Clinical trial NCT02614560
Conditions: Acute Myeloid Leukemia
Keywords: acute myeloid leukemia AML antibody-drug conjugate
Sponsor: Seagen Inc.
Start date: 2015-11-01; Completion date: 2017-09-14
Enrollment: 14 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will examine the safety and anti-leukemic profile of SGN-CD33A (vadastuximab talirine) in patients with relapsed chemo-resistant AML, who are given vadastuximab talirine in sequence with standard treatments before a planned stem cell transplant, or as maintenance therapy after a stem cell transplant. The main purpose of the study is to find the best dose and determine the anti-leukemic activity of vadastuximab talirine, given either pre- or post-allogeneic stem cell transplant (alloSCT) for adults with relapsed or refractory AML. This will be determined by assessing the safety and tolerability of vadastuximab talirine. In addition, the pharmacokinetic profile and anti-leukemic activity of the study treatment will be assessed.

Detailed description:

Arms: arm 1: Pre-allo reduced intensity chemotherapy vadastuximab talirine (melphalan and fludarabine) arm 2: Post-allo vadastuximab talirine
Interventions: intervention 1: Fludarabine intervention 2: Melphalan intervention 3: vadastuximab talirine intervention 4: vadastuximab talirine
Intervention descriptions: intervention 1: 30 mg/m2/day intravenously, 5 to 2 days before the transplant (total dose of 120 mg/m2) intervention 2: Melphalan 140 mg/m2 intravenously, 2 days before the transplant intervention 3: Pre-allo (before stem cell transplant) given 14 days before the stem cell transplant intervention 4: Post-allo (after stem cell transplant) given on Day 1 of each cycle

Protocol documents:
Prot_000.pdf: 


Study SGN33A-003 
Clinical Protocol 
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PROTOCOL SYNOPSIS 
Protocol Number 
SGN33A-003 
Version 
Amendment 3 
Phase 
Phase 1/2 
Product Name 
Vadastuximab talirine (SGN-CD33A) 
Sponsor 
Seattle Genetics, Inc. 
21823 30th Drive SE 
Bothell, WA 98021, USA 
 
Protocol Title 
A phase 1/2 study of vadastuximab talirine administered in sequence with allogeneic hematopoietic stem cell 
transplant in patients with relapsed or refractory acute myeloid leukemia (AML) 
Study Objectives 
Primary 
● Phase 1 
○ 
To assess the safety and tolerability of vadastuximab talirine 
○ 
To determine the recommended dosing levels of vadastuximab talirine pre- and post-allogeneic 
hematopoietic stem cell transplant (alloSCT) 
● Phase 2 
○ 
To assess the 1-year survival rates of patients treated with vadastuximab talirine at the recommended 
doses pre- and post-alloSCT 
○ 
To assess the rate of minimal residual disease (MRD) negativity at Day −1 pre-transplant and Day 30 
post-transplant (Part A only) 
○ 
To assess the safety and tolerability of vadastuximab talirine at the recommended dosing levels 
 
Secondary 
● To assess the best response on study treatment (Part A only) 
● To assess the duration of response (Part A only) 
● To assess overall survival (OS) 
 
Additional 
● To assess the pharmacokinetics, antitherapeutic antibodies (ATA), and pharmacodynamics of 
vadastuximab talirine 
● To assess event-free survival (EFS) 
● To assess the rate of MRD negativity 
● To assess lymphocyte subset recovery after alloSCT 
● To assess CD33 expression levels and post-treatment target (CD33) saturation 
● To assess biomarkers of biological activity, resistance, and outcome 
Study Population 
Eligible patients must have AML (acute promyelocytic leukemia (APL) is excluded).  Patients must be 18 to 
75 years of age with an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, and have 
adequate baseline renal, hepatic, cardiac, and pulmonary function.  Patients with central nervous system 
leukemia are not permitted in the study. Patients with any uncontrolled Grade 3 or higher ongoing infection 
prior to the first dose of study drug will not be eligible; however, prophylaxis or treatment for 


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resolving/controlled infection is acceptable.  Patients with documented history of cerebral vascular events will 
be excluded.  Patients may not participate if they have known hypersensitivity to excipients contained in the 
drug formulations of vadastuximab talirine, fludarabine, melphalan, tacrolimus, or methotrexate. 
Part A 
Patients enrolled in Part A, the pre-alloSCT arm, must have relapsed and/or refractory AML, have received 2 or 
3 previous induction regimens including at least one intensive chemotherapy regimen, and be eligible to 
undergo an alloSCT.  Patients enrolled in Part A will not be eligible to enroll in Part B. 
Part B 
Patients enrolled in Part B must have successfully undergone an alloSCT for relapsed or refractory AML and 
achieved a CR or CR with incomplete blood count recovery (CRi).  Patients must be without significant graft-
versus-host disease (GVHD) and without a history of veno-occlusive disease (VOD) requiring defibrotide. 
Number of Planned Patients 
Approximately 102 patients are expected to participate in the study. 
Part A 
Phase 1 will enroll approximately 18 patients and Phase 2 will enroll up to 36 patients. An additional 36 patients 
may be added to Phase 2 of Part A if exploration of an alternative dose is desired. 
Part B 
Phase 1 will enroll approximately 12 patients. Phase 2 will enroll up to 36 patients. 
Study Design 
This is a 2-part study to evaluate the safety and activity of vadastuximab talirine in patients with relapsed 
chemo-resistant AML:  Part A will examine vadastuximab talirine in cytoreduction pre-conditioning and Part B 
will examine vadastuximab talirine in post-alloSCT maintenance.  Each study part will consist of a phase 1 
safety evaluation followed by a phase 2 expansion for efficacy.  Parts A and B will enroll concurrently.  Phase 2 
will be initiated following dose level recommendation by the Safety Monitoring Committee (SMC) with the 
determination of the MTD or recommended phase 2 doses for Parts A and B, and an evaluation of the overall 
safety profile. At the discretion of the SMC, dose levels may be expanded in phase 1.  All patients will be 
followed for survival status until 5 years after the last patient is enrolled, or until study closure, whichever 
occurs first. 
An SMC consisting of the study medical monitor, investigators, and the study biostatistician will monitor the 
safety of patients treated with vadastuximab talirine on a regular basis throughout the study, including reviews 
of the data pertinent to dose-escalation decisions and evaluation of potential cumulative toxicity.  The SMC 
may recommend investigation of an intermediate dose level during dose escalation.  Dose levels for expansion 
will be selected by the sponsor in consultation with the SMC, based on known safety and activity data. 
Part A 
One dose of vadastuximab talirine will be administered intravenously on Day −14 for patients in the 
cytoreduction pre-conditioning part followed by reduced intensity chemotherapy (RIC) of melphalan and 
fludarabine on Days −5 to −2. AlloSCT will be performed on Day 0. 
Patients will be evaluated for response at Day 30, and every 3 months from transplant for 1 year and then every 
6 months until 3 years post-transplant. 
Part A phase 1 of the study will be conducted using a standard 3+3 design.  Part A phase 2 of the study will be 
an open-label, non-randomized study conducted with doses of vadastuximab talirine at or below the MTD 
established in phase 1. 
Part B 
In Part B, patients will enter the study between 42 and 100 days after the alloSCT and will receive 
vadastuximab talirine on Day 1 of 42-day cycles for up to 12 months. 


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Response assessments will be every 3 months after the first dose of study drug for 2 years (every other cycle 
during treatment), and then every 6 months until 3 years post-transplant.  Patients in Part B who discontinue 
study treatment prior to relapse will be evaluated for response until progression or initiation of new anticancer 
treatment, whichever comes first. 
Part B phase 1 of the study will treat 6 patients at Dose Level 1 (10 mcg/kg) beginning between 42 and 100 
days post transplantation. In the event of dose-limiting toxicity (DLT) occurring in 2 or more patients, 6 
additional patients will be treated at a lower Dose Level −1 (5 mcg/kg). 
Test Product, Dose, and Mode of Administration 
Part A 
Vadastuximab talirine at escalating doses starting at 40 mcg/kg will be administered IV push without routine 
premedication on Day −14 for Part A. 
Pre-alloSCT RIC 
● Fludarabine 30 mg/m2/day IV on Day −5 to Day −2 (total dose of 120 mg/m2) 
● Melphalan 140 mg/m2 IV on Day −2 
 
GVHD prophylaxis 
● Tacrolimus 0.03 mg/kg/day IV (initial dose Day −1); subsequent oral or IV doses target blood trough levels 
5−15 ng/mL 
● Methotrexate 5−10 mg/m2 Day 1 and 5 mg/m2 IV on Days 3, 6, and 11 post-transplant 
Part B 
Vadastuximab talirine at 5−10 mcg/kg will be administered IV push without routine premedication on Day 1 of 
42-day cycles for Part B. 
Duration of Treatment 
Part A 
Patients in Part A will receive 1 dose of vadastuximab talirine. 
Part B 
Patients in Part B will receive vadastuximab talirine on Day 1 of 42-day cycles for up to 8 cycles. Patients who 
derive clinical benefit may continue treatment for up to 8 additional cycles with medical monitor approval. 
Efficacy Assessments 
Response categorization will be based on 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). MRD will be assessed at a central laboratory by 
multiparametric flow cytometry of bone marrow samples according to the Research Specimen Manual (Walter 
2011). 
Pharmacokinetic and Immunogenicity Assessments 
Blood samples for PK and ATA assessment will be collected at protocol-specified time points. 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 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. 


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Biomarker Assessments 
Part A 
Peripheral blood and bone marrow aspirates will be collected at the time points outlined in Table 4 and Table 5.  
Biomarker assessments in Part A may include CD33 expression level and saturation by vadastuximab talirine 
on CD33+ cells, cytogenetic abnormalities and/or mutation of genes with known prognostic significance for 
AML, soluble CD33, lymphocyte subset recovery post-transplant and evaluation of MRD at protocol specified 
time points outlined in Table 4 and Table 5. 
Part B 
Peripheral blood and bone marrow aspirates will be collected at the time points outlined in Table 6.  Part B 
assessments may include soluble CD33, evaluation of MRD, and lymphocyte subset recovery post-transplant to 
monitor changes that may be associated with long term treatment with vadastuximab talirine. 
Safety Assessments 
Safety assessments will consist of the surveillance of AEs, laboratory test measures, physical examination 
findings, and concomitant medication records.  Complete blood count (CBCs) and serum chemistries will be 
obtained regularly.  GVHD will be assessed using GVHD Target Organ Staging (Harris 2016). 
Determination of Sample Size 
Phase 1 of Part A follows the 3+3 dose-escalation design. It is anticipated that 18 patients will be treated. Phase 
1 of Part B follows a dose de-escalation design with 6 patients in each of the 2 planned dose levels. It is 
anticipated that 12 patients will be treated. 
The sample size of Phase 2 of each part of the study is based on the one-year survival rate. The statistical 
hypotheses are 
 
H0: One-year survival rate < 20%, vs H1: One-year survival rate ≥ 20%. 
Assuming that the true one-year survival rate is 40%, a sample size of 36 will provide 83% power at a one-sided 
significance level of 5% using exact binomial test. 
Statistical Methods 
Study measures of safety, PK, baseline biomarkers, pharmacodynamic biomarkers, and efficacy will be 
summarized by descriptive statistics.  The all treated patients analysis set will include patients treated with any 
amount of vadastuximab talirine.  The DLT-evaluable analysis set includes all treated patients who either 
experienced a DLT or were followed for the full DLT evaluation period. All efficacy and safety analyses will be 
based on the all treated patients analysis set. The one-year survival rate and its 95% confidence interval will be 
estimated by Kaplan-Meier method. OS, duration of response and EFS will be analyzed using Kaplan-Meier 
method.  Median OS, duration of response, and EFS will be calculated, where possible, with 95% confidence 
intervals. Each part of the study will be summarized independently. 


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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ....................................................................................................................................... 2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ......................................................................... 9 
1 
INTRODUCTION ......................................................................................................................................... 10 
1.1 
Acute Myeloid Leukemia .................................................................................................................... 10 
1.2 
Allogeneic Transplant in AML ........................................................................................................... 10 
1.3 
CD33 ................................................................................................................................................... 11 
1.3.1 
CD33-Directed Therapies for AML ....................................................................................... 11 
1.4 
Vadastuximab talirine (SGN-CD33A) ................................................................................................ 12 
1.5 
Rationale for Study .............................................................................................................................. 13 
2 
OBJECTIVES ............................................................................................................................................... 13 
2.1 
Primary Objective ............................................................................................................................... 13 
2.2 
Secondary Objectives .......................................................................................................................... 13 
2.3 
Additional Objectives .......................................................................................................................... 14 
2.4 
Endpoints ............................................................................................................................................. 14 
2.4.1 
Safety Endpoints ..................................................................................................................... 14 
2.4.2 
Efficacy Endpoints ................................................................................................................. 14 
2.4.3 
Additional Endpoints .............................................................................................................. 14 
3 
INVESTIGATIONAL PLAN ....................................................................................................................... 15 
3.1 
Summary of Study Design (Parts A and B) ......................................................................................... 15 
3.1.1 
Part A – Pre-AlloSCT ............................................................................................................. 15 
3.1.2 
Part B – Post-AlloSCT ........................................................................................................... 17 
3.1.3 
Study Stopping Criteria .......................................................................................................... 18 
3.2 
Discussion and Rationale for Study Design ........................................................................................ 20 
3.2.1 
Method of Assigning Patients to Treatment Groups .............................................................. 20 
3.2.2 
Rationale for Selection of Doses ............................................................................................ 20 
3.2.3 
Blinding .................................................................................................................................. 21 
4 
STUDY POPULATION................................................................................................................................ 21 
4.1 
Inclusion Criteria ................................................................................................................................. 21 
4.2 
Exclusion Criteria ................................................................................................................................ 22 
4.3 
Removal of Patients from Therapy or Assessment.............................................................................. 24 
4.3.1 
Discontinuation of Study Drug ............................................................................................... 24 
4.3.2 
Patient Withdrawal from Study .............................................................................................. 24 
5 
TREATMENTS ............................................................................................................................................ 24 
5.1 
Treatments Administered .................................................................................................................... 24 
5.2 
Investigational Study Drug .................................................................................................................. 25 
5.2.1 
Description ............................................................................................................................. 25 
5.2.2 
Dose and Administration ........................................................................................................ 25 
5.2.3 
Fludarabine/Melphalan/Tacrolimus/Methotrexate ................................................................. 25 
5.3 
Management of Infusion Reactions ..................................................................................................... 26 
5.4 
Management of Tumor Lysis Syndrome ............................................................................................. 27 
5.5 
Dose Modifications for Part B ............................................................................................................. 27 
5.6 
Storage and Handling .......................................................................................................................... 28 
5.7 
Packaging and Labeling ...................................................................................................................... 29 
5.8 
Preparation .......................................................................................................................................... 29 
5.9 
Required Premedication and Postmedication ...................................................................................... 29 
5.10 Concomitant Therapy .......................................................................................................................... 29 
5.10.1 Required Concomitant Therapy.............................................................................................. 29 
5.10.2 Allowed Concomitant Therapy .............................................................................................. 29 
5.10.3 Prohibited Concomitant Therapy ............................................................................................ 30 
5.11 Treatment Compliance ........................................................................................................................ 30 
6 
STUDY ACTIVITIES ................................................................................................................................... 30 


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6.1 
Part A – pre-AlloSCT (Days relative to transplant Day 0) .................................................................. 30 
6.1.1 
Screening Period (Days –44 to –14) ....................................................................................... 30 
6.1.2 
Day –28 to Day –14 ................................................................................................................ 31 
6.1.3 
Day –21 to Day –14 ................................................................................................................ 31 
6.1.4 
Day –14 .................................................................................................................................. 31 
6.1.5 
Day –13 .................................................................................................................................. 31 
6.1.6 
Day –11 .................................................................................................................................. 31 
6.1.7 
Day –7 .................................................................................................................................... 31 
6.1.8 
Day –5 to –2 ........................................................................................................................... 31 
6.1.9 
Day –1 .................................................................................................................................... 32 
6.1.10 Day 0 ...................................................................................................................................... 32 
6.1.11 Day 1 ...................................................................................................................................... 32 
6.1.12 Days 7, 14, and 21 .................................................................................................................. 32 
6.1.13 Day 30 (±2 days) .................................................................................................................... 32 
6.1.14 End of Treatment Visit (30 to 37 days post-transplant) .......................................................... 32 
6.1.15 Long-Term Follow-Up ........................................................................................................... 33 
6.2 
Part B – post alloSCT (Days relative to the first dose of vadastuximab talirine on Day 1) ................ 33 
6.2.1 
Screening Visit (Days –28 to 1) ............................................................................................. 33 
6.2.2 
Baseline Visit (Day –14 to 1) ................................................................................................. 33 
6.2.3 
Day –7 to 1 ............................................................................................................................. 33 
6.2.4 
Day 1 ...................................................................................................................................... 34 
6.2.5 
Day 2 (Cycle 1 only) .............................................................................................................. 34 
6.2.6 
Day 4 (Cycle 1 only) .............................................................................................................. 34 
6.2.7 
Day 8, 15, 22, and 28 (Cycle 1 only, ±1 day) ......................................................................... 34 
6.2.8 
Day 42 (Cycle 1 only) ............................................................................................................ 34 
6.2.9 
End of Treatment Visit (42 to 49 days after last dose of study drug) ..................................... 34 
6.2.10 Long-Term Follow-up ............................................................................................................ 35 
7 
STUDY ASSESSMENTS ............................................................................................................................. 35 
7.1 
Screening/Baseline Assessments ......................................................................................................... 35 
7.2 
Response/Efficacy Assessments .......................................................................................................... 35 
7.3 
Pharmacokinetic and ATA Assessments ............................................................................................. 36 
7.4 
Biomarker Studies ............................................................................................................................... 36 
7.4.1 
CD33 Expression and Saturation ............................................................................................ 39 
7.4.2 
Lymphocyte Subset Recovery ................................................................................................ 39 
7.4.3 
Cytogenetics and Gene Mutations .......................................................................................... 39 
7.5 
Biospecimen Repository...................................................................................................................... 39 
7.6 
Safety Assessments ............................................................................................................................. 39 
7.6.1 
GVHD Assessments ............................................................................................................... 40 
7.6.2 
Adverse Events ....................................................................................................................... 40 
7.6.3 
Clinical Laboratory Tests ....................................................................................................... 45 
7.6.4 
Physical Examination ............................................................................................................. 46 
7.7 
Appropriateness of Measurements ...................................................................................................... 46 
8 
DATA QUALITY CONTROL AND QUALITY ASSURANCE ................................................................ 46 
8.1 
Site Training and Monitoring Procedures ........................................................................................... 46 
8.2 
Data Management Procedures ............................................................................................................. 47 
8.3 
Access to Source Data ......................................................................................................................... 48 
8.4 
Accuracy and Reliability of Data ........................................................................................................ 48 
8.5 
Quality Assurance Procedures ............................................................................................................. 48 
8.6 
Data Handling and Record Keeping .................................................................................................... 48 
8.6.1 
Data Handling ......................................................................................................................... 48 
8.6.2 
Investigator Record Retention ................................................................................................ 49 
9 
DATA ANALYSIS METHODS ................................................................................................................... 49 
9.1 
Determination of Sample Size ............................................................................................................. 49 
9.2 
Study Endpoint Definitions ................................................................................................................. 50 


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9.2.1 
Overall Survival (OS) and One-year Survival Rate ................................................................ 50 
9.2.2 
Minimal Residual Disease (MRD) Negativity Rate ............................................................... 50 
9.2.3 
Best Response ......................................................................................................................... 50 
9.2.4 
Duration of Response ............................................................................................................. 50 
9.2.5 
Event-free Survival (EFS) ...................................................................................................... 50 
9.3 
Statistical and Analytical Plans ........................................................................................................... 51 
9.3.1 
General Considerations .......................................................................................................... 51 
9.3.2 
Patient Disposition ................................................................................................................. 52 
9.3.3 
Patient Characteristics ............................................................................................................ 52 
9.3.4 
Treatment Compliance ........................................................................................................... 52 
9.3.5 
Efficacy Analyses ................................................................................................................... 52 
9.3.6 
Pharmacokinetic and ATA Analyses ...................................................................................... 53 
9.3.7 
Biomarker Analyses ............................................................................................................... 53 
9.3.8 
Other Analyses ....................................................................................................................... 53 
9.3.9 
Safety Analyses ...................................................................................................................... 53 
9.3.10 Interim Analyses ..................................................................................................................... 54 
10 INFORMED CONSENT, ETHICAL REVIEW, AND REGULATORY CONSIDERATIONS ................. 54 
10.1 Informed Consent ................................................................................................................................ 54 
10.2 Ethical Review .................................................................................................................................... 55 
10.3 Regulatory Considerations .................................................................................................................. 55 
10.3.1 Investigator Information ......................................................................................................... 55 
10.3.2 Protocol Amendments and Study Termination ....................................................................... 55 
10.4 Study Documentation, Privacy and Records Retention ....................................................................... 55 
10.5 Clinical Trial Agreement ..................................................................................................................... 56 
11 REFERENCES .............................................................................................................................................. 57 
APPENDIX A:  SCHEDULE OF EVENTS PART A: PRE-ALLO SCT ............................................................ 62 
APPENDIX B: SCHEDULE OF EVENTS PART B: POST-ALLO SCT ........................................................... 63 
APPENDIX C:  PERFORMANCE STATUS SCALES CONVERSION ............................................................ 64 
APPENDIX D:  NEW YORK HEART ASSOCIATION CLASSIFICATION ................................................... 65 
APPENDIX E: BEARMAN REGIMEN-RELATED TOXICITY ACCORDING TO ORGAN SYSTEM ........ 66 
APPENDIX F:  GVHD TARGET ORGAN STAGING ...................................................................................... 68 
APPENDIX G:  INVESTIGATOR SIGNATURE PAGE ................................................................................... 69 
APPENDIX H:  DOCUMENT HISTORY ........................................................................................................... 70 
 
List of In-Text Tables 
Table 1:  
Part A dose levels .......................................................................................................................... 16 
Table 2: 
Part B dose levels .......................................................................................................................... 18 
Table 3: 
Recommended dose modifications for vadastuximab talirine-associated non-hematological 
toxicity ........................................................................................................................................... 28 
Table 4: 
Part A pharmacokinetic, ATA, and biomarker time points for blood ............................................ 37 
Table 5: 
Part A pharmacokinetic and biomarker time points for bone marrow ........................................... 37 
Table 6: 
Part B pharmacokinetic, ATA, and biomarker time points for blood and bone marrow ............... 38 
 
List of In-Text Figures 
Figure 1: 
Part A Design ................................................................................................................................ 16 
Figure 2: 
Part B Design ................................................................................................................................. 17 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ADC 
antibody-drug conjugate 
AE 
adverse event 
ALT 
alanine aminotransferase 
alloSCT 
allogeneic stem cell transplant 
AML 
acute myeloid leukemia 
AST 
aspartate aminotransferase 
ATA 
antitherapeutic antibodies 
AUC 
area under the concentration-time curve 
β-hCG 
beta human chorionic gonadotropin  
Ceoi 
concentration at the end of infusion 
Cmax 
maximum concentration 
CR 
complete remission 
CRi 
complete remission with incomplete blood count recovery 
Ctrough 
trough concentration 
CBC 
complete blood count 
CRF 
case report form 
DLI 
donor lymphocyte infusion 
DLT 
dose-limiting toxicity  
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EFS 
event-free survival 
EOT 
end of treatment 
GCP 
good clinical practice 
GVHD 
graft-versus-host disease 
ICH 
International Conference on Harmonization  
IEC 
independent ethics committee 
IRB 
institutional review board 
IND 
Investigational New Drug 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRD 
minimal residual disease 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
OS 
overall survival  
PD 
progressive disease 
RIC 
reduced intensity chemotherapy  
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SMC 
safety monitoring committee 
SOS 
Sinusoidal obstruction syndrome 
TLS 
Tumor lysis syndrome  
ULN 
upper limit of normal 
VOD 
veno-occlusive disease 
 


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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 blasts and a deficiency in normal cells 
including red blood cells, normal white blood cells, and platelets.  If untreated, AML 
generally causes death in weeks to months due to infection, bleeding, or complications 
related to leukostasis.  In 2014, it was estimated that approximately 18,000 new cases of 
AML would be diagnosed in the United States, and about 10,000 deaths due to AML would 
occur in that same year (ACS 2012).  The prognosis for AML depends heavily on factors 
such as patient age, cytogenetic and molecular abnormalities, and antecedent myelodysplasia. 
For patients who are age 60 years or younger with newly diagnosed AML, or for relatively fit 
patients above the age of 60 years, standard of care generally consists of induction treatment 
with cytarabine continuous infusion x 7 days and with an anthracycline x 3 days (typically 
called “7+3”) (Dohner 2015).  Generally, the complete remission (CR) rate for these patients 
is approximately 65% (Mayer 1994); For patients achieving a CR, post-remission therapy has 
generally included repeated cycles of cytarabine-based chemotherapy or a hematopoietic 
stem cell transplant, either autologous, or more frequently an allogeneic transplant from an 
HLA-compatible donor (Dohner 2010). Despite achievement of CR, however, approximately 
75% of these patients will experience disease relapse following initial induction therapy 
(Rollig 2011).  For patients whose disease recurs after achieving a remission with induction, 
the treatment options are limited, with reported median survival of approximately 12 months 
or less (Leopold 2002). Accordingly, the development of new therapies for patients resistant 
to standard chemotherapeutic agents is clearly needed. 
1.2 Allogeneic Transplant in AML 
Outcomes for patients with relapsed and/or refractory AML remain poor (Breems 2005).  An 
allogeneic transplantation is the only currently available curative treatment option for the 
majority of these patients.  Transplant survival is significantly improved if patients achieve a 
complete hematologic remission prior to transplantation (Cornelissen 2012) and the standard 
of care at most institutions has been to attempt re-induction chemotherapy and perform 
transplantation if a subsequent remission is achieved. Unfortunately the rates of successful 
re-induction therapy overall remain low with only 20%−30% of patients responding to 
salvage regimens (Leopold 2002). Additional chemotherapy, especially if unsuccessful, often 
leaves patients weak and unfit to undergo further treatment including stem cell 
transplantation.  Thus, despite the increasing availability of compatible donors, many patients 
are not transplanted because of the inability to achieve disease control prior to transplant. 
An alternate strategy has been to identify those patients who are unlikely to benefit from 
salvage chemotherapy and perform an allogeneic transplant in the setting of active disease. 
Data from multiple studies have demonstrated that these patients can be readily identified 
using well validated clinical and laboratory variables (Estey 1997; Breems 2005; Chevallier 


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2011). Despite the toxicities associated with transplant, the administration of 
chemo/radiotherapy in conjunction with immuno-competent allogeneic donor cells has been 
shown to be capable of overcoming chemotherapy resistance (Biggs 1992).  Most reported 
experiences using standard transplant conditioning regimens, have demonstrated that despite 
the achievement of remission in the majority of these chemotherapy-resistant patients, almost 
all relapse and die within one year of the transplant. Data from the CIBMTR as well as others 
have shown that the one year survival rates for transplants performed for AML in active 
disease are approximately 10% to 20% with very few long term survivors (Michallet 2000; 
Duval 2010). 
An alternative strategy for preventing relapse post-transplant has been to administer 
additional antileukemic agents following successful engraftment of stem cells. Clinical trials 
in this setting have included the use of hypomethylating agents such as azacitidine (de Lima 
2010) or tyrosine kinase inhibitors in patients with Flt-3 mutated AML (Chen 2014). These 
studies have demonstrated that it is feasible to give antileukemic therapy post-transplant. 
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).  Like other family members, CD33 possesses aminoterminal V-set and C2-set 
immunoglobulin superfamily domains that facilitate binding to sialic acid as well as 
conserved, intracellular inhibitory signaling motifs (ITIM) (Cao 2011).  Engagement of the 
receptor by ligand-binding or cross-linking leads to tyrosine phosphorylation of the ITIM 
region, recruitment and activation of Src-homology 2 (SH2)-containing phosphatases, Shp-1 
or Shp-2, and endocytosis of the CD33-ligand complex (Ulyanova 1999; Paul 2000; Walter 
2008; Sutherland 2009).  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.  In addition to myeloid and monocytic leukemia cells, CD33 is also expressed on 
normal committed myelomonocytic and erythroid progenitor cells and mature 
myeloid/monocytic cells, mast cells (Escribano 1998) and some NK cells (Eissens 2012) but 
is not thought to be expressed by the earliest pluripotent stem cells, on lymphoid cells or cells 
outside of the hematopoietic system (Sabbath 1985; Andrews 1986).  Upon differentiation, 
CD33 is decreased on mature granulocytes but retained on macrophages, monocytes and 
dendritic cells (Buhring 1989). 
1.3.1 
CD33-Directed Therapies for AML 
Several antibody-based therapies targeting CD33 have been evaluated in the clinic for the 
treatment of AML (FitzGerald 2011; Jurcic 2012).  They include the anti-CD33 antibody 
huM195 (lintuzumab), AVE9633, an anti-CD33-maytansinoid drug conjugate (Lapusan 
2012) and gemtuzumab ozogamicin (marketed as MylotargTM), an anti-CD33 monoclonal 


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antibody conjugated to the cytotoxic agent calicheamicin.  Lintuzumab was tested in clinical 
trials as a single agent, in combination with standard of care therapies, or conjugated to 
radionuclides (Feldman 2005; Raza 2009; Rosenblat 2010; Sekeres 2013).  Overall, the 
effects were modest and insufficient benefit was demonstrated.  Similarly, clinical 
development of AVE9633 was discontinued after a low level of activity was found against 
relapsed or refractory AML patients in 3 phase 1 trials (Lapusan 2012).  In contrast, 
gemtuzumab ozogamicin was granted accelerated approval in 2000 for the treatment of 
relapsed AML, with an overall remission rate of approximately 30% in relapsed or refractory 
disease (Sievers 2001; Fenton 2005).  A subsequent randomized phase 3 study in which a 
standard 7+3 induction regimen was compared to a reduced 7+3 regimen plus a single dose 
of gemtuzumab ozogamicin, failed to show improvement in outcome (Petersdorf 2013).  
Lack of benefit in this study, amidst concerns over increased deaths in the gemtuzumab 
ozogamicin arm, led to voluntary market withdrawal of the drug in 2010.  Recent studies 
have demonstrated that a lower dose of gemtuzumab ozogamicin combined with standard 
induction chemotherapy may improve survival in patients with AML (Burnett 2011; 
Castaigne 2012).  Taken together, these data help confirm validity of CD33 as a drug target, 
but suggest that an improved antibody-drug conjugate (ADC) with a favorable safety and 
toxicity profile is desirable (Jurcic 2012). 
1.4 Vadastuximab talirine (SGN-CD33A) 
Vadastuximab talirine (SGN-CD33A) is a CD33-directed ADC consisting of three functional 
subunits: 
● 
An anti-CD33 antibody with an engineered cysteine residue in position 239 of each 
heavy chain (h2H12ec) 
● 
A DNA-cross linking pyrrolobenzodiazepine dimer drug (SGD-1882) 
● 
A protease-cleavable linker that covalently attaches SGD-1882 to h2H12ec 
 
 
 
 
 
 
The antitumor activity and immunospecificity of vadastuximab talirine have been 
demonstrated in vitro and in vivo with models representing CD33-positive AML.  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 and preliminary 
results were reported (Stein 2014). 


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1.5 Rationale for Study 
Preliminary results from the phase 1 trial of vadastuximab talirine in relapsed/refractory 
AML patients have demonstrated significant leukemic cell cytoreduction which was dose-
dependent (Stein 2014).  Blast clearance from the marrow was uncommon in patients 
receiving doses between 5 and 30 mcg/kg whereas in patients treated with 40−60 mcg/kg, 
approximately 50% of patients experienced blast clearance (mLFS, CRi or CR).  Minimal 
residual disease (MRD) negativity was observed in the majority of patients who achieved a 
CR.  No consistent pattern of off-target toxicity was observed.  These preliminary data 
suggest that dose escalation, starting at 40 mcg/kg is appropriate in the setting of 
hematopoietic stem cell rescue without incurring excess extra-medullary toxicity and 
transplant-related complications.  The administration of vadastuximab talirine could offer 
sufficient leukemic cell cytoreduction, prior to transplantation, with a resultant significant 
decrease in relapse rates in AML patients transplanted with active disease. 
Results from the phase I trial with vadastuximab talirine have shown that patients achieving a 
complete remission have safely tolerated repeated low doses of therapy (5−10 mcg/kg) every 
4 weeks. Since a high percentage of refractory/relapsed AML patients achieve a complete 
hematological remission following transplant for active disease, administration of 
vadastuximab talirine at low-doses post-transplant could also be used to help eradicate 
residual leukemic cells that remain and give rise to relapse. 
2 
OBJECTIVES 
2.1 Primary Objective 
● 
Phase 1 
○ 
To assess the safety and tolerability of vadastuximab talirine 
○ 
To determine the recommended dosing levels of vadastuximab talirine pre- and 
post-allogeneic hematopoietic stem cell transplant (alloSCT) 
● 
Phase 2 
○ 
To assess the 1-year survival rates of patients treated with vadastuximab talirine at 
the recommended doses pre- and post-alloSCT 
○ 
To assess the rate of MRD negativity at Day −1 pre-transplant and Day 30 post-
transplant in the pre-transplant portion of the study (Part A only). 
○ 
To assess the safety and tolerability of vadastuximab talirine at the recommended 
dosing levels 
2.2 Secondary Objectives 
● 
To assess the best response on study treatment (Part A only) 
● 
To assess the duration of response (Part A only) 
● 
To assess overall survival (OS) 


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2.3 Additional Objectives 
● 
To assess the pharmacokinetics, antitherapeutic antibodies (ATA), and 
pharmacodynamics of vadastuximab talirine 
● 
To assess event-free survival (EFS) 
● 
To assess the rate of MRD negativity 
● 
To assess lymphocyte subset recovery after alloSCT 
● 
To assess CD33 expression levels and post-treatment target (CD33) saturation 
● 
To assess biomarkers of biological activity, resistance, and treatment outcome 
2.4 Endpoints 
2.4.1 
Safety Endpoints 
● 
Type, incidence, severity, seriousness, and relatedness of adverse events (AEs) 
● 
Type, incidence, and severity of laboratory abnormalities 
● 
Incidence of dose-limiting toxicity (DLT) 
2.4.2 
Efficacy Endpoints 
● 
One-year survival 
● 
Day −1 and Day 30 rates of MRD negativity (Part A only) 
● 
Complete remission rate (Part A only) 
● 
Best response (Part A only) 
● 
Duration of response (Part A only) 
● 
Overall survival 
2.4.3 
Additional Endpoints 
● 
MRD – negativity 
● 
Event-free survival 
● 
PK parameters for SGN-CD33A, and released SGD-1882 
● 
Incidence of ATA 
● 
Biomarkers of vadastuximab talirine activity 
● 
Quantification of T-, B-, and NK-cell lymphocyte subsets post-transplant 


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3 
INVESTIGATIONAL PLAN 
3.1 Summary of Study Design (Parts A and B) 
This is a phase 1/2, open-label study designed to evaluate the safety and efficacy of 
vadastuximab talirine in patients with relapsed chemo-resistant AML, for cytoreduction pre-
conditioning and post-alloSCT maintenance.  The study will consist of phase 1 (safety) 
followed by phase 2 (expansion) in each part of the study. Parts A and B will enroll 
concurrently.  Phase 2 will be initiated following dose level recommendation by the SMC 
with the determination of the MTD or recommended phase 2 doses for Parts A and B, and an 
evaluation of safety. 
At the discretion of the SMC, dose levels may be expanded in up to 12 patients in the phase 1 
portion of Parts A and B. 
An SMC consisting of the study medical monitor, investigators, and the study biostatistician 
will monitor the safety of patients treated with vadastuximab talirine on a regular basis 
throughout the study, including reviews of the data pertinent to dose-escalation decisions.  
Reviews of the aggregate safety data will be routinely initiated to evaluate any emerging 
safety signals with respect to cumulative toxicity.  The SMC may recommend investigation 
of an intermediate dose level during dose escalation.  Dose levels for expansion will be 
selected by the SMC based on known safety and activity data. 
All patients will be followed for survival status until 5 years after the last patient is enrolled, 
or until study closure, whichever occurs first. 
3.1.1 
Part A – Pre-AlloSCT 
One dose of vadastuximab talirine will be administered intravenously on Day −14 followed 
by reduced intensity chemotherapy (RIC) of melphalan and fludarabine on Days −5 to −2. 
Study days are relative to the day of alloSCT, which occurs on Day 0. 
Patients will be evaluated for response at Day 30 and every 3 months from transplant for 
1 year and then every 6 months until 3 years post-transplant (no longer required once disease 
progression is documented).  A schematic for Part A is presented below. 


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Figure 1: 
Part A Design 
 
a 
Response assessments every 3 months (±2 weeks) from transplant for the 1st year and then every 6 months (±2 weeks) 
until 3 years post-transplant (no longer required once disease progression is documented). 
b 
Long-term follow-up (consisting of a phone call for survival and collection of subsequent therapy information when a 
clinic visit is not required) will occur every month (±1 week) from transplant for the first 2 years, and then every 3 
months (±2 weeks) until death or study closure. 
 
Part A phase 1 of the study will be conducted using a standard 3+3 design starting at Dose 
Level 1.  Cohorts of 3 patients will be enrolled into each new cohort.  If 0 of 3 patients 
experience a DLT (defined in Section 3.1.1.1), the next dose level will be opened to 
enrollment.  If ≥2 of 3 patients in a cohort experience a DLT, the MTD will have been 
exceeded and dose escalation will stop.  If 1 of 3 patients in a cohort experiences a DLT, an 
additional 3 patients will be treated at that same dose level for a total of 6 patients.  If none of 
the 3 additional patients experiences a DLT (1 of 6 patients with a DLT), dose escalation will 
continue to the next higher dose level.  If 1 or more of the 3 additional patients experiences a 
DLT (≥2 of 6 patients with a DLT), the MTD will have been exceeded and dose escalation 
will not continue.  Patients who do not complete the DLT-evaluation period due to non-DLT 
reasons will be replaced.  Dose de-escalation from Dose Level 1 is permitted based on SMC 
recommendation; the planned doses for Part A are summarized in Table 1. 
Table 1:  
Part A dose levels 
Dose Level for Part A 
Part A Dose of Vadastuximab Talirine 
(mcg/kg) 
−1 
30 
1 
40 
2 
60 
3 
80 
4 
100 
 
Part A phase 2 will explore the activity and safety of vadastuximab talirine in 36 patients at a 
dose level, not to exceed MTD, recommended by the SMC.  An additional 36 patients may 
be enrolled in Part A phase 2 at a dose level also recommended by the SMC for further 
characterization of the safety and efficacy profile of vadastuximab talirine. 
3.1.1.1 Dose-Limiting Toxicity – Part A 
The DLT-evaluation period is from the time of vadastuximab talirine administration through 
30 days post-alloSCT.  DLTs in Part A will be defined as the following: 


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● 
Failure to achieve a sustained absolute neutrophil count of 500 by Day 30 (defined as 
the first of 3 consecutive days with an ANC of ≥500) in the absence of leukemia, 
infection, or acute graft-versus-host disease (GVHD). 
● 
Any Grade 3 toxicity within 30 days post-alloSCT according to the Bearman Toxicity 
Criteria (Bearman 1988) (see Appendix E). 
● 
The SMC will review any clinically significant non-hematologic AE ≥ Grade 3 that is 
considered related to vadastuximab talirine and/or vadastuximab talirine + 
fludarabine/melphalan conditioning,  and is not attributed to chemotherapy alone, for 
consideration as a DLT. Adverse events will be assessed according to the National 
Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) 
version 4.03. 
3.1.2 
Part B – Post-AlloSCT 
Patients in Part B of the study will begin treatment between 42 and 100 days post-alloSCT 
and will receive vadastuximab talirine on Day 1 of 42-day cycles for up to 8 cycles. Study 
days are relative to the first dose of vadastuximab talirine, which occurs on Day 1.  Patients 
who receive clinical benefit may continue treatment for an additional 8 cycles (up to a total 
of 16 cycles) with medical monitor approval. 
Response assessments will be every 3 months after the first dose of study drug for 2 years 
(every other cycle during treatment), and then every 6 months until 3 years post-transplant.  
Patients in Part B who discontinue study treatment prior to relapse will be evaluated for 
response until progression or initiation of new anticancer treatment, whichever comes first. 
The study scheme is presented as follows: 
Figure 2: 
Part B Design 
 
a 
For up to 12 months 
b 
Every 3 months (±2 weeks) for 2 years after dosing and every 6 months (±2 weeks) until 3 years post-transplant.  No 
are longer required after documentation of disease progression. 
c 
Long-term follow-up (consisting of a phone call for survival and collection of subsequent therapy information when a 
clinic visit is not required) will occur every 1 month (±1 week) for the first 2 years after receiving the first dose of 
study treatment, and then every 3 months (±2 weeks) until death or study closure. 
 


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The planned doses for Part B are summarized in Table 2. 
Table 2: 
Part B dose levels 
Dose Level for Part B 
Part B Dose of Vadastuximab Talirine 
(mcg/kg) 
−1 
5  
1 
10  
 
Six patients will be treated at Dose Level 1 beginning between 42 and 100 days post-
transplant.  Once these 6 patients have completed the DLT period, the sponsor, in 
consultation with the SMC, may decide to explore safety and activity in an additional 
6 patients. In the event of DLT (as defined below in Section 3.1.2.1) occurring in 2 or more 
patients in either the first or the second 6-patient cohort,  the sponsor, in consultation with the 
SMC, may choose to modify the schedule or dose level for further investigation. If fewer 
than 2 DLTs occur in either the first or second 6-patient cohorts, the sponsor will determine, 
in consultation with the SMC, the day when therapy may start and the recommended dose for 
further evaluation. 
Part B phase 2 will explore the activity and safety of vadastuximab talirine in 36 patients at a 
dose level recommended by the SMC. 
3.1.2.1 Dose-Limiting Toxicity – Part B 
The DLT-evaluation period is the first cycle of treatment. DLT will be defined as the 
following: 
● 
Any hematologic toxicity that delays the start of the second cycle more than 1 week 
will be considered a DLT. 
● 
The SMC will review any clinically significant non-hematologic AE ≥ Grade 3 that is 
considered related to vadastuximab talirine for consideration as a DLT. Adverse 
events will be assessed according to the NCI CTCAE version 4.03. 
3.1.3 
Study Stopping Criteria 
 
 
 
 
 
 
 
 
 
 
 


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3.1.3.1 Rationale for stopping criteria 
For AML patients in first remission, non-relapse mortality rates at 100 days post-transplant 
have ranged from 6% to 20%, many of which are caused by treatment-related toxicity, 
(Schmid 2005; Lim 2015). In contrast, the reported 100 day non-relapse mortality rates in 
patients who are not in CR at time of transplant ranges from 25%−62% (Wong 2005; Lim 
2015; Hamadani 2016), although limited data exist. Patients undergoing transplantation with 
active leukemia often have persistent cytopenias and are at higher risk for non-relapse 
mortality compared to patients transplanted in remission primarily due to their inability to 
recovery from the toxicities of prior chemotherapy (mucositis/colitis) and complications of 
prolonged bone marrow suppression. Given these considerations and as a conservative 
approach, an on-study toxic-death rate in excess of 20% at 100 days post-transplant is 
considered grounds to halt this study. 
The incidence of SOS or VOD of the liver has been reported to range from 11%−40% in 
AML patients undergoing allogeneic stem cell transplantation (Dalle 2016). Severe 
SOS/VOD, defined by Carreras et al. as death directly attributable to SOS/VOD or 
SOS/VOD not resolved on or after Day 100, occurs in approximately 40% of patients who 
develop SOS/VOD after receiving allogeneic transplant for malignancies or bone marrow 
failure syndromes (Carreras 2011).  Several risk factors have been reported to be associated 
with the development of SOS/VOD, such as the presence of advanced disease, a high red cell 
transfusion burden, and use of fludarabine in the transplant conditioning regimen, all of 
which can be commonly seen in our expected treated population.  Although fludarabine and 
melphalan (Flu/Mel) are conventionally considered a RIC regimen, the myelosuppressive 
nature of vadastuximab talirine compounds the effects of Flu/Mel thereby increasing the 
overall intensity of the regimen. In the phase 1 first in human study SGN33A-001, doses of 
50 mcg/kg or higher of vadastuximab talirine induced significant bone marrow suppression 
when used to treat patients with relapsed/refractory AML (Stein 2015). Therefore, the 
intensity of Flu/Mel/vadastuximab talirine should be considered closer to standard 
myeloablative conditioning rather than reduced intensity conditioning. Based upon the 


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totality of historical data and the aforementioned considerations, severe SOS/VOD occurring 
in greater than 10% of treated patients would be unacceptable compared to the anticipated 
rate. 
Acute GVHD (aGVHD) involving the liver, (either single or multi-organ) has been reported 
in 16% of patients receiving tacrolimus/methotrexate GVHD prophylaxis (Yagasaki 2009). 
Additionally, patients undergoing transplant with active AML are at increased risk for 
hepatic aGVHD of any grade, particularly with a trend suggesting increased the risk of 
developing Grade 3 or 4 aGVHD (Arai 2016; Araki 2016). Therefore, Stage 3 liver GVHD 
rate of 20% is an appropriate stopping criterion for this study. 
Failure of engraftment has been reported to occur in 5%–10% of patients undergoing 
transplantation for AML (Blaise 2007). Based on historical rates, graft failure is anticipated 
to occur in 10% of patients transplanted for relapsed/refractory AML (Duval 2010). Patients 
in this trial who undergo transplantation with heavily treated but still active disease are likely 
to be at higher risk of graft failure due to the additive effects of bone marrow infiltration by 
active leukemia and dysfunction secondary to previous treatment with intensive 
chemotherapy. Thus, a graft failure rate of more than 10% is above the expected rate and a 
reasonable stopping criterion for this study. 
3.2 Discussion and Rationale for Study Design 
The initial phase 1 portion of this study will evaluate the safety and tolerability of escalating 
doses of vadastuximab talirine administered as pre-cytoreduction prior to an alloSCT for 
patients with relapsed and/or refractory AML. The study will also assess the safety and 
tolerability of low doses of vadastuximab talirine post-transplant in relapsed/refractory 
patients who have achieved a complete remission following a transplant performed in the 
setting of active disease. Because there is limited experience with the use of vadastuximab 
talirine in the peri-transplant setting, the cohorts will be assessed independently to determine 
the safety and tolerability of vadastuximab talirine as a single high-dose infusion pre-
transplant and as repeated low-dose therapy in the post-transplant setting. 
In the Phase 2 portion of the study, the leukemia effect of vadastuximab talirine will also be 
assessed independently in both cohorts of patients  and the data acquired in this study will 
provide further information to guide the development of this agent in the treatment of AML. 
3.2.1 
Method of Assigning Patients to Treatment Groups 
Parts A and B will enroll concurrently.  Patients cannot be enrolled to both Part A and Part B. 
3.2.2 
Rationale for Selection of Doses 
A first in human phase 1 dose escalation study of vadastuximab talirine (SGN33A-001) 
administered IV every 3 weeks for no more than 4 cycles in patients with CD33-positive 
AML evaluated doses ranging from 5 to 60 mcg/kg.  For patients achieving a response (CR 
or CRi) vadastuximab talirine was administered at doses of 5 and 10 mcg/kg every 3 to 
6 weeks until disease recurrence or unacceptable toxicity.  In patients with active disease at 


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doses ≥50 mcg/kg, significant bone marrow suppression was observed resulting in prolonged 
pancytopenia.  It is postulated that in the setting of an alloSCT, doses >40 mcg/kg may be 
tolerable without incurring prolonged cytopenias due to engraftment of normal stem cells 
leading to timely restoration of hematopoiesis.  Therefore the starting dose for the pre-
transplant part of the study is 40 mcg/kg as a single infusion in combination with a reduced 
intensity conditioning regimen. For patients in Part B who have undergone an alloSCT for 
active disease and have achieved a CR or CRi the starting dose of the trial will be 10 mcg/kg 
administered every 6 weeks, a dose that has been well tolerated in patients treated on the 
initial phase 1 trial of vadastuximab talirine. 
3.2.3 
Blinding 
This is a phase 1/2, open-label study. 
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. Relapsed/refractory acute myeloid leukemia (AML), with the exception of acute 
promyelocytic leukemia (APL). 
● 
The following part-specific criteria: 
For Part A 
● 
Relapsed/refractory AML (>5% blasts) 
○ 
Patients who have received 2 or 3 previous induction regimens including at least 
one intensive chemotherapy regimen.  Patients who receive 2 cycles of therapy as 
part of their initial AML remission induction therapy will be considered as having 
undergone one induction regimen. 
○ 
Patients are eligible after only 1 previous induction regimen if one of the 
following apply: 
■ 
Age ≥60 years (but ≤75 years) 
■ 
First complete remission (CR) duration <6 months 
■ 
Adverse karyotype per Medical Research Council classification (Grimwade 
2001) 
■ 
Secondary AML (prior history of MDS or therapy-related) 
■ 
FLT3-ITD mutation 
 
● 
Availability of an HLA matched related or unrelated donor. 
● 
Eligible for an alloSCT according to institutional guidelines. 


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For Part B 
● 
Transplant (no donor type excluded) must have been performed with active AML 
(>5% blasts) using a conventional conditioning regimen and have achieved CR or 
CRi post-alloSCT (with ANC ≥1,000 and platelet ≥50,000 and platelet transfusion 
independent x1wk prior to dosing).  Documentation of CR or CRi is required within 
14 days of first dose of study treatment. 
● 
Treatment must begin at least 42 days, but no more than 100 days post-transplant. 
2. An Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 (see 
Appendix C). 
3. Age ≥18 and ≤75 years. 
4. The following baseline laboratory data: 
● 
Serum total bilirubin ≤2x upper limit of normal (ULN) or ≤3x ULN for patients with 
Gilbert’s disease. 
● 
Serum creatinine ≤2x ULN and calculated creatinine clearance ≥60 mL/min. 
● 
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3x ULN. 
5. Females of childbearing potential must have a negative serum or urine beta human 
chorionic gonadotropin (β-hCG) pregnancy test result within 7 days prior to the first dose 
of vadastuximab talirine and must agree to use two effective contraception methods 
during the study and for 6 months following the last dose of study drug.  Females of non-
childbearing potential are those who are postmenopausal greater than 1 year or who have 
had a bilateral tubal ligation or hysterectomy. 
6. Males who have partners of childbearing potential must agree to use two effective 
contraceptive methods during the study and for 6 months following the last dose of study 
drug. 
7. Patients must provide written informed consent. 
8. Left ventricular ejection fraction at rest ≥45%. 
9. Diffusing capacity of the lungs for carbon monoxide (DLCO; corrected for hemoglobin), 
forced expiratory volume in 1 second (FEV1), and forced vital capacity (FVC) greater 
than 50% of predicted 
4.2 Exclusion Criteria 
1. Central nervous system leukemia strongly suspected based on altered neurologic status or 
documented by positive cytology in cerebral spinal fluid.  Intrathecal CNS prophylaxis is 
allowed. 
2. Patients may not have received vadastuximab talirine previously. 


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3. Any uncontrolled Grade 3 or higher (per NCI CTCAE, Version 4.03) viral, bacterial, or 
fungal infection ongoing prior to the first dose of any component of study treatment.  
Antimicrobial prophylaxis or ongoing treatment of resolving/controlled infection is 
permitted. 
4. Documented history of a cerebral vascular event (stroke or transient ischemic attack), 
unstable angina, myocardial infarction, or cardiac symptoms consistent with New York 
Heart Association Class III-IV within 6 months prior to the first dose of any component 
of study treatment (see Appendix D). 
5. Any known history of Hepatitis B (HBSAg positive), Hepatitis C, or HIV. 
6. Current therapy (defined as within 14 days prior to first dose of vadastuximab talirine) 
with other systemic antineoplastic, immunosuppressive (except for GVHD 
treatment/prophylaxis in Part B), or investigational agents, other than as described in 
Section 5.10.2, Allowed Concomitant Therapy.  For Part A, hydroxyurea or 6-
mercaptopurine used for cytoreduction may be given up to 1 day prior to treatment. 
7. Known hypersensitivity to excipients contained in the drug formulations of vadastuximab 
talirine, fludarabine, melphalan, tacrolimus, or methotrexate. 
8. Females who are breastfeeding. 
9. Any of the following: 
● 
History of another primary invasive malignancy that has not been in remission for at 
least 3 years.  The following are exempt from the 3-year limit: curatively treated non-
melanoma skin cancer; curatively treated, localized prostate cancer; and low grade 
prostate cancer suitable for active surveillance; locally treated, localized cervical 
cancer. 
● 
Any history of metastatic malignancy. 
10. For Part A 
● 
Partially matched related and unrelated donors, cord blood cells are excluded as the 
source of hematopoietic stem cells. 
● 
Prior alloSCT 
11. For Part B 
● 
Active GVHD Grade 2 or higher 
● 
History of Grade 2 or higher hepatic GVHD 
● 
Concurrent use of corticosteroids equivalent of prednisone at a dose of >0.5 mg/kg 
● 
History of veno-occlusive disease (VOD) requiring defibrotide 


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4.3 Removal of Patients from Therapy or Assessment 
Seattle Genetics or their designee must be notified if a patient is withdrawn from study 
treatment or from the study.  The reason(s) for withdrawal must be documented in the 
patient’s medical records and case report form (CRF). 
4.3.1 
Discontinuation of Study Drug 
A patient’s treatment with study drug may be discontinued for any of the following reasons: 
● 
Completed treatment 
● 
Leukemic relapse/progression 
● 
Adverse event (AE) 
● 
Investigator decision 
● 
Patient decision, Non-AE 
● 
Study termination by sponsor 
● 
Other, Non-AE 
4.3.2 
Patient Withdrawal from Study 
Any patient may be discontinued from the study for any of the following reasons: 
● 
Completed study per protocol 
● 
Patient withdrawal of consent 
● 
Study termination by sponsor 
● 
Lost to follow-up 
● 
Death 
● 
Other 
5 
TREATMENTS 
5.1 Treatments Administered 
Vadastuximab talirine (SGN-CD33A) will be administered IV push without routine 
premedication. 
● 
Part A:  administered on Day –14 (dose levels starting at 40 mcg/kg; see Table 1) 
● 
Part B:  administered on Day 1 of 42-day cycles at either 5 or 10 mcg/kg; see Table 2 
Part A only – (pre-allo SCT) 
Reduced Intensity Conditioning Regimen 
● 
Fludarabine 30 mg/m2/day IV on Day −5 to Day −2 (total dose of 120 mg/m2) 
● 
Melphalan 140 mg/m2 IV on Day −2 
GVHD prophylaxis 


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● 
Tacrolimus 0.03 mg/kg/day IV/PO (initial dose Day –1 strongly preferred; starting 
day may follow institutional practice if approved by the study medical monitor); 
subsequent doses IV or oral target blood trough levels 5−15 ng/mL. 
● 
Methotrexate 5−10 mg/m2 IV on Day 1 and 5 mg/m2 IV on Days 3, 6, and 11 post-
transplant 
5.2 Investigational Study Drug 
Detailed information describing the preparation, administration, and storage of vadastuximab 
talirine (SGN-CD33A) is located in the Pharmacy Binder. 
5.2.1 
Description 
Vadastuximab talirine is a sterile, preservative-free, lyophilized cake or powder for 
reconstitution for IV administration.  Vadastuximab talirine is supplied by Seattle Genetics in 
single-use amber glass vials.  Drug product vial contains vadastuximab talirine, 
 
  Drug product vials are labeled with a nominal content of 
5 mg/vial.  Each vial contains 6 mg of vadastuximab talirine to ensure the labeled quantity 
(5 mg/vial) may be withdrawn for use. 
5.2.2 
Dose and Administration 
Dosing is based on patient actual body weight (to the nearest tenth of a kilogram) assessed 
within 3 days of each cycle.  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. 
Administration of vadastuximab talirine will be performed via IV push.  It is recommended 
that vadastuximab talirine is administered via central venous access port (e.g., peripherally 
inserted central catheter [PICC], Hickman line, or similar according to institutional standard).  
However, if SGN-CD33A is not administered via central venous access port, a secure and 
free-flowing peripheral line must be used.  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). 
A sterile 0.2 µm filter must be used in the administration of SGN-CD33A.  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.  See the Pharmacy 
Binder for details. 
5.2.3 
Fludarabine/Melphalan/Tacrolimus/Methotrexate 
Fludarabine 
Fludarabine alone and in combination with other anticancer agents is indicated for the 
treatment of various lymphoproliferative disorders including chronic lymphocytic leukemia 
and indolent non-Hodgkin lymphomas.  Because of its immunosuppressive effects it is also 
used in conditioning regimens prior to an alloSCT. Fludarabine for intravenous injection 


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contains a sterile lyophilized fludarabine cake which is freely soluble in water. Fludarabine is 
a fluorinated nucleotide analog that is relatively resistant to deamination by adenosine 
deaminase. 
Melphalan 
Melphalan alone and in combination is indicated in the treatment of multiple malignancies 
including multiple myeloma, ovarian and breast cancer.  Because of its myelosuppressive 
properties it is also used in conditioning regimens prior to allogeneic and autologous stem 
cell transplant. Melphalan for injection contains a sterile nonpyrogenic freeze-dried powder 
which is reconstituted with a sterile diluent containing sodium citrate, propylene glycol, 
ethanol and water. Melphalan is a bifunctional alkylating agent which enables covalent 
binding to DNA, cross-linking two DNA strands thereby preventing cell replication. 
Tacrolimus 
Tacrolimus is an immunosuppressive agent that is indicated for prevention of graft rejection 
in patients undergoing solid organ transplantation. It is also used routinely for the prevention 
of GVHD in patients undergoing allogeneic hematopoietic stem cell transplantation.  
Tacrolimus, available in both oral (0.5, 1 and 5 mg capsules) and IV (crystalline powder 
freely soluble in methanol and chloroform) formulations is a calcineurin inhibitor which 
blocks T-lymphocyte activation. 
Methotrexate 
Methotrexate is indicated for the treatment of various malignancies as well as autoimmune 
disorders. It is also commonly used as part of an immunosuppressive regimen for the 
prevention of GVHD in patients undergoing allogeneic hematopoietic stem cell 
transplantation.  Methotrexate for injection is available as a lyophilized powder that is 
reconstituted with sterile water.  It competitively inhibits dihydrofolate reductase resulting in 
the reduction of folic acid production which is essential for DNA, RNA, and protein 
synthesis. 
5.3 Management of Infusion Reactions 
Infusion-related reactions may occur during the infusion of vadastuximab talirine.  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 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 SGN-CD33A 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. 
5.4 Management of Tumor Lysis Syndrome 
Tumor lysis syndrome (TLS) prophylaxis is strongly recommended in patients with 
measurable AML.  Hydration and effective urine ﬂow rates remain a cornerstone of TLS 
prevention and treatment and should be employed as per institutional standards, in addition to 
medications to prevent or treat hyperuricemia (e.g., allopurinol, rasburicase). 
Patients must be monitored for TLS according to the institutional standard.  Recommended 
monitoring measures include frequent assessment of electrolyte levels and cardiac function 
for the first 48–72 hours following study drug administration.  Additionally, it is 
recommended that patients are monitored for signs and symptoms of fluid volume overload, 
such as peripheral edema, neck vein distension, weight gain, and pulmonary crackles, as well 
as signs and symptoms of fluid volume deficit, such as dry mucous membranes, poor skin 
turgor, weight loss, and thirst.  The use of physical assessment, strict intake and output, daily 
weights, and lab work results to monitor renal function are recommended measures to 
monitor for TLS. 
In the event of TLS, immediate treatment must be administered according to the institutional 
standard, including hydration, administration of xanthine oxidase inhibitors or recombinant 
uricase, supportive care for electrolyte disturbances, and hemodialysis or hemofiltration if 
required. 
5.5 Dose Modifications for Part B 
Patients who experience events that meet the criteria for DLT (defined in Section 3.1.2.1) at 
any time in the study must permanently discontinue vadastuximab talirine, unless the 
investigator and medical monitor agree that the patient may receive a lower dose of 
vadastuximab talirine. 
After the DLT evaluation period, treatment delays are permitted for hematological adverse 
events at the discretion of the investigator to allow for recovery of platelets and neutrophils. 
If toxicity is not recovered within 42 days after prior cycle, consideration can be given to 
either resume with dose reduction by one level, or discontinue vadastuximab talirine. 
Additional dose modifications for toxicity are applicable for Cycle 2 and beyond of Part B. 
These modifications are presented in Table 3. The dose modifications provided below should 
serve as guidance; alternative approaches may be discussed with the medical monitor. 
Individual dose decreases are permitted at the discretion of the medical monitor and site 
investigator.  Intrapatient dose escalation is not permitted. Cycles may only be administered 
with a platelet count of ≥50,000 and an ANC of ≥1000. 


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Table 3: 
Recommended dose modifications for vadastuximab talirine-associated 
non-hematological toxicity 
Toxicity 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Non-hematologic  
Continue at same 
level 
Continue at same 
level 
Withhold dose until 
toxicity is ≤ Grade 2 
or baseline, then 
resume treatment at 
the same dose levela,b 
Withhold dose until 
toxicity is ≤ Grade 2 
or baseline, then 
resume treatment, or 
discontinue at the 
discretion of the 
investigatora 
a 
Patients with Grade 3 or 4 electrolyte abnormalities may continue study treatment without interruption. 
b 
Treatment should be discontinued for patients who experience Grade 3 infusion-related reactions, unless otherwise 
discussed with medical monitor. For a second occurrence, reduce by one dose level. 
 
If vadastuximab talirine is permanently discontinued, patients will be considered off study 
treatment. 
5.6 Storage and Handling 
Single-use amber vials containing vadastuximab talirine must be stored under refrigeration at 
2 to 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 to 8°C, protected from light.  However, vadastuximab talirine 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 to 
8°C.  If dilution is needed, the reconstituted drug product should be diluted in 0.9% Sodium 
Chloride Injection, USP, at the time of use.  The prepared dosing solution (reconstituted 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 vadastuximab talirine. 
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. 
Refer to Section 5.2.3 and the fludarabine, melphalan, tacrolimus, and methotrexate package 
inserts for appropriate storage and handling instructions. 


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5.7 Packaging and Labeling 
Vadastuximab talirine is supplied in an amber glass vial to protect from light.  The drug 
product vials are labeled as SGN-CD33A for injection (h2H12ec-SGD-1910) 5 mg/vial. 
Refer to Section 5.2.3 and the fludarabine, melphalan, tacrolimus, and methotrexate package 
inserts for packaging and labeling information. 
5.8 Preparation 
Recommended safety measures for handling and preparation include masks, protective 
clothing, gloves (double glove with nitrile gloves), and vertical laminar airflow safety 
cabinets. 
Before administration, vadastuximab talirine must be reconstituted.  The reconstituted drug 
product may be further diluted depending on the dose level.  Diluted solutions of 
vadastuximab talirine are stable at concentrations ≥0.6 mg/mL and ≤3 mg/mL.  The 
formulation contains no preservative and is intended for single use only; solutions should be 
prepared and transferred using aseptic technique in a biosafety hood. 
Detailed drug preparation instructions are provided in the Pharmacy Binder. 
Preparation of fludarabine, melphalan, tacrolimus and methotrexate should be according to 
the appropriate package insert and in adherence to institutional standards. 
5.9 Required Premedication and Postmedication 
None. 
5.10 Concomitant Therapy 
All concomitant medications and blood products administered will be recorded from time of 
first dose of vadastuximab talirine administration 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. 
5.10.1 Required Concomitant Therapy 
None. 
5.10.2 Allowed Concomitant Therapy 
Routine premedication for infusion reactions should not be administered prior to the first 
dose of vadastuximab talirine.  However, patients who experience an infusion-related 
reaction (with the exception of anaphylaxis) may receive subsequent treatment with 
premedication as described in Section 5.3. 
Donor lymphocyte infusion (DLI) or stem cell boost can be used to treat decreasing 
engraftment. 
Defibrotide is permitted for the treatment of VOD 


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For Part B, immunosuppressive agents are allowed for prophylaxis against and treatment of 
GVHD. 
Antimicrobial prophylaxis measures are strongly recommended, per institutional standard of 
care.  Antiemetics should be used per institutional standard. 
Prophylactic treatment/measures are strongly recommended for patients at risk for TLS, per 
the institutional standard [e.g., treatment with allopurinol or rasburicase, as well as adequate 
hydration (Coiffier 2008)]. 
The use of red blood cell (RBC) and platelet transfusions, and/or colony-stimulating factors 
per institutional practice is permitted.  Intrathecal prophylactic treatment for patients at risk 
for cerebral/meningeal disease is permitted at the discretion of the investigator. 
5.10.3 Prohibited Concomitant Therapy 
Patients may not receive other investigational drugs, radiotherapy, or systemic antineoplastic 
therapy prior to the end of the treatment visit. 
DLI is not permitted as a treatment for a loss of MRD negativity or a loss of molecular 
response. 
Treatment with sirolimus is not permitted in Part A. 
5.11 Treatment Compliance 
Study drug administration will be performed by study site staff and documented in source 
documents and the CRF. 
6 
STUDY ACTIVITIES 
Adverse events and concomitant medications will be recorded from Day –14 for Part A 
(Pre-alloSCT) and from Day 1 for Part B (Post-alloSCT) through the safety reporting period 
(see Section 7.6.2.3).  Any study protocol-related adverse event should be recorded from the 
time of informed consent as well as any concomitant medications given for treatment of the 
adverse event.  A schedule of events is provided in Appendix A for Part A and in Appendix 
B for Part B.  Study activities are listed by visit in this section and descriptions of all study 
assessments are presented in Section 7. 
6.1 Part A – pre-AlloSCT (Days relative to transplant Day 0) 
6.1.1 
Screening Period (Days –44 to –14) 
● 
Informed consent 
● 
Study eligibility per inclusion/exclusion criteria 
● 
Medical history 
● 
Procedures to assess transplant eligibility (does not need to be repeated if performed 
within 42 days of enrollment): 
○ 
Urine creatinine clearance 


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○ 
Spot urine for protein and creatinine 
○ 
HCT-specific comorbidity index. The HCT Comorbidity Index Calculator, 
www.hctci.org/Home/Calculator. Accessed August 25, 2015. 
○ 
ECHO/MUGA 
○ 
DLCO and FEV1 
○ 
CMV antibody test, hepatitis panel (Hep A Ab, HepB Sab, HepB Sag, HepB Core 
Ab, HepC Ab), herpes simplex, HIV and HTLV1 I/II antibody and varicella 
zoster virus 
6.1.2 
Day –28 to Day –14 
● 
Bone marrow examination 
● 
Biomarker sample collection (see Table 4 and Table 5) 
6.1.3 
Day –21 to Day –14 
● 
Physical exam with weight 
● 
Serum chemistry panel 
● 
Complete blood count (CBC) with differential 
● 
ECOG performance status 
● 
β-hCG pregnancy test for females of childbearing potential 
6.1.4 
Day –14 
● 
Physical exam with weight (not required if conducted within prior 24 hours) 
● 
Serum chemistry panel (not required if conducted within prior 24 hours) 
● 
CBC with differential (not required if conducted within prior 24 hours) 
● 
Vadastuximab talirine administration 
● 
ECOG performance status 
● 
Blood samples for PK, ATA, and biomarkers (see Table 4) 
6.1.5 
Day –13 
● 
Blood samples for PK (see Table 4) 
6.1.6 
Day –11 
● 
Blood samples for PK and biomarkers (see Table 4) 
6.1.7 
Day –7 
● 
Serum chemistry panel 
● 
CBC with differential 
● 
Spot urine for protein and creatinine 
● 
Blood samples for PK and biomarkers (see Table 4) 
6.1.8 
Day –5 to –2 
● 
Fludarabine 30 mg/m2/day IV on Day –5 to Day –2 (total dose of 120 mg/m2) 


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● 
Melphalan 140 mg/m2 IV on Day –2 
6.1.9 
Day –1 
● 
Bone marrow aspirate for MRD and PK (see Table 5) 
● 
Blood samples for PK, ATA, and biomarkers (see Table 4) 
● 
Start tacrolimus 0.03 mg/kg/day IV (subsequent oral or IV doses target blood trough 
levels 5–15 ng/mL) 
6.1.10 Day 0 
● 
Serum chemistry panel 
● 
CBC with differential 
● 
AlloSCT 
6.1.11 Day 1 
● 
Methotrexate 5–10 mg/m2 (and subsequent doses at 5 mg/m2 IV on Days 3, 6, and 
11 post-transplant). 
6.1.12 Days 7, 14, and 21 
● 
Serum chemistry panel 
● 
CBC with differential 
6.1.13 Day 30 (±2 days) 
● 
Serum chemistry panel 
● 
CBC with differential 
● 
Blood samples for biomarkers (see Table 4) 
● 
Spot urine for protein and creatinine 
● 
BM aspirate for MRD and biomarkers (see Table 5) 
● 
BM examination for response assessment 
● 
Chimerism assay per institutional guidelines and schedule 
● 
GVHD assessments 
6.1.14 End of Treatment Visit (30 to 37 days post-transplant) 
End of Treatment (EOT) visits should occur 30 to 37 days post-transplant.  However, EOT 
evaluations must be performed before initiation of a new therapy.  If EOT evaluations are 
completed before 30 days post-transplant, the patient will be contacted 30 to 37 days 
following transplant to assess for adverse events. 
● 
Physical exam (does not need to be repeated if done within 7 days prior) 
● 
Serum chemistry panel (does not need to be repeated if done within 7 days prior) 
● 
CBC with differential (does not need to be repeated if done within 7 days prior) 
● 
Pregnancy test 
● 
ECOG performance status 


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6.1.15 Long-Term Follow-Up 
In the absence of disease progression, the following assessments should be obtained every 
3 months (±2 weeks) from transplant for the first year and then every 6 months (±2 weeks) 
until 3 years post-transplant: 
● 
If a response assessment is conducted per site standard, sites should report the 
assessment results to the sponsor  
● 
GVHD assessment, if conducted per site standard 
 
The above assessments are no longer required once disease progression is documented. 
Long-term follow-up (consisting of a phone call for survival and collection of subsequent 
therapy information when a clinic visit is not required) will occur every month (±1 week) 
from transplant for the first 2 years, and then every 3 months (±2 weeks) until death or study 
closure. Events of SOS/VOD that occur within 180 days of the last dose of vadastuximab 
talirine will be reported to the sponsor, regardless of causality. Patients who undergo 
subsequent allo-SCT within 180 days of the last dose of vadastuximab talirine in the absence 
of relapse and additional therapy will be followed for SOS/VOD for 100 days post-transplant 
(Section  7.6.2.4 Adverse Events of Special Interest). 
6.2 Part B – post alloSCT (Days relative to the first dose of vadastuximab 
talirine on Day 1) 
6.2.1 
Screening Visit (Days –28 to 1) 
● 
Informed consent 
● 
Study eligibility per inclusion/exclusion criteria 
● 
Medical history 
● 
GVHD assessments 
6.2.2 
Baseline Visit (Day –14 to 1) 
● 
BM examination 
● 
Bone marrow aspirate for MRD 
● 
Biomarker sample collection (see Table 6) 
6.2.3 
Day –7 to 1 
● 
Physical exam with weight 
● 
β-hCG pregnancy test for females of childbearing potential 
● 
ECOG performance status 
● 
Serum chemistry panel 
● 
CBC with differential 
● 
Spot urine for protein and creatinine 


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6.2.4 
Day 1 
● 
Physical exam with weight (not required if conducted within prior 24 hours) 
● 
Serum chemistry panel (not required if conducted within prior 24 hours) 
● 
CBC with differential (not required if conducted within prior 24 hours) 
● 
Vadastuximab talirine administration 
● 
Blood samples for PK, ATA, and biomarker assessments (see Table 6) (on Day 1 of 
Cycles 1, 2, 3, 5 and 7) 
● 
Bone marrow aspirate for MRD and biomarker assessments (Day 1 of Cycle 3 and 
every 2 cycles while on treatment) 
● 
GVHD assessments (on Day 1 of all cycles) 
● 
Bone marrow examination (Day 1 of Cycle 3 and every 2 cycles while on treatment) 
6.2.5 
Day 2 (Cycle 1 only) 
● 
Blood samples for PK (see Table 6) 
6.2.6 
Day 4 (Cycle 1 only) 
● 
Blood samples for PK (see Table 6) 
6.2.7 
Day 8, 15, 22, and 28 (Cycle 1 only, ±1 day) 
● 
Serum chemistry panel 
● 
CBC with differential 
6.2.8 
Day 42 (Cycle 1 only) 
The following assessments are not required if ANC recovers ≥1000 and platelets recover to 
≥50,000: 
● 
Serum chemistry panel 
● 
CBC with differential 
6.2.9 
End of Treatment Visit (42 to 49 days after last dose of study drug) 
If any of the following evaluations have already been performed, they do not need to be 
repeated.  If any of the following samples have not been obtained, collection is not required 
(Amendment 3). 
End of Treatment (EOT) visits should occur 42 to 49 days following the last dose of study 
drug.  However, EOT evaluations must be performed before initiation of a new therapy.  If 
EOT evaluations are completed before 42 days after the last study treatment, the patient will 
be contacted 42 to 49 days following the last treatment to assess for AEs. 
● 
Serum chemistry panel 
● 
CBC with differential 
● 
Spot urine for protein and creatinine 
● 
Blood samples for PK, ATA, and biomarker assessments (see Table 6) 


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● 
Bone marrow aspirate for MRD and biomarker assessments (see Table 6) 
● 
BM examination (if not performed within 42 days prior) 
● 
Pregnancy test 
● 
GVHD assessments 
● 
ECOG performance status 
6.2.10 Long-Term Follow-up 
In the absence of disease progression, the following assessments should be obtained every 
3 months (±2 weeks) for the first 2 years after receiving the first dose of study treatment and 
then every 6 months (±2 weeks) until 3 years post-transplant. 
● 
If a response assessment is conducted per site standard, sites should report the 
assessment results to the sponsor  
● 
GVHD assessment, if conducted per site standard 
 
The above assessments are no longer required once disease progression is documented. 
Long-term follow-up (consisting of a phone call for survival and collection of subsequent 
therapy information when a clinic visit is not required) will occur every 1 month (±1 week) 
for the first 2 years after receiving the first dose of study treatment, and then every 3 months 
(±2 weeks) until death or study closure. Events of SOS/VOD that occur within 180 days of 
the last dose of vadastuximab talirine will be reported to the sponsor, regardless of causality. 
Patients who undergo subsequent allo-SCT within 180 days of the last dose of vadastuximab 
talirine in the absence of relapse and additional therapy will be followed for SOS/VOD for 
100 days post-transplant (Section  7.6.2.4 Adverse Events of Special Interest).  
7 
STUDY ASSESSMENTS 
7.1 Screening/Baseline Assessments 
Only patients who meet all inclusion and exclusion criteria specified in Section 4 will be 
enrolled in this study. 
Patient medical history includes a thorough review of significant past medical history, 
current conditions, any treatment for prior malignancies and response to prior treatment, and 
any concomitant medications. 
7.2 Response/Efficacy Assessments 
Treatment response will be assessed by pathology review of bone marrow aspirate/biopsy 
and flow cytometry analysis of the number of blasts in bone marrow at protocol-specified 
time points (Section 6, Appendix A, Appendix B). Institutional standard frequency is 
sufficient for response status assessment in long-term follow up. 
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. 


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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).  The 
category of CR with incomplete platelet recovery (CRp), which has been reported in prior 
AML trials, will be combined with CRi. 
MRD will be assessed at a central laboratory by multiparametric flow cytometry of bone 
marrow samples obtained as described in Table 4, Table 5, and Table 6 and in the Research 
Specimen Manual (Walter 2011). 
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 and ATA Assessments 
Blood samples for PK and ATA assessment will be collected at the time points outlined in 
Table 4, Table 5, and Table 6. 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 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. 
7.4 Biomarker Studies 
Sampling timepoints are listed in Table 4, Table 5, and Table 6. 
Peripheral blood and bone marrow aspirates will be collected at the time points outlined in 
Table 4, Table 5, and Table 6.  Biomarker assessments may include CD33 expression level 
and saturation by vadastuximab talirine on CD33+ cells, cytogenetic abnormalities and/or 
mutation of genes with known prognostic significance for AML, soluble CD33, lymphocyte 
subset recovery post-transplant, and evaluation of MRD at protocol specified time points. 
 


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Table 4: 
Part A pharmacokinetic, ATA, and biomarker time points for blood 
Cycle 
Study Day 
Time 
Window 
PK 
ATA 
sCD33 & 
Research 
CD33 RO & 
Expression 
Lymphocyte Subset 
Recovery (TBNK)B 
Research 
Pre-allo 
Day –28 to −14 
Baseline 
NA 
X 
Day –14 
Pre-dose 
Within 24 hr prior to 
vadastuximab talirine 
dose 
X 
X 
X 
X 
 
 
End of IV flush 
Within 15 min 
X 
X 
2 h 
± 15 min 
X 
6 h 
± 2 hr 
X 
X 
Day –13 
24 h 
± 4 hr 
X 
Day –11 
72 h 
± 4 hr 
X 
X 
Day –7 
168 h 
± 24 hr 
X 
X 
X 
Day –1 
312 h 
Up to 24 hr pre-
transplant 
X 
X 
X 
 
 
 
Day 30 
 
(±2days) 
X 
X 
Long-term follow up  
Every 3 mos A 
±2 weeks 
A 
Every 3 months (±2 weeks) for the first year from transplant; subsequently, every 6 months (±2 weeks) until 3 years post-transplant. No longer required once progression is documented. 
B 
Collected for local laboratory assessment. Window ±3 days. 
 
 
Table 5: 
Part A pharmacokinetic and biomarker time points for bone marrow 
Cycle 
Study Day 
Window 
Aspirate, MRD 
Aspirate, CD33 
Expression 
Aspirate for Research  
Aspirate for PK & 
sCD33 
Pre-allo 
Day –28 to −14 
Baseline 
 
X 
X 
X 
Day –1 
Up to 24 hr pre-transplant 
X 
 
 
XC 
Day 30 
(±2days) 
X 
 
X 
 
Long-term follow up 
Every 3 mosA, B 
 
 
 
 
A 
Every 3 months (±2 weeks) for the first year from transplant; subsequently, every 6 months (±2 weeks) until 3 years post-transplant. No longer required once progression is documented. 
B 
Submit sample for assessment upon disease progression and whenever bone marrow examination is conducted. 
C 
Sample only required for PK 
 


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Table 6: 
Part B pharmacokinetic, ATA, and biomarker time points for blood and bone marrow 
Sample Origin 
 
 
 
Blood 
Bone marrow 
Cycle 
Study Day 
Time 
Window 
PK 
ATA 
sCD33 & 
Research 
CD33 RO & 
Expression 
Lymphocyte 
Subset Recovery 
(TBNK)D  
MRD 
Research 
NA 
Baseline 
D −14 to 1 
X 
X 
1 
Day 1 
Pre-dose 
Within 24 hr prior 
to vadastuximab 
talirine dose 
X 
X 
X 
X 
X 
  
 
End of IV 
flush 
Within 15 min 
X 
 
 
  
 
 
 
2 h 
±15 min 
X 
 
6 h 
±2 hr 
X 
 
Day 2 
24 h 
±4 hr 
X 
 
Day 4 
72 h 
±4 hr 
X 
 
2 
Day 1 
Pre-dose 
Within 8 hr prior 
to vadastuximab 
talirine dose 
X 
X 
X 
 
X 
 
 
End of IV 
flush 
Within 15 min 
X 
 
 
 
 
 
 
3+ 
Day 1 
Pre-dose 
±2 weeks  
 
 
 
XB, C 
XB, C 
Within 8 hr prior 
to vadastuximab 
talirine dose 
 
XA 
XA 
 
XA 
 
 
End of IV 
flush 
Within 15 min 
XA  
 
 
 
 
 
 
EOT 
 
 
42 to 49 days 
post-study 
treatment 
X 
X 
X 
X 
X 
XC 
XC 
LTFU 
 
Every 3 
months 
±2 weeks 
 
 
 
 
 
 
 
A 
Day 1 of Cycle 3 and every 2 cycles while on treatment. 
B 
Every 3 months (±2 weeks) for the first 2 years after receiving the first dose of study treatment (Day 1 of Cycle 3 and every other cycle thereafter while on treatment) and then every 6 months (±2 weeks) 
until 3 years post-transplant.  No longer required after disease progression is documented. 
C 
Submit sample for assessment upon disease relapse and whenever a bone marrow examination is conducted. 
D 
Collected for local laboratory assessment. Window ±3 days . 
 


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7.4.1 
CD33 Expression and Saturation 
Total CD33 expression level will be assessed in peripheral blood and bone marrow blasts 
obtained throughout the study using flow cytometry analysis at a central laboratory, as will 
detection of free CD33 on the surface of leukemic blasts, (i.e., unoccupied by vadastuximab 
talirine).  Samples will be obtained at the time points specified in Table 4, Table 5, Table 6, 
and in the Research Specimen Manual. All samples will be assessed at a central laboratory 
using flow cytometry analysis. 
7.4.2 
Lymphocyte Subset Recovery 
Recovery of T-, B- and NK-cell lymphocyte subsets post-transplant will be monitored in 
peripheral blood by the local laboratory according to institutional standard. 
7.4.3 
Cytogenetics and Gene Mutations 
Cytogenetic abnormalities and/or mutation of genes with known prognostic significance for 
AML (e.g., NPM1, FLT3, WT1, and MLL), will be assessed by a local laboratory and 
correlated with the vadastuximab talirine treatment outcome. 
Local laboratory assessment of cytogenetics and gene mutation will be conducted according 
to the institutional standard.  Cytogenetic risk groups will be categorized according to the 
Medical Research Council classification (Grimwade 1998), and according to European 
LeukemiaNet  (Dohner 2010).  Scanned copies or photocopies of all available source 
documentation for each assessment will be submitted to the sponsor. Any additional 
mutational data obtained beyond those required for risk categorization will be included in 
this report. 
7.5 Biospecimen Repository 
For patients who provide additional consent, remaining de-identified unused blood and/or 
tissue will be retained by Seattle Genetics and used for future research, including but not 
limited to the evaluation of targets for novel therapeutic agents, the biology of ADC 
sensitivity and resistance mechanisms, and to identify biomarkers of ADCs.  Blood and 
tissue samples donated for future research will be retained for a period of up to 25 years.  If 
additional consent is not provided, any remaining biological samples will be destroyed 
following study completion. 
7.6 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 SMC as described in Section 3.1. 


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7.6.1 
GVHD Assessments 
For patients in Part A, GVHD assessment will be performed at Day 30, 3, 6, and 12 months 
post-transplant, and every 6 months thereafter (see Section 6.1 and Appendix A). 
For patients in Part B, a history and physical exam to assess GVHD will be performed at 
baseline prior to the start of treatment with vadastuximab talirine, and on Day 1 of every 
cycle (see Section 6.2 and Appendix B). 
GVHD evaluation and grading will be performed according to the GVHD Target Organ 
Staging (Harris 2016); refer to Appendix F. 
7.6.2 
Adverse Events 
7.6.2.1 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 CRF: 
● 
From the time of informed consent prior to the first dose of vadastuximab talirine 
[Part A: D −14 and Part B: D1], 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 at time of first study drug dose [Part A: 
D −14 and Part B: D1] should be recorded. 
● 
All AEs (regardless of relationship to study drug) should be recorded from the first 
dose of vadastuximab talirine [Part A: D −14 and Part B: D1] (during and postdose) 
through the end of the safety reporting period (see Section 7.6.2.3).  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 SAE, 
or results in study termination or interruption/discontinuation of study treatment.  
When recording an AE resulting from a laboratory abnormality, the resulting medical 


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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 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). 
Relationship of the Adverse Event to Study Treatment 
The relationship of each AE to each study treatment (vadastuximab talirine, fludarabine, 
melphalan, tacrolimus, or methotrexate) 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) 


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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 
7.6.2.2 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.’  
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. 


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● 
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 7.6.2.1) should be reported as SAEs. 
7.6.2.3 Reporting Periods for Adverse Events and Serious Adverse Events 
Part A: The safety reporting period for all AEs and SAEs is from study Day –14 (predose) 
through Day 30 or the EOT visit after the last study treatment, whichever is later; although, 
all study protocol-related AEs are to be collected from the time of informed consent. SAEs 
and events of special interest that occur from Day 31 to Day 100, regardless of relation to 
study drug, should be reported to the sponsor immediately.  Events of special interest are 
those that meet the following criteria: 
● 
Any pulmonary event not related to infection with interstitial changes requiring 
mechanical ventilation 
● 
Any renal event requiring dialysis, nephrostomy or surgical procedure 
● 
Severe hepatic dysfunction (including SOS/VOD and hepatic acute Graft vs Host 
Disease); see Section 7.6.2.4  


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● 
Sudden cardiac death, fatal myocardial infarction, heart failure unresponsive to 
medical management 
● 
Sepsis and septic shock 
 
Events of special interest considered by the investigator to be study drug related will be 
expedited. All SAEs that occur after the safety reporting period and are considered related to 
study treatment in the opinion of the investigator should also be reported to the sponsor. 
Deaths occurring up to Day 100 post-transplant, regardless of causality or relation to study 
drug, should be reported to the sponsor immediately. 
Part B: The safety reporting period for all AEs and SAEs is from study Day 1 (predose) 
through the EOT visit or Day 42 after the last study treatment, whichever is later; although, 
all study protocol-related AEs are to be collected from the time of informed consent. All 
SAEs occurring after the safety reporting period that are considered study treatment related 
in the opinion of the investigator should be reported to the sponsor. Events of special interest 
(as listed above) occurring after the safety reporting period up to Day 100 post-transplant, 
regardless of relation, should be reported to the sponsor immediately.  Deaths occurring up to 
Day 100 post-transplant, regardless of causality or relation to study drug, should be reported 
to the sponsor immediately. 
Part A and Part B: 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, the patient dies or withdraws consent, or study closure.  All non-serious AEs 
will be followed through the safety reporting period.  Certain non-serious AEs of interest 
may be followed until resolution, return to baseline, or study closure. 
7.6.2.4 Adverse Events of Special Interest 
Hepatobiliary serious adverse events, including cases of 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. Additionally, they 
should be reported to the sponsor if they occur as part of long term follow-up regardless of 
causality. Events of SOS/VOD that occur within 180 days of the last dose of vadastuximab 
talirine will be reported. For patients who undergo subsequent allogeneic stem cell transplant 
in the absence of relapse and additional therapy, patients will be followed for SOS/VOD for 
100 days post-transplant. 
7.6.2.5 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: 


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● 
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 within 24 hours (see email address or fax number 
specified on the SAE report form). 
Relevant follow-up information is to be submitted to the sponsor as soon as it becomes 
available. 
7.6.2.6 Sponsor Safety Reporting to Regulatory Authorities 
Investigators are required to report all SAEs, including anticipated SAEs, to the sponsor (see 
Section 7.6.2.4). 
The sponsor will report all SAEs to regulatory authorities as required per local regulatory 
reporting requirements.  In the United States, endpoints that assess disease-related mortality 
or major morbidity as well other SAEs that are not study endpoints, but are known 
consequences of the underlying disease or condition that are anticipated to occur in the study 
population should not be reported to the Food and Drug Administration (FDA) as individual 
IND safety reports per the final rule amending the IND safety reporting requirements under  
21 CFR 312.32 and the FDA’s final guidance Safety Reporting Requirements for INDs and 
BA/BE Studies (December 2012). 
In this study, SAEs of leukemic relapse do not require individual IND safety reports. Events 
of febrile neutropenia are anticipated in this population and individual IND safety reports 
will not be submitted to the FDA. 
These anticipated SAEs will be reviewed periodically by the Seattle Genetics Drug Safety 
Department. If, upon review, these SAEs are occurring at a higher rate than that which would 
be expected for the study population, then IND safety reports for the SAE will be submitted 
to the FDA. 
7.6.3 
Clinical Laboratory Tests 
Samples will be drawn for both central and local labs.  Local laboratory testing will include 
institutional standard tests for evaluating safety and making clinical decisions, and will not 
necessarily include all of the analytes required in the central evaluation.  The following 
laboratory assessments will be performed by the central lab to evaluate safety at scheduled 
timepoints (see Appendix A and Appendix B) during the course of the study: 
● 
The chemistry panel is to include the following tests: albumin, alkaline phosphatase, 
alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea 
nitrogen, calcium, creatinine, chloride, lactate dehydrogenase, phosphorus, potassium, 
sodium, total bilirubin, uric acid, lipase, and amylase. 


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● 
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, hemoglobin, and hematocrit. 
The following laboratory assessment(s) will be performed by local laboratories at scheduled 
timepoints (see Appendix A and Appendix B) during the course of the study: 
● 
A serum or urine β-hCG pregnancy test for females of childbearing potential 
● 
Urinalysis with reflexive microscopy – samples will be tested for creatinine.  These 
laboratory results will be used to calculate a urine protein:creatine (UPC) ratio. 
● 
T-, B- and NK-cell lymphocyte subsets 
7.6.4 
Physical Examination 
Physical examinations should include assessments of the following body parts/systems:  
abdomen, extremities, head, heart, lungs, neck, and neurological.  For adult patients only, 
measurements of height obtained within the prior 12 months may be utilized. 
7.7 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. 
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) will be used to categorize any 
antitumor activity observed.  These criteria are considered standard in oncological practice, 
and the intervals of evaluation in this protocol are appropriate for disease management. The 
one-year survival rate will also be used to categorize the safety and antitumor activity 
observed. This is a standard measurement post allogeneic transplant for patients with AML. 
ATA 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. 
Exploratory biomarker measurements in peripheral blood samples to enable correlation with 
pharmacokinetic assessments are common in clinical studies.  Assessments conducted on 
bone marrow aspirates are also common in clinical studies of AML.  The majority of bone 
marrow biomarker samples are to be collected at times when bone marrow examination is 
already indicated for disease assessment. 
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 


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clinical and medical personnel will review the following items with the investigator and 
clinic staff: 
● 
The protocol, study objectives, eligibility requirements, study procedures, registration 
and withdrawal processes 
● 
Current Investigator’s Brochure/package insert 
● 
Recording and reporting AE and SAE 
● 
Enrollment goals and study timelines 
● 
The CRF completion process and source documentation requirements 
● 
Monitoring requirements 
● 
Institutional Review Board/Independent Ethics Committee (IRB/IEC) review and 
approval process 
● 
Informed consent process 
● 
GCP guidelines and related regulatory documentation requirements 
● 
Key study team roles and responsibilities 
● 
Investigational product storage, accountability, labeling, dispensing and record 
keeping 
● 
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. 


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8.3 Access to Source Data 
The investigator will permit the sponsor’s representatives to monitor the study as frequently 
as the sponsor deems necessary to determine that protocol adherence and data recording are 
satisfactory.  Appropriate measures to protect patient confidentiality are to be employed 
during monitoring.  The CRFs and related source documents will be reviewed in detail by the 
monitor at each site visit.  Original source documents or certified copies are needed for 
review.  This review includes inspection of data acquired as a requirement for participation in 
this study and other medical records as required to confirm that the information contained in 
the CRFs, such as disease assessments, AEs, and concomitant medications, is complete and 
correct.  Other study records, such as correspondence with the sponsor and the IRB/IEC and 
screening and drug accountability logs will also be inspected.  All source data and study 
records must also be available for inspection by representatives of regulatory authorities. 
8.4 Accuracy and Reliability of Data 
Steps to be taken to assure the accuracy and reliability of data include: 
● 
The selection of qualified investigators and appropriate study centers. 
● 
Review of protocol procedures with the investigators and associated personnel prior 
to the study. 
● 
Periodic monitoring visits by the designated monitor(s). 
● 
CRFs will be reviewed for accuracy and completeness by the designated monitor(s) 
during monitoring visits to the study centers.  Any discrepancies will be resolved with 
the investigator or designees as appropriate. 
8.5 Quality Assurance Procedures 
The Research and Development Quality 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 Research and Development Quality 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. 


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8.6.2 
Investigator Record Retention 
The investigator shall retain study drug disposition records and all source documentation 
(such as original ECG tracings, laboratory reports, inpatient or office patient records) for the 
maximum period required by the country and institution in which the study will be 
conducted, or for the period specified by Seattle Genetics, whichever is longer.  The 
investigator must contact Seattle Genetics prior to destroying any records associated with the 
study.  If the investigator withdraws from the study (due to relocation, retirement, etc.), the 
records shall be transferred to a mutually agreed upon designee (such as another investigator 
or IRB/IEC).  Notice of such transfer will be provided in writing to Seattle Genetics, Inc. 
9 
DATA ANALYSIS METHODS 
9.1 Determination of Sample Size 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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9.2 Study Endpoint Definitions 
Study endpoints are presented in Section 2.4. The endpoints that need to be defined are 
presented in this section. 
9.2.1 
Overall Survival (OS) and One-year Survival Rate 
OS is defined as the time from the day of alloSCT to date of death due to any cause.  In the 
absence of confirmation of death, survival time will be censored at the last date the patient is 
known to be alive.  Patients lacking data beyond the day of first dose will have their survival 
time censored at 1 day. 
One-year survival rate will be estimated by Kaplan-Meier method. 
9.2.2 
Minimal Residual Disease (MRD) Negativity Rate 
The MRD negativity rate is defined as the proportion of patients with MRD negativity. 
9.2.3 
Best Response 
The best response is defined as the best disease response determined by the investigator 
during the study. 
9.2.4 
Duration of Response 
Duration of response is defined as the time from the start of the first documented CR/CRi to 
the first documentation of relapse or death due to any cause, whichever comes first.  Duration 
of response will be censored on the date of the last disease assessment documenting absence 
of progressive disease (PD) for patients who have not progressed and are still on study at the 
time of analysis, who have received antitumor treatment other than the study treatment, or 
have been removed from study prior to documentation of PD.  Duration of response will only 
be calculated for the patients achieving CR/CRi. 
9.2.5 
Event-free Survival (EFS) 
Event-free survival is defined as the time from the day of alloSCT to the first documentation 
of treatment failure (defined below). Censoring for EFS is the same as that for duration of 
response. 
Part A 
Treatment failure is defined as failure to achieve CR/CRi by Day 30, relapse from CR/CRi, 
or death, due to any cause, whichever comes first. 
Part B 
Treatment failure is defined as relapse of AML or death due to any cause, whichever comes 
first. 


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9.3 Statistical and Analytical Plans 
The statistical and analytical plans presented below summarize the more complete plans to be 
detailed in the statistical analysis plan (SAP).  A change to the data analysis methods 
described in the protocol will require a protocol amendment only if it alters site conduct (e.g., 
adding baseline assessments to define a subgroup).  The SAP will be finalized prior to 
database lock.  Any changes to the methods described in the final SAP will be described and 
justified in the clinical study report. 
9.3.1 
General Considerations 
Part A and Part B will be summarized separately. 
9.3.1.1 Randomization and Blinding 
This is an open-label, non-randomized study.  Blinding is not applicable. 
9.3.1.2 Adjustments for Covariates 
Adjustments for covariates are not planned for this phase 1/2 study. 
9.3.1.3 Handling of Dropouts and Missing Data 
In general, missing data will not be imputed. Patients with missing values of a variable other 
than the time-to-event endpoints (OS, duration of response, and EFS) will be excluded from 
the analysis of that endpoint.  Censoring rules will be applied to the estimation of the 
distribution of the time-to-event endpoints, details will be provided in the SAP. 
9.3.1.4 Multicenter Studies 
Due to the expected small number of patients in each site, adjustments for sites are not 
planned. Descriptive summary of selected variables or endpoints by site may be provided. 
9.3.1.5 Multiple Comparisons and Multiplicity 
No adjustments for multiple comparisons are planned. 
9.3.1.6 Data Transformations and Derivations 
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. 
Baseline values used in all statistical analyses will be the most recent measurement prior to 
the first dose of vadastuximab talirine. 
For Part A, Day 0 is defined as the date of the alloSCT. For Part B, Day 1 is defined as the 
first dose of vadastuximab talirine. 


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9.3.1.7 Analysis Sets 
All Treated Patients Set 
The all treated patients analysis set includes all patients who receive any positive amount of 
vadastuximab talirine. 
DLT-Evaluable Set 
The DLT-evaluable analysis set includes all treated patients who received vadastuximab 
talirine and either experienced a DLT or were followed for the full DLT evaluation period. 
9.3.1.8 Examination of Subgroups 
All analyses will be presented by dose level and study part. 
As exploratory analyses, subgroup analyses may be conducted for selected endpoints.  
Detailed methodology will be provided in the SAP. 
9.3.1.9 Timing of Analyses 
Each part of the study will be conducted separately. For phase 1 portion of the study, data 
will be evaluated for dose-escalation for each dose cohort. Formal interim analysis of the 
phase 2 data is not planned. The final analysis of the study will be conducted after all patients 
have been followed for 5 years after the last patient is enrolled, or until study closure, 
whichever occurs first. 
In addition, interim data from the study may be presented at scientific meetings such as the 
American Society of Hematology (ASH) or the American Society of Clinical Oncology 
(ASCO). 
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 will be assessed and dose intensity will be summarized.  
Details will be provided in the SAP. 
9.3.5 
Efficacy Analyses 
Efficacy analyses will be performed by cohort and study part using the all treated patients set. 


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The one-year survival rate and its 95% confidence interval will be estimated by Kaplan-
Meier method. OS, duration of response and EFS will be analyzed using Kaplan-Meier 
method.  Median time will be calculated, where possible, with 95% confidence intervals. 
The best response rate and the MRD negativity rate will be provided with their 95% 
confidence intervals. 
Detailed methodology will be provided in the SAP. 
9.3.6 
Pharmacokinetic and ATA Analyses 
The PK of vadastuximab talirine ADC and SGD-1882 (if measurable) will be evaluated by 
noncompartmental analysis.  The following PK parameters will be evaluated, as appropriate: 
● 
Area under the curve (AUC) 
● 
Concentration at the end of infusion (Ceoi) or maximum observed concentration 
● 
(Cmax) 
● 
Trough concentration (Ctrough) 
● 
Terminal or apparent terminal half-life (t1/2) 
● 
Systemic clearance and volume of distribution at steady state 
 
The incidence of ATA will be summarized by descriptive statistics. 
9.3.7 
Biomarker Analyses 
Biomarker assessments and relationship to clinical and biological variables will be 
summarized using descriptive statistics.  The relationship of vadastuximab talirine PK and 
relevant biomarkers, safety, or efficacy may be explored. The relationship of exploratory 
endpoints to clinical activity may be explored. These analyses, if conducted, will be 
descriptive. 
9.3.8 
Other Analyses 
Not applicable. 
9.3.9 
Safety Analyses 
9.3.9.1 Extent of Exposure 
Duration of treatment, number of cycles (for Part B only), total dose and dose intensity will 
be summarized by dose cohort and study part.  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). 


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AEs will be listed and summarized by study part, dose cohort, 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. 
In addition, AEs will be summarized by the Bearman Toxicity Criteria (Bearman 1988). 
9.3.9.3 Deaths and Serious Adverse Events 
SAEs 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 
Laboratory values (e.g., chemistry, hematology, urinalysis, and pulmonary function tests) 
may be presented graphically for each lab test by scheduled visit.  Summary statistics may be 
tabulated where appropriate.  Laboratory values will be listed with NCI CTCAE v4.03 grades 
and out-of-normal range flags. 
9.3.9.5 Other Safety Analyses 
ECOG Status 
ECOG status will be summarized by visit. 
9.3.10 Interim Analyses 
No interim analyses are planned. See Section 9.3.1.9 for the timing of the analyses. 
10 INFORMED CONSENT, ETHICAL REVIEW, AND REGULATORY 
CONSIDERATIONS 
10.1 Informed Consent 
The investigator is responsible for presenting the risks and benefits of study participation to 
the subject in simple terms using the IRB/IEC approved informed consent document and for 
ensuring patients are re-consented when the informed consent document is updated during 
the study, if required.  The investigator will ensure that written informed consent is obtained 
from each patient, or legally authorized representative, if applicable to this study, by 
obtaining the signature and date on the informed consent document prior to the performance 
of protocol evaluations or procedures. 
If informed consent is obtained from a legally authorized representative for a patient who is 
unable to provide informed consent at study entry (if applicable), but the patient is later able 
to provide informed consent, the investigator must obtain written informed consent from the 
patient. 


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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 GCP, 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. 
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, 


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the investigator will provide the sponsor, its licensees and collaborators, applicable 
regulatory agencies, and applicable IRB/IEC with direct access to original source documents 
or certified copies. 
Records containing patient medical information must be handled in accordance with 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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receptor with differential ITIM function in recruiting the phosphatases SHP-1 and SHP-2. Blood 96: 483-90. 
Petersdorf SH, Kopecky KJ, Slovak M, Willman C, Nevill T, Brandwein J, Larson RA, Erba HP, Stiff PJ, 
Stuart RK, Walter RB, Tallman MS, Stenke L and Appelbaum FR (2013). A phase 3 study of gemtuzumab 
ozogamicin during induction and postconsolidation therapy in younger patients with acute myeloid leukemia. 
Blood 121: 4854-60. 
Raza A, Jurcic JG, Roboz GJ, Maris M, Stephenson JJ, Wood BL, Feldman EJ, Galili N, Grove LE, Drachman 
JG and Sievers EL (2009). Complete remissions observed in acute myeloid leukemia following prolonged 
exposure to lintuzumab: a phase 1 trial. Leuk Lymphoma 50: 1336-44. 
Rollig C, Bornhauser M, Thiede C, Taube F, Kramer M, Mohr B, Aulitzky W, Bodenstein H, Tischler HJ, 
Stuhlmann R, Schuler U, Stolzel F, von Bonin M, Wandt H, Schafer-Eckart K, Schaich M and Ehninger G 
(2011). Long-term prognosis of acute myeloid leukemia according to the new genetic risk classification of the 
European LeukemiaNet recommendations: evaluation of the proposed reporting system. J Clin Oncol 29: 2758-
65. 
Rosenblat TL, McDevitt MR, Mulford DA, Pandit-Taskar N, Divgi CR, Panageas KS, Heaney ML, Chanel S, 
Morgenstern A, Sgouros G, Larson SM, Scheinberg DA and Jurcic JG (2010). Sequential cytarabine and alpha-
particle immunotherapy with bismuth-213-lintuzumab (HuM195) for acute myeloid leukemia. Clin Cancer Res 
16: 5303-11. 
Sabbath KD, Ball ED, Larcom P, Davis RB and Griffin JD (1985). Heterogeneity of clonogenic cells in acute 
myeloblastic leukemia. J Clin Invest 75: 746-53. 
Schmid C, Schleuning M, Ledderose G, Tischer J and Kolb HJ (2005). Sequential regimen of chemotherapy, 
reduced-intensity conditioning for allogeneic stem-cell transplantation, and prophylactic donor lymphocyte 
transfusion in high-risk acute myeloid leukemia and myelodysplastic syndrome. J Clin Oncol 23: 5675-87. 
Schulmeister L (2010). Preventing and managing vesicant chemotherapy extravasations. J Support Oncol 8: 
212-5. 
Sekeres MA, Lancet JE, Wood BL, Grove LE, Sandalic L, Sievers EL and Jurcic JG (2013). Randomized, 
phase IIb study of low-dose cytarabine and lintuzumab versus low-dose cytarabine and placebo in older adults 
with untreated acute myeloid leukemia. Haematologica 98: 119-28. 
Sievers EL, Larson RA, Stadtmauer EA, Estey E, Lowenberg B, Dombret H, Karanes C, Theobald M, Bennett 
JM, Sherman ML, Berger MS, Eten CB, Loken MR, van Dongen JJ, Bernstein ID and Appelbaum FR (2001). 
Efficacy and safety of gemtuzumab ozogamicin in patients with CD33-positive acute myeloid leukemia in first 
relapse. J Clin Oncol 19: 3244-54. 
Stein AS, Walter RB, Erba HP, Fathi AT, Advani AS, Lancet JE, Ravandi F, Kovacsovics TJ, DeAngelo DJ, 
Bixby D, Faderl S, Jillella AP, O'Meara MM, Zhao B and Stein EM (2015). A Phase 1 Trial of SGN-CD33A As 
Monotherapy in Patients with CD33-Positive Acute Myeloid Leukemia (AML). Blood 126: Abstract 324. 
Stein EM, Stein A, Walter RB, Fathi AT, Lancet JE, Kovacsovics TJ, Advani AS, DeAngelo DJ, O'Meara MM, 
Zhao B, Kennedy DA and Erba HP (2014). Interim Analysis of a Phase 1 Trial of SGN-CD33A in Patients with 
CD33-Positive Acute Myeloid Leukemia (AML). Blood 124: Abstract 623. 
Sutherland MK, Yu C, Lewis TS, Miyamoto JB, Morris-Tilden CA, Jonas M, Sutherland J, Nesterova A, 
Gerber HP, Sievers EL, Grewal IS and Law C-L (2009). Anti-leukemic activity of lintuzumab (SGN-33) in 
preclinical models of acute myeloid leukemia. mAbs 1: 481-90. 
Taylor VC, Buckley CD, Douglas M, Cody AJ, Simmons DL and Freeman SD (1999). The myeloid-specific 
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Chem 274: 11505-12. 


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Ulyanova T, Blasioli J, Woodford-Thomas TA and Thomas ML (1999). The sialoadhesin CD33 is a myeloid-
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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. 
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82. 
Walter RB, Othus M, Borthakur G, Ravandi F, Cortes JE, Pierce SA, Appelbaum FR, Kantarjian HA and Estey 
EH (2011). Prediction of early death after induction therapy for newly diagnosed acute myeloid leukemia with 
pretreatment risk scores: a novel paradigm for treatment assignment. J Clin Oncol 29: 4417-24. 
Walter RB, Raden BW, Zeng R, Hausermann P, Bernstein ID and Cooper JA (2008). ITIM-dependent 
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phosphatases, Shp1 and Shp2. J Leukoc Biol 83: 200-11. 
Wong R, Shahjahan M, Wang X, Thall PF, de Lima M, Khouri I, Gajewski J, Alamo J, Couriel D, Andersson 
BS, Donato M, Hosing C, Komanduri K, Anderlini P, Molldrem J, Ueno NT, Estey E, Ippoliti C, Champlin R 
and Giralt S (2005). Prognostic factors for outcomes of patients with refractory or relapsed acute myelogenous 
leukemia or myelodysplastic syndromes undergoing allogeneic progenitor cell transplantation. Biology of 
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Yagasaki H, Kojima S, Yabe H, Kato K, Kigasawa H, Sakamaki H, Tsuchida M, Kato S, Kawase T, Muramatsu 
H, Morishima Y and Kodera Y (2009). Tacrolimus/Methotrexate versus cyclosporine/methotrexate as graft-
versus-host disease prophylaxis in patients with severe aplastic anemia who received bone marrow 
transplantation from unrelated donors: results of matched pair analysis. Biol Blood Marrow Transplant 15: 
1603-8. 
 


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APPENDIX A:  SCHEDULE OF EVENTS PART A: PRE-ALLO SCT 
 
A 
EOT eval. obtained before initiation of nonprotocol therapy.  If EOT eval is completed before 30 days after 
transplant, the site will conduct a phone screen 30 –37 days after transplant to ensure no changes in AE profile. 
B 
LTFU (consisting of a phone call for survival and collection of subsequent therapy information when a clinic 
visit is not required) will occur every month (±1 wk) from transplant for the first 2 years, and then every 3 
months (±2 wks) until death or study closure.  See Section 6.1.15. 
C 
May be obtained within 24 hrs prior to dose; does not need to be repeated if done within 24 hrs prior. 
D 
Fludarabine 30 mg/m2/day on Day –5 to Day –2 (total dose of 120 mg/m2).  Melphalan 140 mg/m2 on Day –2 
E 
Does not need to be repeated if performed within 42 days of enrollment. 
F 
Every 3 mos (±2 wks) from transplant for the 1st yr and then every 6 mos (±2wks) until 3 yrs post-
transplant.  No longer required once progression is documented. 
G 
See Section 7.6.2 for additional information on AE and SAE reporting 
H 
See Section 5.1 for details 
I 
Please see Table 4, Section 7.4 
J 
Please see Table 5, Section 7.4 
K 
Does not need to be repeated if done within 7 days prior. 
L 
Females of childbearing potential only. 
M 
See Section 6.1.15 and 7.6.2.4 
 
 
Screening/ Baseline 
Enrollment 
 
 
 
 
 
 
 
 
 
EOTA 
Long-term 
F/UM 
 
Day 
−44 to 
−14 
−28 to 
−14 
−21 to 
−14 
Within 7 days 
of first dose 
D −14 
D −13 
D −11 
D −7 
D −5 
to −2 
D −1 
D 0 
D 7, D 14, 
D 21 
D 30 
30−37 days 
post-transplant 
 
 
Visit Window 
 
 
 
 
 
 
 
 
±2 days 
 
±2 wks 
Screening 
and Safety 
Assessments 
Inclusion/Exclusion, patient history 
X 
 
 
Submit confirmation prior to treatment 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam with  weight 
 
 
X 
XC 
 
 
 
 
 
 
 
 
X 
 
CMV antibody test 
XE  
 
 
 
 
 
 
 
 
 
 
 
 
 
HCT-specific comorbidity index 
XE 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV and HTLV1 I/II antibody test 
XE 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum chemistry panel 
 
 
X 
XC 
 
 
X 
 
 
X 
X 
X 
XK  
 
CBC with differential 
 
 
X 
XC 
 
 
X 
 
 
X 
X 
X 
XK 
 
Urine creatinine clearance  
XE 
 
 
 
 
 
 
 
 
 
 
 
 
 
Spot urine for protein and creatinine 
XE 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
Pregnancy test  
 
 
XL 
 
 
 
 
 
 
 
 
 
XL 
 
ECHO/MUGA 
XE 
 
 
 
 
 
 
 
 
 
 
 
 
 
DLCO and FEV1 
XE 
 
 
 
 
 
 
 
 
 
 
 
 
 
Herpes simplex 
XE 
 
 
 
 
 
 
 
 
 
 
 
 
 
Varicella zoster virus 
XE 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis panel 
XE 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG performance status 
 
 
X 
X 
 
 
 
 
 
 
 
 
X 
 
GVHD assessments 
 
 
 
 
 
 
 
 
 
 
 
X 
 
XF 
Concomitant medications 
Related to study procedures 
Collect from predose D −14 to D 30 post-transplant or EOT whichever is later 
 
Adverse event collectionG 
Treatment 
Vadastuximab talirine administration 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
RIC treatmentH 
 
 
 
 
 
 
 
 
X D  
 
 
 
 
 
 
Allogeneic SCT 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
TacrolimusH 
 
 
 
 
 
 
 
 
 
Start D-1H  
 
 
MethotrexateH 
 
 
 
 
 
 
 
 
 
 
 
Start D1H 
 
 
Samples 
Samples for PK, ATA, and biomarker 
testingI, J 
 
X 
 
 
X 
X 
X 
X 
 
X 
 
 
X 
 
 
Chimerism assay per institutional 
guidelines. 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Response 
Assessment 
BM Aspirate for MRD AssessmentJ 
 
 
 
 
 
 
 
 
 
X 
 
 
X  
 
 
BM examination 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Contact for survival status and 
subsequent therapies 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
XB 


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APPENDIX B: SCHEDULE OF EVENTS PART B: POST-ALLO SCT 
 
A 
Day 1 of all cycles and in the absence of disease progression, continue to assess on the same schedule as 
BM examinations in follow-up. 
B 
LTFU (consisting of a phone call for survival and collection of subsequent therapy information when a 
clinic visit is not required) will occur every 1 month (±1 wk) for the first 2 years after receiving the first 
dose of study treatment, and then every 3 months (±2 wks) until death or study closure.  See Section 
6.2.10. 
C 
May be obtained within 24 hours prior to dose; does not need to be repeated if done within 24 hours prior. 
D 
If not done within 42 days prior to EOT assessment. 
E 
Not required if ANC recovers ≥1000 and platelets recover to ≥50,000. 
F 
See Table 6 
G 
Every 3 mos (±2 wks) for the first 2 years year after dosing (approximately every 2 cycles while on 
treatment) and then every 6 mos (±2 wks) until 3 years post-transplant. 
H 
See Section 7.6.2 for additional information on AE and SAE reporting 
I 
Continue to be obtained on the schedule described in Footnote G.  No longer required after disease 
progression is documented. 
J 
Females of childbearing potential only. 
K 
See Section 6.2.10 and 7.6.2.4 
 
 
Visit Window 
Baseline/ 
Screening 
Enrollment 
Cycle 1 
Cycle 2 
Cycle 3+ 
EOT 
(42 to 49 days post-
study treatment) 
Long-
term 
F/UK 
D1 
D2 
D4 
D8 
D15 
D22 
D28 
D42 
D1 
D1 
 
 
D –28 to 
1 
D −14 
to 1 
D –7 to 
1 
D –7 to 1 
 
 
 
±1D 
±1D 
±1D 
±1D 
±1D 
 
 
 
±2 wks 
Baseline and 
Safety 
Assessments 
Inclusion/exclusion 
X 
 
 
Eligibility documentation submitted  
to sponsor prior to study start 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history and 
transplant  details 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam with 
weight  
 
 
X 
XC 
 
 
 
 
 
 
 
XC 
XC  
 
 
Pregnancy testJ 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
ECOG performance 
status 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
Serum chemistry panel 
 
 
X 
XC 
 
 
X 
X 
X 
X 
XE 
X 
X 
X 
 
CBC with differential 
 
 
X 
XC 
 
 
X 
X 
X 
X 
XE 
X 
X 
X 
 
Spot urine for protein 
and creatinine 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
GVHD assessment 
X 
 
 
 
XA 
 
 
 
 
 
 
 
XA 
XA 
X 
X A  
Con meds & AEsH 
Collect any related to study protocol 
procedures 
 
Collect from pre-dose D1 to 42 days after study treatment or EOT, whichever is later 
 
Treatment 
Vadastuximab talirine 
administration 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
 
Samples 
Samples for PK, ATA, 
and biomarkersF 
 
X 
 
 
X 
X 
X 
 
 
 
 
 
X 
X 
X 
 
Response 
Assessments 
BM examination 
 
X 
 
 
 
 
 
 
 
 
 
 
 
XG 
XD 
 
BM aspirate for MRD 
 
X 
 
 
 
 
 
 
 
 
 
 
 
XG 
XD 
 
Contact for survival 
status and subsequent 
therapies 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
XB 


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APPENDIX C:  PERFORMANCE STATUS SCALES CONVERSION 
Karnofsky  
 
Lansky  
 
ECOG 
Percent Description 
 
Percent Description 
 
Score 
Description 
100 
Normal, no complaints, 
no evidence of disease. 
 
100 
Fully active, normal. 
 
0 
Normal activity.  Fully 
active, able to carry on all 
pre-disease performance 
without restriction. 
90 
Able to carry on normal 
activity; minor signs or 
symptoms of disease. 
 
90 
Minor restrictions in 
physically strenuous 
activity. 
 
80 
Normal activity with 
effort; some signs or 
symptoms of disease. 
 
80 
Active, but tires more 
quickly. 
 
1 
Symptoms, but 
ambulatory.  Restricted in 
physically strenuous 
activity, but ambulatory 
and able to carry out work 
of a light or sedentary 
nature (e.g., light 
housework, office work). 
70 
Cares for self, unable to 
carry on normal activity 
or to do active work. 
 
70 
Both greater restriction 
of, and less time spent in, 
play activity. 
 
60 
Requires occasional 
assistance, but is able to 
care for most of his/her 
needs. 
 
60 
Up and around, but 
minimal active play; 
keeps busy with quieter 
activities. 
 
2 
In bed <50% of the time.  
Ambulatory and capable 
of all self-care, but unable 
to carry out any work 
activities.  Up and about 
more than 50% of waking 
hours. 
50 
Requires considerable 
assistance and frequent 
medical care. 
 
50 
Gets dressed, but lies 
around much of the day; 
no active play; able to 
participate in all quiet 
active play and activities. 
 
40 
Disabled, requires special 
care and assistance. 
 
40 
Mostly in bed, 
participates in quiet 
activities. 
 
3 
In bed >50% of the time.  
Capable of only limited 
self-care, confined to bed 
or chair more than 50% of 
waking hours. 
30 
Severely disabled, 
hospitalization indicated.  
Death not imminent. 
 
30 
In bed, needs assistance 
even for quiet play. 
 
20 
Very sick, hospitalization 
indicated.  Death not 
imminent. 
 
20 
Often sleeping, play 
entirely limited to very 
passive activities. 
 
4 
100% bedridden.  
Completely disabled.  
Cannot carry on any self-
care.  Totally confined to 
bed or chair. 
10 
Moribund, fatal processes 
progressing rapidly. 
 
10 
No play, does not get out 
of bed. 
 
0 
Dead. 
 
0 
Dead. 
 
5 
Dead. 
 


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APPENDIX D:  NEW YORK HEART ASSOCIATION CLASSIFICATION 
A Functional and Therapeutic Classification for Prescription of Physical Activity for Cardiac 
Patients 
Class I:  
Patients with no limitation of activities; they suffer no symptoms from ordinary 
activities. 
Class II:  
Patients with slight, mild limitation of activity; they are comfortable with rest or with 
mild exertion. 
Class III:  Patients with marked limitation of activity; they are comfortable only at rest. 
Class IV:  Patients who should be at complete rest, confined to bed or chair; any physical 
activity brings on discomfort and symptoms occur at rest. 
 
Online source: 
Classes of Heart Failure, http://www.heart.org/HEARTORG/Conditions/HeartFailure/ 
AboutHeartFailure/Classes-of-Heart-Failure_UCM_306328_Article.jsp. Accessed August 25, 
2015. 
 


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APPENDIX E: BEARMAN REGIMEN-RELATED TOXICITY ACCORDING TO ORGAN 
SYSTEM 
 
Grade I 
Grade II 
Grade III 
Cardiac toxicity 
Mild EKG abnormality,  
not requiring  medical  
intervention; or  noted  
heart  enlargement on 
CXR  with  no clinical 
symptoms 
Moderate EKG 
abnormalities requiring 
and  responding  to 
medical  intervention; or 
requiring continuous 
monitoring without 
treatment; or congestive  
heart  failure responsive to 
digitalis or diuretics 
Severe  EKG 
abnormalities with no or 
only partial  response  to 
medical  intervention;  or  
heart failure with no or  
only minor response  to 
medical intervention; or  
decrease in voltage  by 
more than 50% 
Bladder toxicity 
Macroscopic  hematuria  
after  2 d from last 
chemotherapy dose with 
no subjective symptoms of 
cystitis and  not caused  by 
infection 
Macroscopic  hematuria  
after  7 d from last 
chemotherapy dose not 
caused  by infection; or 
hematuria  after  2 d with 
subjective symptoms of 
cystitis not caused  by 
infection 
Hemorrhagic  cystitis with 
frank blood,  necessitating  
invasive local intervention  
with installation  of 
sclerosing agents, 
nephrostomy  or other 
surgical  procedure 
Renal toxicity 
Increase  in creatinine  up 
to twice the baseline  value 
(usually the last recorded 
before  start  of 
conditioning) 
Increase  in creatinine  
above  twice baseline but 
not requiring dialysis 
Requirement of dialysis 
Pulmonary toxicity 
Dyspnea without CXR 
changes  not caused  by 
infection or congestive 
heart  failure; or CXR 
showing isolated  infiltrate  
or mild interstitial  
changes  without 
symptoms  not caused  by 
infection or congestive  
heart failure 
CXR  with extensive 
localized infiltrate or  
moderate interstitial  
changes  combined with 
dyspnea  and  not caused 
by Infection or CHF; or 
decrease of P02 (> 10%  
from baseline)  but not 
requiring mechanical 
ventilation or >50% 02 on 
mask and  not caused  by 
infection or CHF 
Interstitial changes  
requiring mechanical  
ventilatory  support or  
>50% oxygen  on mask 
and not caused  by 
infection or CHF 
Hepatic toxicity 
Mild hepatic  dysfunction 
with 2.0 mg%  s bilirubin s 
6.0mg%; or weight  gain  
>2.5%  and <5% from  
baseline,  of noncardiac 
origin; at SGOT increase  
more than  2-fold  but less 
than 5-fold  from lowest 
preconditioning 
Moderate hepatic  
dysfunction with bilirubin 
>6 mg%  <20 mg%; or 
SGOT  increase  >5-fold 
from preconditioning;  or 
clinical ascites  or  image 
documented ascites  
>100 mL; or weight gain  
>5% from baseline of 
noncardiac origin 
Severe  hepatic  
dysfunction with bilirubin 
>20 mg%; or  hepatic 
encephalopathy; or ascites 
compromising  respiratory 
function 


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Grade I 
Grade II 
Grade III 
CNS toxicity 
Somnolence  but the 
patient  is easily  arousable 
and  oriented after  arousal 
Somnolence  with 
confusion after arousal; or 
other  new objective CNS 
symptoms with no loss of 
consciousness not more 
easily explained  by other  
medication, bleeding,  or 
CNS  infection 
Seizures  or coma  not 
explained (documented)  
by other medication,  CNS  
infection, or bleeding 
Stomatitis 
Pain and/or ulceration  not 
requiring  a continuous  IV 
narcotic  drug 
Pain and/or ulceration  
requiring  a continuous IV  
narcotic drug (morphine 
drip) 
Severe  ulceration  and/or 
mucositis requiring  
preventive intubation; or 
resulting  in documented 
aspiration pneumonia with 
or without intubation 
Gl toxicity 
Watery stools  >500 mL 
but <2,000 mL every d not 
related to infection 
Watery stools >2,000 mL 
every d not related to 
infection; or macroscopic. 
hemorrhagic stools with 
no effect on cardiovascular 
status  not caused  by 
infection; or  subileus not 
related to infection 
Ileus requiring  nasogastric 
suction and/or surgery  and  
not related to infection; or  
hemorrhagic enterocolitis  
affecting cardiovascular 
status  and requiring 
transfusion 
(Bearman 1988) 
NOTE. Grade IV regimen-related toxicity is defined as fatal toxicity. 
Abbreviations:  CXR, chest x-ray; IV, intravenous 
 


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APPENDIX F:  GVHD TARGET ORGAN STAGING 
 
Stage 
Skin (Active Erythema Only) 
Liver 
(bilirubin) 
Upper GI 
Lower GI (stool 
output/day) 
0 
No active (erythematous) GVHD rash 
< 2 mg/dl 
No intermittent 
nausea, vomiting, 
or anorexia 
<500 mL/day or <3 
episodes/day 
1 
Maculopapular rash< 25% BSA 
2–3 mg/dl 
Persistent nausea, 
vomiting or 
anorexia 
500–999 mL/day or 
3-4 episodes/day 
2 
Maculopapular rash 25–50% BSA 
3.1–6 
mg/dl 
 
1000–1500 mL/day 
or 5-7 episodes/day 
3 
Maculopapular rash >50% BSA 
6.1–15 
mg/dl 
 
>1500 mL/day or >7 
episodes/day 
4 
Generalized erythroderma (>50% BSA) 
plus bullous formation and 
desquamation >5% BSA 
>15 mg/dl 
 
Severe abdominal 
pain with or without 
ileus or grossly 
bloody stool 
(regardless of stool 
volume). 
Overall clinical grade (based on most severe target organ involvement): 
Grade 0: 
No Stage 1-4 of any organ. 
Grade 1: 
Stage 1-2 skin without liver, upper GI, or lower GI involvement. 
Grade 2: 
Stage 3 rash and/or stage 1 liver and/or stage 1 upper GI and/or stage 1 lower GI. 
Grade 3:  
Stage 2-3 liver and/or stage 2-3 lower GI, with stage 0-3 skin and/or stage 0-1 upper GI 
Grade 4:  
Stage 4 skin, liver, or lower GI involvement, with stage 0-1 upper GI. 
(Harris 2016) 
 


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APPENDIX G:  INVESTIGATOR SIGNATURE PAGE 
 
Investigator Statement and Signature 
 
I have read the attached protocol entitled A phase 1/2 study of vadastuximab talirine 
administered in sequence with allogeneic hematopoietic stem cell transplant in patients with 
relapsed or refractory 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 H:  DOCUMENT HISTORY 
Version 
Date 
Original 
25-Aug-2015 
Amendment 1 
16-Feb-2016 
Amendment 2 
12-Oct-2016 
Amendment 3 
15-Mar-2017 
 


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Summary of Changes in Amendment 1 
Section(s) 
Change 
Rationale 
Title page 
Medical monitor and contact info has been updated from 
 
 
 update medical staff info. 
2.1, 2.2 2.4.2, 
Synopsis 
Clarified that objectives and endpoints for rate of MRD negativity, best 
response on treatment, and duration of response are applicable to Part A only. 
Clarification. 
3.1.1, 6.1.15, 
Appendix A, 
Synopsis 
Clarified the response assessment schedule for Part A:  Patients will be 
evaluated for response at Day 30 and every 3 months from transplant for 1 
year and then every 6 months until 3 years post-transplant (no longer required 
once disease progression is documented).   
Clarification. 
3.1.1 
Added a possible Dose Level -1 to Part A (30 mcg/kg), to be studied only 
upon SMC recommendation. 
Additional dose level to allow possible dose 
exploration at lower vadastuximab talirine doses. 
3.1.2, 6.2.10, 
Appendix B, Synopsis 
Clarified the response assessment schedule for Part B:  Response assessments 
will be every 3 months after the first dose of study drug for 2 years (every 
other cycle during treatment), and then every 6 months until 3 years post-
transplant.   
Clarification. 
4.1, Criterion 1, 
Synopsis 
Added/clarified requirements for confirmation of patient eligibility: 
● Relapsed/refractory AML 
● Part A: 
○ 
Clarified number of previous induction regimens required 
○ 
Specified the risk factors that would cause a patient to be eligible 
after only 1 induction regimen 
● Part B: 
○ 
Clarified conditioning regimen permitted 
○ 
Specified that CR/CRi must be documented within 14 days of first 
dose of study treatment 
To ensure patient eligibility for the study. 
4.1, Criterion 4 
Specified total bilirubin measurement required at baseline. 
Clarification of criterion. 
4.1, Criterion 8 and 9, 
Synopsis 
Added criteria for baseline left ventricular ejection fraction, DLCO, FEV1, 
and FVC. 
To ensure patient safety. 


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Section(s) 
Change 
Rationale 
4.2, Criterion 6 
The following changes: 
● Current therapy is defined as within 14 days prior to first dose of 
vadastuximab talirine 
● For Part B, immunosuppressive agents are allowed for prophylaxis 
against and treatment of GVHD. 
● Moved following text from Exclusion #2:  For Part A, hydroxyurea or 6-
mercaptopurine used for cytoreduction may be given up to 1 day prior to 
treatment 
Clarification. 
4.2, Criterion 9 
Updated to exclude patients with a history of primary invasive malignancy 
that has not been in remission for 3 years (previously was 1 year), and to 
exclude patients with any history of metastatic malignancy. 
To ensure patient eligibility for treatment with 
vadastuximab talirine. 
4.2, Criterion 10 
Clarified that patients with partially matched donors or cord blood cell sources 
are not eligible in Part A.   
Clarification. 
4.2, Criterion 11, 
Synopsis 
Patients with a history of VOD requiring defibrotide are not permitted in Part 
B. 
To ensure patient safety. 
5.10.2 
Specified permitted concomitant therapy:  DLI or stem cell boost to treat 
decreasing engraftment, defibrotide for VOD (Part A), and 
immunosuppressive agents for GVHD treatment and prophylaxis (Part B). 
To permit required concomitant therapy during 
the study treatment period.  
5.10.3 
Specified prohibited concomitant therapy:  DLI to treat loss of response and 
sirolimus (Part A).  Added exception to treatment with investigational drugs 
for defibrotide to treat VOD.   
Added prohibited concomitant therapies to 
improve patient safety. 
6.1.4, 6.1.9, 6.1.11, 
6.1.13, 6.1.14, 6.1.15, 
6.2.4, 6.2.9, 6.2.10, 
7.4, Appendix A, 
Appendix B 
Clarified assessments and visit schedule (including windows) for each study 
day, including specifying the start dates for tacrolimus and methotrexate in 
Part B. 
Clarification. 
7.4.2, 7.6.3 
Specified that lymphocyte subset recovery will be monitored by a local 
laboratory.  Added clarifications regarding central and local laboratory 
assessments. 
Clarification. 
7.6.1, Appendix F 
GVHD assessment clarifications were added, and a reference to the Modified 
Keystone Criteria for GVHD grading was provided. 
To aid in the grading and assessment of GVHD. 
7.6.2, 9.3.9.5 
Vital signs sections have been deleted. 
Correction.  
References 
Updated reference for AML standard of care. 
Clarification. 
Throughout document 
Administrative changes and corrections 
For clarity. 



SAP_001.pdf: 
 
 
 
Part or all of the information in this statistical analysis plan may be unpublished material. Accordingly, this 
document is to be treated as confidential and restricted to its intended use. This material is the property of 
Seattle Genetics, Inc. and must not be disclosed or used except as authorized in writing by Seattle Genetics, Inc. 
STATISTICAL ANALYSIS PLAN 
 
Protocol Number: 
SGN33A-003 
Version: 
Amendment 3; 15-Mar-2017 
Protocol Title: 
A Phase 1/2 study of vadastuximab talirine administered in 
sequence with allogeneic hematopoietic stem cell transplant in 
patients with relapsed or refractory acute myeloid leukemia 
(AML) 
Sponsor: 
Seattle Genetics, Inc. 
21823 30th Drive SE 
Bothell, WA 98021, USA 
 




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Table of Contents 
STATISTICAL ANALYSIS PLAN ....................................................................................................................... 1 
APPROVAL SIGNATURES .......................................................................................................................... 2 
List of Abbreviations ....................................................................................................................................... 5 
1 
INTRODUCTION ........................................................................................................................................... 6 
2 
STUDY OBJECTIVES ................................................................................................................................... 6 
2.1 
Primary Objectives ................................................................................................................................ 6 
2.2 
Secondary Objectives ............................................................................................................................ 6 
2.3 
Additional Objectives ............................................................................................................................ 6 
3 
STUDY ENDPOINTS .................................................................................................................................... 7 
3.1 
Safety Endpoints ................................................................................................................................... 7 
3.2 
Efficacy Endpoints ................................................................................................................................ 7 
3.3 
Additional Endpoints ............................................................................................................................. 7 
4 
STUDY DESIGN ............................................................................................................................................ 7 
5 
ANALYSIS SETS ........................................................................................................................................... 9 
5.1 
All Treated Patients Analysis Set .......................................................................................................... 9 
5.2 
DLT Evaluable (DE) 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 ............................................................................................................................................ 12 
6.10 Timing of Analyses ............................................................................................................................. 12 
7 
PLANNED ANALYSES .............................................................................................................................. 12 
7.1 
Disposition .......................................................................................................................................... 12 
7.2 
Demographic and Baseline Characteristics ......................................................................................... 12 
7.3 
Protocol Deviations ............................................................................................................................. 13 
7.4 
Treatment Administration ................................................................................................................... 13 
7.4.1 
Vadastuximab Talirine  .......................................................................................................... 13 
7.4.2 
Reduced Intensity Chemotherapy (Part A Only) .................................................................... 13 
7.4.3 
GVHD Prophylaxis (Part A Only) .......................................................................................... 14 
7.5 
Efficacy Analyses ................................................................................................................................ 14 
7.5.1 
One-year Survival (Phase 2 Only) .......................................................................................... 14 
7.5.2 
Day -1 and Day 30 Rates of MRD (Minimal Residual Disease) Negativity (Part A only) .... 14 
7.5.3 
Complete Remission Rate (Part A only) ................................ Error! Bookmark not defined. 
7.5.4 
Best Response (Part A only) ................................................................................................... 14 
7.5.5 
Duration of Response (Part A only) ....................................................................................... 14 
7.5.6 
Overall Survival (OS) from alloSCT ...................................................................................... 14 
7.6 
Safety Analyses ................................................................................................................................... 14 
7.6.1 
Adverse Events ....................................................................................................................... 15 
7.6.2 
Clinical Laboratory Parameters .............................................................................................. 16 
7.6.3 
ECOG Performance Status ..................................................................................................... 16 
7.6.4 
Concomitant Medications ....................................................................................................... 16 
7.6.5 
Deaths ..................................................................................................................................... 16 


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7.6.6 
GVHD Assessments ............................................................................................................... 16 
7.6.7 
Allogeneic Stem Cell Transplant ............................................................................................ 16 
7.7 
Additional Analyses  ........................................................................................................................... 16 
7.7.1 
MRD Status ............................................................................................................................ 16 
7.7.2 
Event-free Survival (EFS) ...................................................................................................... 17 
7.7.3 
Pharmacokinetics .................................................................................................................... 17 
7.7.4 
Antitherapeutic Antibody (ATA) Incidence Rate ................................................................... 17 
7.7.5 
Biomarker Analysis ................................................................................................................ 17 
7.7.6 
Quantification of T-, B-, and NK-cell Lymphocyte Subsets Post-transplant ......................... 17 
8 
INTERIM ANALYSIS.................................................................................................................................. 18 
9 
CHANGES FROM PLANNED ANALYSES .............................................................................................. 18 
9.1 
Changes from the Original Protocol .................................................................................................... 18 
9.2 
Changes from the Original SAP .......................................................................................................... 18 
REFERENCES ..................................................................................................................................................... 19 
APPENDIX A: IMPUTATION OF PARTIALLY UNKNOWN ADVERSE EVENT DATES ......................... 20 
APPENDIX B: DEFINITION OF THE TERM “TREATMENT-EMERGENT” WITH RESPECT TO AE 
CLASSIFICATION ...................................................................................................................................... 23 
 


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LIST OF ABBREVIATIONS 
ADC 
antibody-drug conjugate 
AE 
adverse event 
alloSCT 
allogeneic stem cell transplant 
AML 
acute myeloid leukemia 
ATA 
antitherapeutic antibodies 
AUC 
area under the concentration-time curve 
CR 
complete remission 
CRi 
complete remission with incomplete blood count recovery 
CBC 
complete blood count 
CRF 
case report form 
DLT 
dose-limiting toxicity  
ECOG 
Eastern Cooperative Oncology Group 
EFS 
event-free survival 
EOT 
end of treatment 
GCP 
good clinical practice 
GVHD 
graft-versus-host disease 
ICH 
International Conference on Harmonization  
IND 
Investigational New Drug 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRD 
minimal residual disease 
NCI  
National Cancer Institute 
CTCAE 
Common Terminology Criteria for adverse events 
OS 
overall survival  
RIC 
reduced intensity chemotherapy  
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SMC 
safety monitoring committee 
ULN 
upper limit of normal 
VOD 
veno-occlusive disease 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1 
INTRODUCTION 
This document outlines the statistical methods to be implemented within the scope of 
Protocol SGN33A-003, entitled “A Phase 1/2 study of vadastuximab talirine administered in 
sequence with allogeneic hematopoietic stem cell transplant in patients with relapsed or 
refractory acute myeloid leukemia (AML)”. Results of the proposed analyses will become 
the basis of the clinical study report for this protocol. 
The purpose of this plan is to provide specific guidelines from which the analysis will 
proceed.  All planned analyses specified in this document will be performed.  Any changes to 
this plan, in the form of “post hoc” or “data driven” analyses will be identified as such in the 
final clinical study report.  Any changes will either be reflected in amendments to this plan 
before the database lock or specifically documented in the clinical study report. 
2 
STUDY OBJECTIVES 
2.1 Primary Objectives 
● 
Phase 1 
○ 
To assess the safety and tolerability of vadastuximab talirine  
○ 
To determine the recommended dosing levels of vadastuximab talirine pre- and post-
allogeneic hematopoietic stem cell transplant (alloSCT) 
● 
Phase 2 
○ 
To assess the 1-year survival rates of patients treated with vadastuximab talirine at the 
recommended doses pre- and post-alloSCT 
○ 
To assess the rate of MRD negativity at Day −1 pre-transplant and Day 30 post-
transplant in the pre-transplant portion of the study (Part A only). 
○ 
To assess the safety and tolerability of vadastuximab talirine at the recommended 
dosing levels 
2.2 Secondary Objectives 
● 
To assess the best response on study treatment (Part A only) 
● 
To assess the duration of response (Part A only)  
● 
To assess overall survival (OS) 
2.3 Additional Objectives 
● 
To assess the pharmacokinetics, antitherapeutic antibodies (ATA), and 
pharmacodynamics of vadastuximab talirine 
● 
To assess event-free survival (EFS) 
● 
To assess the rate of MRD negativity 
● 
To assess lymphocyte subset recovery after alloSCT 


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● 
To assess CD33 expression levels and post-treatment target (CD33) saturation 
● 
To assess biomarkers of biological activity, resistance, and outcome 
3 
STUDY ENDPOINTS 
3.1 Safety Endpoints 
● 
Type, incidence, severity, seriousness, and relatedness of adverse events (AEs) 
● 
Type, incidence, and severity of laboratory abnormalities 
● 
Incidence of dose-limiting toxicity (DLT) 
3.2 Efficacy Endpoints 
● 
One-year survival 
● 
Day −1 and Day 30 rates of MRD negativity (Part A only) 
● 
Complete remission rate (Part A only) 
● 
Best response (Part A only) 
● 
Duration of response (Part A only) 
● 
Overall survival  
3.3 Additional Endpoints 
● 
MRD – negativity 
● 
Event-free survival 
● 
PK parameters for SGN-CD33A, and released SGD-1882 
● 
Incidence of ATA 
● 
Biomarkers of vadastuximab talirine activity 
● 
Quantification of T-, B-, and NK-cell lymphocyte subsets post-transplant 
4 
STUDY DESIGN 
This is a 2-part study to evaluate the safety and efficacy of vadastuximab talirine in patients 
with relapsed chemo-resistant AML:  Part A will examine vadastuximab talirine in 
cytoreduction pre-conditioning and Part B will examine vadastuximab talirine in post-
alloSCT maintenance.  Each study part will consist of a Phase 1 safety evaluation followed 
by a Phase 2 expansion for efficacy.  Parts A and B will enroll concurrently.  Phase 2 will be 
initiated following dose level recommendation by the Safety Monitoring Committee (SMC) 
with the determination of the MTD or recommended Phase 2 doses for Parts A and B, and an 
evaluation of the overall safety profile. At the discretion of the SMC, dose levels may be 


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expanded in Phase 1.  All patients will be followed for survival status until 5 years after the 
last patient is enrolled, or until study closure, whichever occurs first. 
In part A, one dose of vadastuximab talirine will be administered intravenously on Day −14 
for patients in the cytoreduction pre-conditioning part followed by reduced intensity 
chemotherapy (RIC) of melphalan and fludarabine on Days −5 to −2. AlloSCT will be 
performed on Day 0. Patients will be evaluated for response at Day 30, and every 3 months 
from transplant for 1 year and then every 6 months until 3 years post-transplant. Part A Phase 
1 of the study will be conducted using a standard 3+3 design starting from Dose Level 1. 
Dose cohorts are specified in the following Table 1. Dose de-escalation from Dose Level 1 is 
permitted based on SMC recommendation. 
Table 1:  
Part A dose levels 
Dose Level for Part A 
Part A Dose of Vadastuximab Talirine 
(mcg/kg) 
−1 
30 
1 
40 
2 
60 
3 
80 
4 
100 
 
In Part B, patients will enter the study between 42 and 100 days after the alloSCT and will 
receive vadastuximab talirine on Day 1 of 42-day cycles for up to 8 cycles. Response 
assessments will be every 3 months after the first dose of study drug for 2 years (every other 
cycle during treatment), and then every 6 months until 3 years post-transplant.  Patients in 
Part B who discontinue study treatment prior to relapse will be evaluated for response until 
progression or initiation of new anticancer treatment, whichever comes first. Part B Phase 1 
of the study will treat 6 patients at Dose Level 1 (10 mcg/kg). Once these 6 patients have 
completed the DLT period, the sponsor, in consultation with the SMC, may decide to explore 
safety and activity in an additional 6 patients. In the event of DLT occurring in 2 or more 
patients in either the first or the second 6-patient cohort, the sponsore, in consultation with 
the SMC, may choose to modify the schedule or dose level for further investigation.  If fewer 
than 2 DLTs occur in either the first or second 6-patient cohorts, the sponsor will determine, 
in consultation with the SMC, the day when therapy may start and recommended dose for 
further evaluation. The planned doses for Part B are summarized in Table 2. 


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Table 2: 
Part B dose levels 
Dose Level for Part B 
Part B Dose of Vadastuximab Talirine 
(mcg/kg) 
−1 
5  
1 
10  
5 
ANALYSIS SETS 
This section defines each of the analysis sets that will be utilized. The use of each analysis set 
will be discussed in Section 7. 
5.1 All Treated Patients Analysis Set 
The All Treated Patients analysis set includes all patients who receive any positive amount of 
vadastuximab talirine. 
5.2 DLT Evaluable (DE) Set 
The DLT-evaluable (DE) analysis set includes all treated patients in Phase 1 who received 
vadastuximab talirine and either experienced a DLT or were followed for the full DLT 
evaluation period. 
6 
STATISTICAL CONSIDERATIONS 
6.1 General Principles 
This is a Phase 1/2 study including dose-escalation. All analyses will be descriptive; 
however, confidence intervals may be presented to describe precision of estimates. Part A 
and Part B will be summarized separately. Patients will be grouped by dose level across 
Phase 1 and Phase 2 within study part. 
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. Median of a time-to-event endpoint will be estimated by the 
Kaplan-Meier method. Analyses will be presented by dose level. 
Any analysis not described in this plan will be considered exploratory, and will be 
documented in the clinical study report (CSR) as a post hoc analysis or a change to the 
planned analysis. 
To comply with regulatory electronic submission guidelines, listings of all clinical data will 
be submitted as electronic data sets.  To facilitate data review for the study report, only 
pertinent data listings will be created and attached to the appendix of the CSR. All statistical 
output will be produced using SAS®, version 9.3 or more recent. Other statistical software, if 
used, will be described in the clinical study report. 


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6.2 Determination of Sample Size 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.3 Randomization and Blinding 
Not applicable. 


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6.4 Data Transformations and Derivations 
Age in years will be calculated with the SAS INTCK function (with method specified as 
“continuous”) using informed consent date and birth date. 
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. 
For both Part A and Part B, Study Day will be calculated as Date–First Dose Date+1 for 
dates on or after the first dose date.  For dates prior to the first dose date, Study Day will be 
calculated as Date–First Dose Date.   
The following unit conversion will be implemented unless otherwise specified: 
• Months = Days / 30.4375 
• Years =Days / 365.25 
Unless otherwise specified, baseline values used in all statistical analyses will be the most 
recent non-missing measurement prior to the first dose of vadastuximab talirine. 
The end-of-treatment (EOT) date will be the date the EOT visit is performed; if an EOT visit 
is not performed then the EOT date will be either the end-of-study (EOS) date or 30 days for 
Part A and 42 days for Part B after the last dose of any study drug, whichever is earlier. 
For efficacy assessments, the date of the response assessment will be the bone marrow exam 
date or local lab CBC date (if applicable) at the corresponding visit. If the response is 
determined to be anything except ‘Relapse from CR/CRi’, the latest date of the bone marrow 
exam or the local lab CBC exam will be the response assessment date. For the response 
‘Relapse from CR/CRi’, the earliest date of the bone marrow exam or the local lab CBC 
exam will be the response assessment date.  
6.5 Handling of Dropouts and Missing Data 
In general, missing data will not be imputed. But missing AE dates will be imputed while 
calculating duration of events and treatment-emergent status (see Appendix A for imputation 
details and Appendix B for the treatment-emergent definition).  
The algorithm below will be used to impute the start date of subsequent anti-cancer treatment 
when only the day part is missing. 
• If the month and year of the new anti-cancer treatment start date are the same as the 
month and year of the documented relapse date, the new anti-cancer treatment will be 
assumed to start on the same day as relapse. 
• Otherwise, the new anti-cancer treatment will be assumed to start on the first day of 
that month. 
Censoring rules for the time-to-event endpoints will be described in Section 7 with each 
planned analysis, as applicable.  


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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 
No multiple comparisons are planned and no alpha adjustment is needed in this Phase 1/2 
study. 
6.8 Examination of Subgroups 
As exploratory analyses, subgroup analyses may be conducted for selected endpoints. 
Subgroups may include but are not limited to the following: 
● 
Age (≤65, and >65) 
● 
Age (≤50, and >50) 
● 
Current disease status (relapsed and refractory, Part A only) 
● 
HCT comorbidity index (low (0), intermediate (1 to 2), and high (≥3) , Part A only) 
● 
Cytogenetic risk category (favorable, intermediate and adverse) 
● 
Number of prior AML systemic therapies (1, 2, and ≥3)  
● 
Bone marrow blast prior to alloSCT (<25%, and ≥25%, Part A only) 
 
6.9 Covariates 
Covariates are not considered for adjustment in the analyses. 
6.10 Timing of Analyses 
Each part of the study will be conducted separately. Section 8 will provide details of the 
timing.  
7 
PLANNED ANALYSES 
7.1 Disposition 
An accounting of study patients by disposition will be tabulated by cohort and total using All 
Enrolled Patients analysis set.  Reasons for discontinuation of treatment and study will be 
summarized by cohort and total. The number and percentage of patients who signed informed 
consent forms and the number of patients in each analysis set will be summarized for all 
patients by cohort and total. 
7.2 Demographic and Baseline Characteristics 
Demographics and baseline characteristics, including age, gender, ethnicity, race, baseline 
height, weight, and ECOG score will be listed and summarized; summaries will be presented 
for each cohort and total using the All Treated Patients analysis set. Disease specific 
characteristics, including time from diagnosis, current disease status, baseline HCT 


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comorbidity index, cytogenetic risk, and previous cancer-related treatments will be listed and 
summarized for each cohort and the total using the All Treated Patients analysis set.  
7.3 Protocol Deviations 
Important protocol deviations (defined as protocol violations by Seattle Genetics) are those 
that represent a divergence from the protocol that could have a significant effect on the 
integrity of the study data, or on the subject’s rights, safety, or welfare.  Important protocol 
deviations also include exemptions to the study inclusion/exclusion criteria and will be 
summarized by category.  A list of patients with important protocol deviations will be 
presented. 
7.4 Treatment Administration 
7.4.1 Vadastuximab Talirine  
Treatment administration will be summarized by cohort using the All Treated Patients 
analysis set. For Part B, summary statistics for treatment period (weeks) and the number of 
cycles per patient will be presented, as well as the number and percentage of patients who 
were treated at each cycle. Cumulative dose, absolute dose intensity (ADI), and relative dose 
intensity (RDI) will be summarized with descriptive statistics. The number and percentage of 
patients whose dose was ever modified will be summarized in tables by modification type, 
cycle, and overall (i.e. over all drug administrations for a patient); listings may be presented 
as well.  
Treatment period is defined as time from the first vadatuximab talirine dose to 44 days for 
Part A, and 42 days after the last study dose for Part B, or death, whichever occurs earlier: 
• Part A: minimum of (death date – first dose date + 1, 44) 
• Part B: minimum of (death date – first dose date + 1, last dose date – first dose date + 
42). 
Intended Dose Intensity (IDI) is defined as the intended dose of drug (mcg/kg) per week. For 
example, the IDI for the 40 mcg/kg cohort in Part A is 40/(44/7) = 6.36 mcg/kg/wk.  The IDI 
for the 10 mcg/kg cohort in Part B is 10/(42/7) = 1.67 mcg/kg/wk. 
Absolute Dose Intensity (ADI) is defined as the actual dose (mcg/kg) per week that the 
patient received over the entire treatment period. 
Relative dose intensity (RDI) is defined as the absolute dose intensity as a percentage of the 
intended dose intensity. 
RDI = ADI/IDI * 100. 
7.4.2 Reduced Intensity Chemotherapy (Part A Only)  
Dose administration of each of the two RIC therapies (fludarabine and melphalan) will be 
listed using the All Treated Patients analysis set. 


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7.4.3 GVHD Prophylaxis (Part A Only)  
Dose administration of each of the two GVHD prophylaxes (tacrolimus and methotrexate) 
will be listed using the All Treated Patients analysis set. 
7.5 Efficacy Analyses 
All efficacy analyses will be presented using the All Treated Patients analysis set. Analyses 
may also be performed using the subgroups listed in Section 6.8. Efficacy endpoints for each 
patient will be presented in listings. 
7.5.1 One-year Survival  
One year survival rate is the percentage of patients in the study who are still alive for one 
year after their alloSCT. The one-year survival rate will be summarized by cohorts using 
Kaplan Meier method. The associated two sided 95% CIs will be calculated using 
complementary log-log transformation method. 
7.5.2 Day -1 and Day 30 MRD (Minimal Residual Disease) Negativity (Part A 
only)  
MRD detected in bone marrow will be listed at Day -1 and Day 30.  
7.5.3 Best Response (Part A only) 
The best response is defined as the best disease response determined by the investigator 
based on the response criteria for AML (Cheson 2003) during the study before other 
anticancer treatment. The response categories are CR, CRi, mLFS, PR, and SD. The patients’ 
best response will be listed.  
7.5.4 Duration of Response (Part A only) 
Duration of response is defined as the time from the start of the first documented CR/CRi to 
the first documentation of relapse or death due to any cause, whichever comes first. Duration 
of response information will be listed.  
7.5.5 Overall Survival (OS) from alloSCT 
Overall survival (OS) is defined as the time from the date of alloSCT to date of death due to 
any cause. Specifically, 
OS = date of death – date of alloSCT + 1. 
OS information will be listed.  
7.6 Safety Analyses 
The All Treated Patients analysis set will be used to summarize all safety endpoints. 
Adverse events will be coded using Medical Dictionary for Regulatory Activities (MedDRA, 
Version 18.0 or higher). 


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Laboratory values will be graded according to the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE version 4.03 or higher). 
Concomitant medications will be coded using WHO Drug (version: June 2015 or more 
recent). 
7.6.1 Adverse Events 
Adverse events will be summarized by MedDRA preferred term in descending frequency of 
occurrence by cohort and total, and separately for Part A and Part B unless otherwise 
specified.  For incidence reporting, if a patient reports more than one AE that was coded to 
the same system organ class or preferred term, the patient will be counted only once for that 
specific system organ class or preferred term. 
A treatment-emergent AE is defined as a newly occurring or worsening AE after the first 
dose of study drug. See Appendix B for details regarding treatment-emergent classification. 
Summaries of AEs will be provided by dose cohort and total within study part for the 
following: 
● 
Treatment-emergent Adverse Events by preferred term 
● 
Treatment-emergent AEs by system organ class and preferred term 
● 
AEs related to vadastuximab talirine by preferred term 
● 
AEs related to reduced intensity chemotherapy (RIC) by preferred term (Part A only) 
● 
AEs related to GVHD by preferred term 
● 
Serious Adverse Events (SAEs) by preferred term 
● 
SAEs related to vadastuximab talirine by preferred term 
● 
SAEs related to RIC by preferred term (Part A only) 
● 
SAEs related to GVHD by preferred term 
● 
AEs leading to dose delay of vadastuximab talirine by preferred term (Part B only) 
● 
AEs leading to treatment discontinuation by preferred term (Part B only) 
● 
AEs leading to treatment discontinuation related to vadastuximab talirine by preferred 
term (Part B only) 
● 
Infusion related reactions by preferred term 
● 
DLTs by preferred term 
● 
Treatment-emergent AEs by system organ class, preferred term and maximum grade.  
At each system organ class or preferred term, multiple occurrences of events within a 
patient are counted only once at the highest grade 


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● 
Grade 3 - 5 treatment-emergent AEs by preferred term 
All adverse events, Treatment-emergent adverse events, serious adverse events, adverse 
events leading to treatment discontinuation, adverse events as the primary cause of death, and 
adverse events of special interest (including pulmonary event, renal event, severe hepatic 
dysfunction, cardiac death, and sepsis) will be listed. 
7.6.2 Clinical Laboratory Parameters 
Laboratory values (e.g., chemistry, hematology, urinalysis, and pulmonary function tests) 
may be presented graphically for each lab test by scheduled visit, dose cohort and total within 
study part.  Summary statistics may be tabulated where appropriate. Shift tables for the 
laboratory parameters with CTCAE grade may also be provided. Laboratory values will be 
listed with NCI CTCAE v4.03 grades and out-of-normal range flags.  
7.6.3 ECOG Performance Status 
ECOG performance status will be listed by patient.  
7.6.4 Concomitant Medications 
Concomitant medications will be listed by patient. 
7.6.5 Deaths 
The number of total deaths, deaths that occur within 30 days and 60 days of first study 
treatment, deaths that occur within 30 days of last study treatment, and deaths that occur 
more than 30 days after last study treatment, as well as the relationship to disease, will be 
summarized separately for Part A and B. In addition, cause of death will be identified by 
descending MedDRA preferred term (unless otherwise specified) and listed by patient. 
7.6.6 GVHD Assessments 
GVHD assessment will be listed for each scheduled assessment.  
7.6.7 Allogeneic Stem Cell Transplant 
The number and percentage of patients who received reduced intensity conditioning regimen, 
the time from transplant to first dose of SGN-CD33A (Part B), the time from last dose of 
SGN-CD33A to transplant (Part A), and SOS/VOD rate will be summarized. 
Part A patients’ post-alloSCT VOD assessment information will be listed using all treated 
patients set. 
7.7 Additional Analyses  
7.7.1 MRD - negativity 
MRD detected in bone marrow will be listed at each bone marrow exam. The MRD 
negativity rate is defined as the proportion of patients with MRD negativity. The MRD 
negativity rate at each bone marrow exam will also be summarized. 


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7.7.2 Event-free Survival (EFS) 
Event-free survival is defined as the time from the day of alloSCT to the first documentation 
of treatment failure (defined below). EFS information will be listed.     
• Part A 
Treatment failure is defined as failure to achieve CR/CRi by Day 30, relapse from 
CR/CRi, or death, due to any cause, whichever comes first. Treated patients who die 
or withdraw from study before receiving alloSCT will be excluded from the analysis. 
• Part B 
Treatment failure is defined as relapse of AML or death due to any cause, whichever 
comes first. 
7.7.3 Pharmacokinetics 
The observed plasma vadatuximab talirine ADC and SGD-1882 (if measurable) will be 
summarized with descriptive statistics at each PK sampling time point using the All Treated 
Patients analysis set. PK/PD analyses will be performed outside of Biometrics and may be 
presented in a separate PK report. 
7.7.4 Antitherapeutic Antibody (ATA) Incidence Rate 
The antitherapeutic antibody (ATA) incidence rate is defined as the proportion of patients 
who develop ATA at any time during the study.  
ATA incidence rate may be summarized by cohort and total within study part for all treated 
patients. An exact two-sided 95% confidence interval using the Clopper-Pearson method 
(Clopper 1934) may be calculated. 
7.7.5 Biomarker Analysis 
Biomarker assessments may be summarized using descriptive statistics. Biomarker 
assessments may include the following: CD33 expression level and saturation by 
vadastuximab talirine on CD33+ cells, cytogenetic abnormalities and/or mutation of genes 
with known prognostic significance for AML, soluble CD33, lymphocyte subset recovery 
post-transplant, and evaluation of MRD at protocol specified time points.  
7.7.6 Quantification of T-, B-, and NK-cell Lymphocyte Subsets Post-
transplant 
Recovery of T-, B- and NK-cell lymphocyte subsets post-transplant may be monitored in 
peripheral blood by the local laboratory according to institutional standard. In Part A, 
whether actual values for each post baseline test are in normal range or not may be 
summarized by cohort and total. In Part B, the changes from baseline (within 3 days prior to 
first dose of vadastuximab talirine) test may be summarized for each post baseline test by 
cohort and total.  
 


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8 
INTERIM ANALYSIS 
No formal interim analyses are planned.  
A SMC consisting of all principal investigators, and the sponsor’s medical monitor will 
monitor the trial for safety and DLTs.  Each Phase 1 dose cohort will be evaluated for DLTs 
prior to enrolling the subsequent cohort. The SMC will also review aggregate safety data and 
efficacy data from Phase 2 in a regular basis. The process for dose escalation decisions and 
the roles and responsibilities of the SMC is documented in the SMC Charter. 
In addition, interim data from the study may be presented at scientific meetings such as the 
American Society of Hematology (ASH) or the American Society of Clinical Oncology 
(ASCO). 
The final analysis for this study will occur after all patients have completed treatment and the 
follow-up period, or after study termination by the sponsor. 
9 
CHANGES FROM PLANNED ANALYSES 
9.1 Changes from the Original Protocol 
There is one change from original protocol: the study stopping criteria is added. 
9.2 Changes from the Original SAP 
The sponsor decided to terminate the study earlier.There are some changes from the original 
SAP:  1) the study stopping criteria is added; 2) New algorithm for missing data imputation is 
added; and 3) GVHD and allogeneic stem cell transplant are included; 4) Summary of AE 
outputs are modified. 
 


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REFERENCES 
Carreras E, Diaz-Beya M, Rosinol L, Martinez C, Fernandez-Aviles F and Rovira M (2011). The incidence of 
veno-occlusive disease following allogeneic hematopoietic stem cell transplantation has diminished and the 
outcome improved over the last decade. Biol Blood Marrow Transplant 17: 1713-20. 
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. 
Clopper CJ and Pearson ES (1934). The use of confidence or fiducial limits illustrated in the case of the 
binomial. Biometrika 26: 404-413. 
Collett D (1994). Interval-censored survival data. Modelling survival data in medical research. Boca Raton, 
Fla., Chapman & Hall/CRC: 237-251. 
Harris AC, Young R, Devine S, Hogan WJ, Ayuk F, Bunworasate U, Chanswangphuwana C, Efebera YA, 
Holler E, Litzow M, Ordemann R, Qayed M, Renteria AS, Reshef R, Wolfl M, Chen YB, Goldstein S, Jagasia 
M, Locatelli F, Mielke S, Porter D, Schechter T, Shekhovtsova Z, Ferrara JL and Levine JE (2016). 
International, Multicenter Standardization of Acute Graft-versus-Host Disease Clinical Data Collection: A 
Report from the Mount Sinai Acute GVHD International Consortium. Biol Blood Marrow Transplant 22: 4-10. 
 
  
 


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


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


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


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


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