<80, ≥80 years old)  
● 
Gender  
● 
Race 
● 
Geographic region (North America/Australia, Western Europe/Israel, Eastern 
Europe, Asia) 
● 
Type of AML (de novo AML, secondary AML) 
● 
AML subtype (AML with recurrent genetic abnormalities, AML with 
myelodysplasia-related changes, AML with therapy-related myeloid neoplasms, 
AML not otherwise specified) 
● 
Underlying myelodysplasia (yes, no) 
● 
Prior hematological disorder (yes, no) 
● 
Mutational abnormalities (NPM1+, NPM1-) 
● 
Medically unfit for intensive therapy (yes, no) 
● 
Baseline bone marrow blast percentage (20% - 30%, >30%) 
● 
Baseline bone marrow blast percentage (20% - 50%, >50%) 
● 
Baseline WBC (≤5,000, >5,000/µL) 
● 
Baseline WBC (<10,000, ≥10,000/µL)  
● 
Baseline WBC (<15,000, ≥15,000/µL) 
● 
Remission status (CRc, non-responders) 
● 
MRD-negative remission status (MRD-negative CRc, MRD-positive CRc, non-
responders) 
● 
Charlson Comorbidity Index (low, moderate, high) 
● 
Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI; low, 
intermediate, high) 
● 
Wheatley Risk group (good, standard, poor) 
● 
European ALMA score (favorable, intermediate, unfavorable) 
● 
Treatment-related mortality (TRM) score (low, intermediate, high) 
6.9 Covariates 
Stratified analyses specified in Section 7.5 will include adjustment for the stratification 
factors as recorded at randomization.  Selected baseline values may be used as covariates in 
the exploratory analysis of efficacy endpoints. 


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6.10 Timing of Analyses 
Due to safety concerns raised by the IDMC, the study was terminated early prior to the 
formal interim analyses planned in the protocol.  Final analysis will be performed based on 
240 patients randomized into the study by the time enrollment was closed. 
7 
PLANNED ANALYSES 
7.1 Disposition 
Patient enrollment and disposition will be summarized by treatment group and total using the 
ITT analysis set.  The table will present the number and percentage of patients who were 
randomized, received study drug, received treatment per randomization assignment, and in 
follow-up visits.  The number and percentage of patients who discontinued treatment will be 
summarized by the primary reason for treatment discontinuation.  The number and 
percentage of patients who discontinued the study will be summarized by the primary reason 
for study discontinuation. 
The number and percentage of patients randomized in each country and at each site will be 
summarized by treatment group and total.  Disposition data will be listed by patient using the 
ITT analysis set. 
7.2 Demographic and Baseline Characteristics 
Demographics and baseline characteristics, including age, gender, ethnicity, race, height, 
weight, and ECOG score will be listed and summarized; summaries will be presented by 
treatment group and total using the ITT analysis set.   
Disease specific characteristics, including time from initial AML diagnosis, baseline bone 
marrow blast percentage, baseline WBC, AML subtype, prior hematologic disorder, 
cytogenetic risk group, mutational abnormalities, Wheatley risk group, European ALMA 
score, TRM score, Charlson comorbidity index and HCT-CI, will be summarized by 
treatment group and total using the ITT analysis set.  In addition, the number and percentage 
of patients who receive at least one prior anticancer therapy for hematological disorder will 
be summarized. 
Reasons for enrollment and reasons patients are medically unfit to receive intensive therapy 
will be summarized by treatment group and total using the ITT analysis set. 
The stratification factors entered at the time of randomization and the actual strata at baseline 
for each patient will be presented in a listing. 
7.3 Protocol Deviations 
Important protocol deviations (defined as protocol violations by Seattle Genetics) are those 
that represent a divergence from the protocol that could have a significant effect on the 
integrity of the study data, or on the subject’s rights, safety, or welfare.  Important protocol 
deviations also include exemptions to the study inclusion/exclusion criteria and will be 


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summarized by category.  A list of patients with important protocol deviations will be 
presented. 
7.4 Treatment Administration 
Treatment administration will be summarized by treatment group using the safety analysis 
set.  Summary statistics for duration of therapy (weeks), number of cycles per patient, and the 
number and percentage of patients who were treated at each cycle will be presented.  In 
addition, the cumulative dose, number of doses, average dose per cycle, absolute dose 
intensity (ADI) and relative dose intensity (RDI) will be described for the blinded study 
treatment.  The number and percentage of patients whose blinded study treatment dose was 
ever modified will be summarized by modification type (delay, reduction, unplanned dose 
adjustment), cycle and overall (i.e., overall drug administrations for a patient) for each 
treatment group.  The number and percentage of doses that were modified may also be 
summarized.  Kit errors will be listed. 
Duration of therapy is defined as time from the first dose of study drug to the earliest of the 
following: 
• Day 28 of the last treatment cycle 
• EOT visit 
• Date of death 
• Last contact date if the patient is still on treatment at the time of the analysis  
Person-time exposure for a treatment group will be calculated by adding the duration of 
therapy of all patients from the same treatment group. 
Intended Dose Intensity (IDI) is defined as the intended dose of drug (e.g., mcg/kg) per unit 
of time.  IDI will be calculated in 2 ways, with and without accounting for the dose 
modification intended by the investigator. 
Absolute Dose Intensity (ADI) is defined as the actual dose (e.g., mcg/kg) per unit of time 
that the patient received over the entire treatment period.  For the purpose of calculating ADI, 
treatment period is defined as time from the first dose of study drug to Day 28 of the last 
treatment cycle. 
Relative Dose Intensity (RDI) is defined as the absolute dose intensity over the intended dose 
intensity. 
RDI = ADI/IDI * 100. 
Cycle length will be calculated as the interval between Day 1 of 2 consecutive cycles.  Cycle 
length will not be calculated for the last treatment cycle of each patient.  The number and 
percentage of patients with cycle length ≥5 weeks will be summarized by cycle and treatment 
group. 


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7.5 Efficacy Analyses 
All efficacy analyses will be descriptive in nature and will be presented using the ITT 
analysis set.   
7.5.1 Primary Endpoint 
7.5.1.1 Composite Complete Remission (CRc) Rate 
CRc rate is defined as the proportion of patients achieving CR or CRi prior to the start of 
subsequent anticancer therapy or stem cell transplant.  Patients whose disease response 
cannot be assessed will be considered non-responders in the calculation of CRc rate. The 
CRc rate and the 2-sided 95% CI will be summarized by treatment group.   
7.5.1.2 Overall Survival (OS) 
Overall survival (OS) is defined as the time from randomization to death due to any cause.  
Specifically, 
 
OS = Date of death – Date of randomization + 1. 
For a patient who is not known to have died by the end of study follow up, observation of OS 
is censored on the date the patient was last known to be alive (i.e., date of last contact).  
Patients lacking data beyond the day of randomization will have their survival time censored 
on the date of randomization (i.e., OS duration of 1 day). 
Specifically, censored OS will be calculated as: 
Censored OS = max(1, last contact date - date of randomization + 1), 
The Kaplan-Meier method will be used to estimate OS.  Kaplan-Meier curves depicting OS 
in the two arms will be generated.  Additionally, the median OS, and survival rates at 30 
days, 60 days, 3 months and every 3 months thereafter to the end of the follow-up period will 
be reported.  The associated two-sided 95% CIs will be calculated. 
Subgroup analysis of OS will be performed by the stratification factors and may be 
performed for the subgroups specified in Section 6.8. 
7.5.2 Secondary Endpoints 
7.5.2.1 Minimum Residual Disease-Negative CRc Rate 
MRD-negative CRc rate is defined as the proportion of patients achieving both morphologic 
remission (CR or CRi) and MRD-negative status prior to the start of subsequent anticancer 
therapy or stem cell transplant.  Patients whose morphologic response or MRD status cannot 
be assessed will be considered non-responders in the calculation of MRD-negative CRc rate. 
The MRD-negative CRc rate and the 2-sided 95% CI will be summarized by treatment 
group.  


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7.5.2.2 Duration of Remission 
Duration of remission will be not analyzed given the limited follow-up of the study. 
7.5.2.3 Event-Free Survival (EFS) 
EFS will not be analyzed given the limited follow-up of the study. 
7.5.2.4 Leukemia-Free Survival (LFS) 
LFS will not be analyzed given the limited follow-up of the study. 
7.5.2.5 Time to Complete Remission  
Time to complete remission will not be analyzed given the limited follow-up of the study. 
7.5.2.6 Mortality Rate 
The 30-day mortality rate is defined as the proportion of patients who die within 30 days of 
randomization.  The 60-day mortality rate is defined as the proportion of patients who die 
within 60 days of randomization.  The 30-day and 60-day mortality rates and the associated 
95% CIs will be summarized by treatment group.  In addition, the cause of early mortality 
will be summarized by descending MedDRA preferred term and treatment group. 
7.6 Safety Analyses 
The safety analysis set will be used to summarize all safety endpoints. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA, Version 19.0 or higher). 
Laboratory values will be graded according to the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE version 4.03 or higher). 
Concomitant medications will be coded using the WHO Drug Dictionary (version: June 2015 
or more recent). 
7.6.1 Adverse Events 
Adverse events (AEs) will be summarized by descending MedDRA preferred term (PT) 
unless otherwise specified.  For incidence reporting, if a patient reports more than one AE 
that was coded to the same system organ class (SOC) or PT, the patient will be counted only 
once for that specific SOC or PT. 
A treatment-emergent AE is defined as a newly occurring or worsening AE after the first 
dose of any study treatment.  See Appendix C for details regarding treatment-emergent 
classification.  Summaries of AEs will be provided by treatment group and total for the 
following: 
● 
Pre-existing AEs 
● 
All treatment-emergent AEs 


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● 
AEs related to blinded study treatment 
● 
AEs related to azacitidine 
● 
AEs related to decitabine 
● 
Serious Adverse Events (SAEs) 
● 
SAEs related to blinded study treatment 
● 
SAEs related to azacitidine 
● 
SAEs related to decitabine 
● 
AEs leading to blinded study treatment dose delay  
● 
AEs leading to azacitidine dose delay 
● 
AEs leading to decitabine dose delay 
● 
AEs leading to blinded study treatment dose reduction  
● 
AEs leading to azacitidine dose reduction 
● 
AEs leading to decitabine dose reduction 
● 
AEs leading to overall treatment discontinuation 
● 
AEs leading to blinded study treatment discontinuation 
● 
AEs leading to azacitidine discontinuation   
● 
AEs leading to decitabine discontinuation  
● 
Grade 3 or higher treatment-emergent AEs 
● 
Infusion-related reactions (within 24 hours of blinded study drug dose)  
● 
Treatment-emergent AEs by SOC and PT 
● 
Treatment-emergent AEs by SOC, PT, and maximum severity.  At each SOC or 
PT, multiple occurrences of events within a patient are counted only once at the 
highest severity 
● 
Grade 3 or higher treatment-emergent AEs by SOC and PT  
● 
TEAEs with incidence ≥5% by SOC and PT 
● 
SAEs with incidence ≥5% by SOC and PT 
AEs in the categories below as defined by the Standardized MedDRA Queries (SMQs) or 
customized searches will be summarized by SOC, PT, and maximum severity.  SAEs will be 
summarized by PT. 


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• Serious infection 
• Bleeding 
• Thrombocytopenia 
• Neutropenia 
• Anemia 
• Hepatotoxicity 
• Edema 
• Pulmonary 
• Cardiomyopathy 
• Cardiac failure 
• Myocardial infarction 
All AEs, SAEs, grade 3 or higher treatment-emergent AEs, AEs leading to treatment 
discontinuation, and AEs with fatal outcome will be listed. 
7.6.2 Clinical Laboratory Parameters 
Clinical laboratory data (hematology and serum chemistry) will be summarized by treatment 
group and total.  Summary statistics of actual value and change from baseline will be 
presented by scheduled visit.  In addition, laboratory data will be summarized in shift tables 
comparing the baseline value to the worst post-baseline value by NCI CTCAE grade for each 
parameter. 
All clinical laboratory data and NCI CTCAE grades will be presented in data listings.  A 
separate listing of laboratory results with CTCAE grade 3 or higher will also be presented.  
Normal ranges will be documented and out-of-range values will be flagged.   
Patients with the liver function test results (AST, ALT, ALP, and total bilirubin) meeting the 
Hy’s law will be listed. 
7.6.3 ECOG Performance Status 
ECOG performance status will be summarized for each visit by treatment group and total.  
Shifts from baseline to the best and worst post-baseline scores will be tabulated.   
7.6.4 Concomitant Medications 
Concomitant medications will be summarized by the WHO Drug substance name by 
treatment group and total, and listed by patient. 


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The number and percentage of patients who receive myeloid growth factor as a concomitant 
medication and the reason for administration will be summarized by treatment group and 
total.   
7.6.5 Deaths 
The number of total deaths, deaths that occured within 30 days of last study treatment, and 
deaths that occured more than 30 days after last study treatment, as well as the relationship to 
disease, will be summarized by treatment group and total.  In addition, cause of death will be 
identified by descending MedDRA preferred term (unless otherwise specified) and 
summarized by treatment group and total.  Death information will be listed by patient. 
7.7 Additional Analyses 
7.7.1 Stem Cell Transplant 
Patients who received stem cell transplant after study treatment discontinuation will be listed, 
including the reason patient became eligible for transplant, the level of match of the donor, 
time from last dose of blinded study treatment to transplant, and transplant conditioning 
regimens administered. 
7.7.2 Pharmacokinetics 
The observed plasma vadastuximab talirine ADC and SGD-1882 may be summarized with 
descriptive statistics at each PK sampling time point.  Any additional PK and PK/PD 
analyses may be performed and presented in a separate report. 
7.7.3 Antitherapeutic Antibody Incidence Rate 
The antitherapeutic antibody (ATA) incidence rate is defined as the proportion of patients 
who develop ATA at any time during the study.  The ATA incidence rate will be summarized 
by treatment group and total. 
7.7.4 Biomarker Analyses 
Biomarker assessments may be summarized using descriptive statistics.  The relationship 
between biomarkers and efficacy and safety endpoints may be explored and presented in a 
separate report.   
8 
INTERIM ANALYSIS 
Due to safety concerns raised by the IDMC, the study was terminated early prior to the 
formal interim analyses planned in the protocol.  No interim analyses will be conducted.  
Final analysis will be performed based on 240 patients randomized into the study by the time 
enrollment was closed. 
9 
CHANGES FROM PLANNED ANALYSES 
9.1 Changes from the Protocol 
Not Applicable. 


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9.2 Changes from the Original SAP 
9.2.1 Version 2 Changes 
The SAP was updated to reflect changes in protocol amendment 2 and to add additional 
details to the analysis.  Changes from version 1 are summarized below: 
• Sec 2.2, 3.2, 5.2, 5.3, and 7.5.2.4: update per protocol amendment 2 
o Add “duration of remission” as secondary objective/endpoint 
o Add mITT analysis set and clarify the definition of safety analysis set 
• Sec 6.2: clarify the 12-month follow-up is from the last patient enrolled to the final 
analysis of OS after approximately 334 deaths occurred. 
• Sec 6.5 and Appendix B: add language or missing data handling for subsequent 
anticancer therapy start date 
• Sec 6.8: add additional subgroups to allow subgroup analysis 
• Sec 7.5 and 7.6: add additional details to efficacy and safety analysis and data 
presentation 
• Sec 7.7.4 and 7.7.5: add additional analysis for subsequent anticancer therapy and 
stem cell transplant  
9.2.2 Version 3 Changes 
The SAP was updated to reflect changes in protocol amendment 3 and to add additional 
details to the analysis.  Changes from version 2 are summarized below: 
• Sec 2.1, 2.2, 3.1, 3.2, 7.5.1 and 7.5.2: update per protocol amendment 3 to change the 
CRc rate from a secondary endpoint to an independent primary endpoint and to 
clarify that the MRD-negative CRc rate will be compared between the treatment arms 
• Sec 6.2, 6.7, 6.10, and 8: update the sample size, multiplicity strategy, timing of the 
analysis, and interim analysis to account for 2 independent primary endpoints 
• Sec 6.8: add additional subgroups to allow subgroup analysis 
• Sec 7.4: add additional details for the calculation of duration of therapy 
• Sec 7.6.1: add analysis for AEs of special interest (i.e., hepatobiliary AEs) 
• Sec 7.6.3: add analysis for vital sign measurements  
• Sec 7.7.5: add analysis for SOS/VOD  


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9.2.3 Version 4 Changes 
The study was terminated early due to safety concerns raised by the IDMC.  The SAP was 
updated to include only analyses required for the abbreviated CSR.  Changes from version 3 
are summarized below: 
• Sec 6.7: Clarify that all efficacy analyses will be descriptive in nature and no multiple 
testing procedure will be applied 
• Sec 6.10: Clarify that no interim analysis will be conducted and final analysis will be 
based on 240 patients randomized into the study by the time enrollment was closed 
• Sec 7.1: Remove the summary of screen failed patients 
• Sec 7.5: Remove all efficacy analyses other than the descriptive summary of CRc 
rate, OS, MRD-neg CRc rate, and early mortality rate 
• Sec 7.6.1: Add additional summary of AEs of special interest 
• Sec 7.6.2: Add additional summary to evaluate the extent of neutropenia 
• Sec 7.7: Remove the analyses of PRO endpoints, transfusion, MRU, and subsequent 
therapy 
• Sec 8: Clarify that no interim analysis will be conducted and final analysis will be 
based on 240 patients randomized into the study by the time enrollment was closed  
9.2.4 Version 5 Changes 
The SAP was updated to remove analyses that are limited by data availability as a result of 
early study termination. Changes from version 4 are summarized below: 
• Sec 6.8: Remove subgroup analysis by FLT3 and ELN risk group 
• Sec 7.2: Remove ELN risk group from disease characteristics summary 
• Sec 7.4: Remove dose intensity summary for HMA because azacitidine and 
decitabine were administered according to package inserts  
• Sec 7.6.2: Remove the exploratory analyses of laboratory results 
• Sec 7.6.5: Remove the summary of growth factor cumulative dose  
• Remove the vital signs listing 
 


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10 REFERENCES 
Cheson BD, Bennett JM, Kopecky KJ, Buchner T, Willman CL, Estey EH, Schiffer CA, Doehner H, Tallman 
MS, Lister TA, Lo-Coco F, Willemze R, Biondi A, Hiddemann W, Larson RA, Lowenberg B, Sanz MA, Head 
DR, Ohno R and Bloomfield CD (2003). Revised recommendations of the International Working Group for 
Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic 
Trials in Acute Myeloid Leukemia. J Clin Oncol 21: 4642-9. 
Collett D (1994). Interval-censored survival data. Modelling survival data in medical research. Boca Raton, 
Fla., Chapman & Hall/CRC: 237-251. 
Dmitrienko A, Millen BA, Brechenmacher T and Paux G (2011). Development of gatekeeping strategies in 
confirmatory clinical trials. Biom J 53: 875-93. 
Lan KG and deMets DL (1983). Discrete sequential boundaries for clinical trials. Biometrika 70: 659-663. 
Wiens BL and Dmitrienko A (2005). The fallback procedure for evaluating a single family of hypotheses. J 
Biopharm Stat 15: 929-42. 
 
 
 


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


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If the month/year is before the month/year of first dose of investigational agent: 
AE start date will be imputed as the minimum of (AE condition end date*, last day of 
the month) 
If the month/year is after the month/year of first dose of investigational agent: 
AE start date will be imputed as the minimum of (AE condition end date*, last day of 
the month) 
* only use condition end date if known and full end date is available. 
 
The following algorithm should be used to impute AE condition end dates.  The AE records 
for a condition/event should be sorted by the imputed start dates then record position (order 
of entry into the eCRF). After sorting, if any condition end date month/year is greater than 
any subsequent record end date month/year, then change the imputed start day only to end of 
month. Repeat as necessary.  
After sorting the AE records, apply the following rules to partial or missing AE condition end 
dates: 
For all records excluding the last chronological record for a condition/event 
AE condition end date will be imputed as the start date of the subsequent record 
For the last chronological record for a condition/event 
If outcome is “recovered/resolved”, ”recovered/resolved with sequelae”, or “fatal” apply the 
following:  
• 
If only year is provided for the end date and year is equal to the year of the last 
dose date: 
o AE condition end date will be imputed as the minimum of (last dose date 
+ 30, death date, data extraction date, December 31st of the end date year) 
• 
If only year is provided for the end date and year is not equal to the year of the 
last dose date: 
o AE condition end date will be imputed as the minimum of (death date, 
data extraction date, December 31st of the end date year) 
• 
If month and year are provided for the end date: 
o AE condition end date will be imputed as the minimum of (death date, 
data extraction date, last day of the end date month/year) 
 
If outcome is “recovering/resolving”, “not recovered/resolved”,“unknown”, or blank: 
AE condition end date will not be imputed. 
Example 1 
AESPID 1: Condition/Event HEADACHE 
First dose date 01JAN2012 


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


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APPENDIX B: IMPUTATION OF PARTIALLY MISSING SUBSEQUENT 
ANTICANCER THERAPY START DATE 
The algorithm below should be used to impute subsequent anticancer therapy start dates for 
which only day is missing. 
• If the month and year of the subsequent anticancer therapy start date is the same as 
the month and year of the response assessment date, and the response is a disease 
progression or relapse: 
o Subsequent anticancer therapy start date will be imputed as the date of 
response assessment. 
• If the month and year of the subsequent anticancer therapy start date is the same as 
the month and year of the response assessment date, and the response is not a disease 
progression or relapse: 
o Subsequent anticancer therapy start date will be imputed as the first day of the 
month. 
 
 


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APPENDIX C: DEFINITION OF THE TERM “TREATMENT-EMERGENT” WITH 
RESPECT TO AE CLASSIFICATION  
The algorithm below should be used to determine whether an adverse event (AE) is classified 
as a treatment-emergent adverse event (TEAE).  A TEAE is defined as any AE which is 
newly occurring or worsening in severity, where newly occurring means that the AE was not 
present at baseline.  For ease of reading, both pre-existing conditions and AEs will be 
referred to as AEs for the remainder of this document.  AE dates should be imputed in 
accordance with the algorithm detailed in Appendix A prior to determination of TEAE 
classification.  Details of the TEAE classification are as follows: 
1) Determine the first/earliest dose date/time of any study treatment (for combination 
studies this includes any component of the regimen) 
2) Classify an AE as a baseline AE if it satisfies both of criteria a and b below: 
a) The onset period field is: “started before the signing of informed consent”; or “started 
after consent but before the first dose of any study treatment”; or, the onset period 
field is missing and the AE start date is prior to the first dose date of any study 
drug(step 1, above). 
b) The stop date satisfies either of i or ii below: 
i) The stop date is the same as or a later date than the first dose date of any study 
treatment 
ii) The stop date is missing with outcome equal to: recovering/resolving (this 
outcome may or may not be associated with a date); or not recovered/not 
resolved; or unknown. 
iii) Note: if the AE has no outcome or stop date provided it should be queried 
c) Note: If the event ended on Day 1 (the date of first dose of any study drug) it will be 
considered a baseline event. 
3) Classify an AE as post-baseline if it meets either of criteria a or b below: 
a) The onset period of the AE is “started after the first dose of any study treatment” 
b) The onset period of the AE is missing and the AE start date is the same as or a later 
date than the first dose date of any study treatment 
4) Compare post-baseline AEs to baseline AEs using the lower level term (LLT). If the 
post-baseline AE meets any of the following criteria then classify it as a TEAE: 
a) There is a baseline AE with the same LLT but the post-baseline AE has a greater 
CTC grade. 
b) There are no baseline AEs with a matching LLT for the post-baseline AE. 
c) The post-baseline AE is uncoded.