Clinical trial NCT02706899
Conditions: Myelodysplastic Syndrome
Keywords: Antibody-Drug Conjugate CD33 Antigen
Sponsor: Seagen Inc.
Start date: 2016-02-01; Completion date: 2017-11-06
Enrollment: 19 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a phase 1/2 study to evaluate the combination of vadastuximab talirine (SGN-CD33A; 33A) and azacitidine in subjects with previously untreated International Prognostic Scoring System (IPSS) Intermediate-2 or high risk myelodysplastic syndrome (MDS).

Detailed description:
In the phase 1 portion of the study, escalating doses of 33A will be evaluated in combination with azacitidine, and a dose of 33A will be selected to proceed to phase 2. The phase 2 portion of the study is randomized, double-blind and placebo-controlled; it is designed to compare the overall response rate (ORR) between 2 study arms.

Arms: arm 1: Vadastuximab talirine plus azacitidine arm 2: placebo plus azacitidine
Interventions: intervention 1: vadastuximab talirine intervention 2: Azacitidine intervention 3: Placebo (for 33A)
Intervention descriptions: intervention 1: Intravenous (IV) push every 4 weeks intervention 2: 75 mg/m\^2 given intravenously or subcutaneously for 7 days every 4 weeks intervention 3: Placebo supplied in single-use vials matching 33A, IV push every 4 weeks

Protocol documents:
Prot_000.pdf: 


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1. 
SIGNAT
URES 
URepresentatives of Sponsor 
I have read and agree to the protocol, SGN33A-004, titled 'A phase 1/2 study of 
vadastuximab talirine (SGN-CD33A) in combination with azacitidine in patients with 
previously untreated Intenational Prognostic Scoring System (IPSS) Intermediate-2 or High 
risk myelodysplastic syndrome ( MDS)'. I am aware of my responsibilities under the 
guidelines of GCP, local regulations (as applicable), and the study protocol. I agree to 
conduct the study according to these responsibilities. 
Study SGN33A-004 
Vadastuximab talirine 
Protocol V03 
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Investigator
I have read and agree to the protocol, SGN33A-004, titled ‘A phase 1/2 study of vadastuximab 
talirine (SGN-CD33A) in combination with azacitidine in patients with previously untreated 
International Prognostic Scoring System (IPSS) Intermediate-2 or High risk myelodysplastic 
syndrome (MDS)’. I am aware of my responsibilities as an Investigator under the guidelines 
of GCP, local regulations (as applicable), and the study protocol. I agree to conduct the study 
according to these responsibilities and to appropriately direct and assist the staff under my 
control, who will be involved in the study.
Clinical Site: 
Site Number:
Site Principal Investigator:
Print Name
Title
Signature
Date


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2.
SYNOPSIS
NAME OF SPONSOUR:Seattle Genetics, Inc.
PUROTOCOL No.:SGN33A-004
NAME OF STUDY TUREATMENT:Azacitidine with or without Vadastuximab Talirine 
TITLE OF STUDY:A phase 1/2 study of vadastuximab talirine (SGN-CD33A) in combination with 
azacitidine in patients with previously untreated International Prognostic Scoring System (IPSS) 
Intermediate-2 or High risk myelodysplastic syndrome (MDS)
STUDY CENTEURS:Subjectswill be enrolled at approximately 35 sites in North America.
STUDY PEURIOD: First subject enrolled: May 2016 
All subjects completed treatment: May 2019 
PHASE OF 
DEVELOPMENT:
Phase1/2
OBJECTIVES:
Primary Objective:
• To determine the recommended vadastuximab talirine (SGN-CD33A) dose in combination with 
azacitidine in the open-label Phase 1 Portion of study
• To compare the overall response rate (OURUR = complete response + partial response [Complete 
response (CUR)+PUR]) between treatment arms in the randomized, double-blind, placebo-controlled 
Phase 2 Portion of study
Secondary Objectives:
• To evaluate the safety of the combination of vadastuximab talirine and azacitidine(Phase 1 and 
Phase 2 Portions)
• To compare the CUR rate between treatment arms (Phase2 Portion)
• To compare the hematologic improvement (HI) rate between treatment arms (Phase 2 Portion)
• To compare the duration of response (DOUR) between treatment arms (Phase 2 Portion)
• To compare progression-free survival (PFS) between treatment arms (Phase 2 Portion)
• To compare the rate of transformation to acute myeloid leukemia (AML)between treatment arms 
(Phase 2 Portion)
• To compare the overall survival (OS) between treatment arms (Phase 2 Portion)
Exploratory Objectives:
• To assess the pharmacokinetics(PK) and pharmacodynamics of vadastuximab talirine (Phase 1 
and Phase 2 Portions)
• To assess the incidence of antitherapeutic antibodies (ATAs) against vadastuximab talirine 
(Phase1 and Phase 2 Portions)
• To assess exploratory biomarkers of clinical activity of vadastuximab talirine in combination with 
azacitidine (Phase 1 and Phase2 Portions)
• To assess quality of life (QoL; Phase 2 Portion)
STUDY DESIGN AND METHODOLOGY:This is a phase 1/2 study to evaluate the combination of 
vadastuximab talirine and azacitidine in subjects with previously untreated IPSS Intermediate-2 or High 
risk MDS. In the Phase 1 Portion of the trial, escalating doses of vadastuximab talirine will be evaluated in 
combination with azacitidine, and 1 dose will be selected for the randomized, double-blind, placebo-
controlled Phase 2 Portion of the study, which is designed to compare the OURUR between 2 study arms.
Phase 1 Portion –Open-Label Dose Evaluation 
Cohorts of 6 dose-limiting toxicity (DLT)-evaluable subjects will be enrolled inan open-label fashion to 
receive vadastuximab talirine (intravenous [IV]) push in combination with azacitidine (75mg/m2; 
subcutaneously [SC] or IV) in 28-day cycles, starting at 5mcg/kg vadastuximab talirine. The DLT-
evaluable population will include all Phase 1 subjects who have completed at least Cycle 1 of treatment 


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(Cycle 1 of treatment is completed when the patient receives the first dose of azacitidine on Day 1 of Cycle 
2) ordiscontinued study treatment because of adverse events (AEs), or for a safety-related reason before 
having had the opportunity to receive the first dose of azacitidine on Day 1 of Cycle 2. In the Phase 1 
Portion of the study, DLTs will be defined as posttreatment grade 4 neutropenia or grade 4 
thrombocytopenia lasting >42days from the start of therapy, in the absence of evidence of active MDS, or 
any grade 3 or higher non-hematologic toxicity that is clearly NOT resulting from underlying MDS or 
azacitidine, with the exception of:
a. Grade 3 allergic reaction, fatigue, asthenia, anorexia, or constipation
b. Grade 3 nausea, vomiting, or diarrhea not requiring tube feeding or total parenteral nutrition or 
hospitalization 
c. Febrile neutropenia (which resolves with appropriate treatment or marrow recovery), infection, 
bleeding, or other expected direct complications of cytopenias due to active MDS
If 2 or more subjects in a 6-subject cohort have DLTs, that dose level will be considered to have exceeded 
the maximum tolerated dose (MTD). If 5 mcg/kg vadastuximab talirine in combination withazacitidine is 
considered tolerable (≤1 of 6 subjects experiences a DLT), a cohort of 6DLT-evaluable subjects will 
receive 10 mcg/kg vadastuximab talirine and azacitidine. If 10mcg/kg vadastuximab talirine in 
combination with azacitidine is considered tolerable, a cohort of 6DLT-evaluable subjects will receive 
15mcg/kg, and if 15mcg/kg vadastuximab talirine in combination with azacitidine is considered tolerable, 
a cohort of 6DLT-evaluable subjects will receive 20 mcg/kg. If 5mcg/kg vadastuximab talirine in 
combination with azacitidine is not considered tolerable (>1 of 6 subjects experiences a DLT), a cohort of 
6DLT-evaluable subjects will receive 3 mcg/kg vadastuximab talirine and azacitidine. 
Azacitidine will be given 7 times per cycle, either on the first 7 days or 5 days on/2 days off/2 days on; 
vadastuximab talirine will be given after azacitidine on the last day of azacitidine administration in each 
cycle. UResponse assessments (bone marrow examination and complete blood count [CBC]) will be 
conducted on Day 22-29 of even-numbered cycles until CUR, then every 4 cycles thereafter. Subjects may 
continue on study treatment until disease progression, relapse, or unacceptable toxicity. After 
discontinuation of study treatment, subjects who have not experienced progression or relapse will continue 
to be assessed for response every 4 months through 24 months after end of treatment (EOT) or until 
initiation of another anticancer treatment, progression, or relapse, whichever comes first. All subjects will
be contacted for survival status every 2 months after EOT in follow-up until death or study closure, 
whichever comes first. Safety will be monitored through the surveillance of AEs, laboratory test measures, 
physical examination findings, and concomitant medication records. An additional bone marrow 
examination will be conducted for research purposes for subjects in the Phase 1 Portion of the study only. 
After 6 DLT-evaluable subjects have had the opportunity to complete at least Cycle 1 (Cycle 1 of treatment 
is completed when the patient receives the first dose of azacitidine on Day 1 of Cycle 2) of treatment in 
each planned dose cohort, the data will be aggregated and analyzed by a Safety Monitoring Committee 
(SMC). Based on the evaluation of the data, including the incidence of DLT in each cohort, the SMC may 
recommend the dose of vadastuximab talirine for the Phase 2 Portion of the study at the time of the 
evaluation. If additional safety information is required to recommend a phase 2 dose, the SMC could 
recommend enrollment of up to 12 additional treated subjects to continue to evaluate the safety of the 
combination at vadastuximab talirine dose(s) of 3, 5, 10, or 20 mcg/kg. Subsequently, upon completion of 
dose escalation, up to 12 more expansion patients may be enrolled (maximum of 24 expansion patients 
total), at any dose level not previously shown to exceed the MTD, to further characterize safety, PK, and 
activity.
Phase 2 Portion –URandomized, Placebo-Controlled 
Subjects will be randomized in a 1:1manner to one of the study arms described in the following table. 
URandomization will be stratified by Eastern Cooperative Oncology Group (ECOG) performance score 
(0vs1or2) and IPSS score (Intermediate-2 vs High risk). 


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Treatment Arm
Study Treatment 
Experimental
Comparator
Open-Label Study 
Treatment
Azacitidine 75 mg/m2SC or IV for 7 days 
X
X
Blinded Study 
Treatment
Vadastuximab talirine (SGN-CD33A) every 4 weeks 
(after azacitidine on the last day of azacitidine 
administration) via IV push at SMC-recommended 
dose
X
Placebo every 4 weeks (after azacitidine on the last 
day of azacitidine administration) via IV push 
X
UResponse assessments (bone marrow examination and CBC) will be conducted once between Day 22 and 
Day 29 of even-numbered cycles until CUR, then every 4 cycles thereafter. Subjects may continue on study 
treatment until disease progression, relapse, or unacceptable toxicity. After discontinuation of study 
treatment, subjects who have not experienced progression or relapse will continue to be assessed for 
response every 4 months through 24 months after EOT or until initiation of another anticancer treatment, 
progression, or relapse, whichever comes first. All subjects will be contacted for survival status every 
2months after EOT in follow-up until death or study closure, whichever comes first. Safety will be 
monitored through the surveillance of AEs, laboratorytest measures, physical examination findings, and 
concomitant medication records. An Independent Data Monitoring Committee (IDMC) will also 
periodically assess the ongoing safety data and make recommendations to either continue evaluating the 
combination or to stop the study due to toxicity concerns. 
STUDY POPULATION AND MAIN CURITEURIA FOUR INCLUSION/EXCLUSION: 
Subjects cannot be enrolled before all inclusion criteria (including test results) are confirmed.
Inclusion Criteria: 
Eligible subjects must meet the following criteria: 
1. Subjects with cytologically/histologically confirmed MDS according to the World Health 
Organization (WHO) 2008 classification, that is determined to be Intermediate-2 (1.5-2 points) or 
High risk (≥2.5 points) according to the IPSS risk category, with ≥5% and <20% bone marrow 
blasts.
2. Previously untreated for MDS with the exception of transfusions, hematopoietic growth factors, or 
immunosuppressive therapy (IST).
3. Age ≥18 years.
4. Subject is eligible for therapy with azacitidine.
5. Life expectancy of at least 12 weeks.
6. ECOG performance status ≤2.
7. The following baseline laboratory data:
a. white blood cell (WBC) count <20,000/mcL; pre-study use of hydroxyurea to control WBC is 
acceptable up to 24 hours prior to firstdose of study treatment.
b. direct bilirubin ≤2 x upper limit of normal (ULN) and/or total serum bilirubin ≤1.5 x ULN (or 
total serum bilirubin ≤3 x ULN for subjects with Gilbert’s disease).
c. serum creatinine ≤2.5 x ULN and creatinine clearance ≥30 mL/min.
d. alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3 x ULN.
8. 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 studytreatment. 
Females of non-childbearing potential are those who are postmenopausal greater than 1year or 
who have had a bilateral tubal ligation or hysterectomy.
9. Females of childbearing potential and males who have partners of childbearing potential must 
agree to use 2 effective contraception methods during the study and for 6 months following the 
last dose of study drug. 
Acceptable methods of contraception include: hormonal (birth control pills, injections, implants), 
intrauterine device (IUD), intrauterine hormone-releasing system (IUS), vasectomy (for males), 


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barrier methods (male and female condoms, diaphragms, and spermicides), and complete 
abstinence. Complete abstinence is acceptable when this is in line with the preferred and usual 
lifestyle of thepatient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, 
post-ovulation methods] and withdrawal are not acceptable methods of contraception.) 
10.Subjects must provide written informed consent. 
Exclusion Criteria: 
If any of the following apply, the subject MUST NOT enter the study: 
1. UReceived prior treatment for MDS with lenalidomide or hypomethylating agents (HMAs). 
2. History of one of the following myeloproliferative neoplasms: essential thrombocythemia, 
polycythemia vera, and primary myelofibrosis.
3. Second malignancy currently requiring active therapy (except for hormonal/anti-hormonal 
treatment, eg, prostate or breast cancer).
4. Central nervous system leukemia based on imaging or documented positive cytology in cerebral 
spinal fluid.
5. Anyuncontrolled grade 3 or higher (per National Cancer Institute [NCI] Common Terminology 
Criteria for Adverse Events [CTCAE], Version 4.03) viral, bacterial, or fungal infection within 
14days prior to the first dose of study treatment. Antimicrobial prophylaxis or ongoing treatment 
of resolving/controlled infection is permitted.
6. Known to be positive for hepatitis B by surface antigen expression. Known to have active hepatitis 
C infection (positive by polymerase chain reaction or on antiviral therapy for hepatitis C within 
the last 6 months).
7. Known to be positive for human immunodeficiency virus (HIV).
8. Documented history of a cerebral vascular event (stroke or transient ischemic attack), unstable 
angina, or myocardial infarction within 6 months prior to theirfirst dose of study drug, or 
refractory congestive heart failure unresponsive to medical treatment.
9. Therapy with the following agents within the specified timeframe prior to first study treatment:
a. systemic anti-neoplastic or investigational agents within prior 14 days.
b. hematopoietic growth factors within 7 days (erythropoietin, granulocyte colony stimulating 
factor, granulocyte-macrophage colony stimulating factor, or thrombopoietin receptor 
agonists).
10.Known hypersensitivity to any excipient contained in the drug formulation of any study treatment.
11.Prior allogeneic hematopoietic stem cell transplant, for any indication.
12.Hypocellular MDS, defined as bone marrow cellularity <30% in subjects ≤60 years old or <20% 
cellularity in subjects >60 years old.
13.Candidates for allogeneic stem cell transplant at the time of screening.
14.History of clinically significant liver disease (e.g. liver cirrhosis) or ongoing alcohol abuse.
NUMBEUR OF SUBJECTS: Approximately 142 subjects; up to 36 in phase 1 and approximately 106 in 
phase 2
STUDY TUREATMENT(S): 
Test Product, Dose and Mode of Administration:
Phase 1 Portion:
Vadastuximab talirine (SGN-CD33A) every 4 weeks (after azacitidine on the last day of azacitidine 
administration) via IV push at 5 mcg/kg up to 20 mcg/kg (with possible de-escalation to 3 mcg/kg), based on 
the dose escalation.
Azacitidine 75 mg/m2SC or IV for 7 days (7 consecutive days or 5 days on/2 days off/2 days on), beginning 
on Day 1 of repeated 4-week cycles.
Phase 2 Portion:
Vadastuximab talirine or placebo every 4 weeks (after azacitidine on the last day of azacitidine 
administration) via IV push at the dose determined in the Phase 1 Portion.


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Azacitidine 75 mg/m2SC or IV (at the Investigator’s discretion) for 7 days (7 consecutive days or 5days on/
2days off/2days on), in repeated 4-week cycles.
UReference Therapy, Dose and Mode of Administration:
Inactive placebo matching vadastuximab talirine will be provided for the Phase 2 Portion.
DUURATION OF TUREATMENT: Study treatment consists of repeated 4-weekcycles of combination 
treatment. Subjects may continue on study treatment until disease progression, relapse, or unacceptable 
toxicity, whichever comes first.
STUDY EVALUATIONS:
Efficacy Evaluations: 
Activity will be assessed by routine laboratory tests(blood counts) and bone marrow examinations. 
UResponse categorization will be based on the International Working Group (IWG) UResponse Criteria in 
Myelodysplasia (Cheson 2006).
Primary Efficacy Criteria:
Overall response rate (OURUR), defined as the proportion of subjects who achieve any category of CUR (CUR 
includes CUR and Marrow CUR) or PUR based on the 2006 IWG criteria for MDS. 
Secondary Efficacy Criteria:
Secondary efficacy endpoints include the following: 

Complete response (CUR) rate

Hematologic improvement(HI) rate

Duration of response (DOUR)

Progression-free survival (PFS)

URate of transformation to AML

Overall survival (OS)
Pharmacokinetic (PK) and Antitherapeutic Antibody (ATA) Assessments:
Blood samples for PK and ATA assessment will be collected at baseline and throughout the treatment 
period. Sensitive, qualified assays will be used to measure concentrations of antibody-drug conjugate 
(ADC; vadastuximab talirine) and SGD-1882 in plasma and ATAs in serum. The remaining PK samples 
will be archived forpossible analysis of vadastuximab talirine-related species. The assays will include 
enzyme-linked immunosorbent assays (ELISA) and liquid chromatography/tandem mass spectrometry 
assays, as well as other assays if further characterization is required. A qualified electrochemiluminescence 
assay will be used to assess ATA.
Biomarker Assessments:
Peripheral blood and bone marrow aspirates will be collected at baseline and throughout the treatment 
period. Biomarker assessments may include CD33 expression level,abundance of myeloid-derived 
suppressor cells (MDSC), characterization of leukocyte subpopulations in peripheral blood, variation in 
sequence of CD33 and genes commonly mutated in MDS and hematologic malignancies, soluble CD33, 
abundance of a variety of cytokines, and testing for Paroxysmal Nocturnal Hemoglobinuria (PNH) and 
human leukocyte antigen (HLA)-DUR15 at protocol-specified time points. Methods of analysis may include 
flow cytometry, ELISA, and DNA and URNA sequencing. 
Safety Criteria: 
Safety assessments will consist of the surveillance of AEs, laboratory test measures, physical examination 
findings, and concomitant medication records. 
Quality of Life (QoL): 
Quality of life will be assessed with the patient reported outcomes (PURO) tool Quality of Life 
Questionnaire (QLQ)-C30 at protocol-defined time points. 
STATISTICAL METHODS: 
Stratification (Phase 2 Portion only)


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Subjects will be stratified by baseline ECOG performance score (0 vs 1 or 2) and IPSS risk category 
(Intermediate-2 vs High risk).
Sample Size Considerations
Phase 1 Portion (minimum of 6 subjects per cohort): Six subjects are adequate to appropriately assess the 
safety profiles and DLT rates of differing dose levels of vadastuximab talirine in combination with 
azacitidine. If the trueincidence rate of DLT is 10%, the probability of considering a dose level tolerable 
(ie, ≤1 of 6 subjects experiences a DLT) will be 88.6%. If the true incidence rate of DLT is 50%, the 
probability of considering a dose level tolerable will be 10.9%.
Phase 2 Portion (106 subjects): A sample size of 106 subjects will provide 85% power to detect a treatment 
difference in OURUR, assuming an OURUR of 30% for azacitidine alone vs 55% for the combination of 
vadastuximab talirine with azacitidine, at a 2-sided 0.1 alpha level.
Analysis Methods
The primary efficacy endpoint of the study is OURUR in the Phase 2 Portion, defined as the proportion of 
subjects who achieve any category of CUR (CUR and Marrow CUR) or PUR based on the 2006 IWG criteria for 
MDS. Subjects who receive other MDS therapies before a response has been observed will be considered 
non-responders. The OURUR will be summarized by treatment group and the corresponding 90% confidence 
intervals will be calculated. The treatment difference in OURUR will be tested using a Cochran-Mantel-
Haenszel test. 
Secondary efficacy endpoints include CUR rate, HI rate, DOUR, PFS, rate of transformation to AML, and OS. 
Treatment differences in the rate of CUR, HI, and transformation to AML will be analyzed by the same 
method as forOURUR. DOUR, PFS, and OS will be estimated with the Kaplan-Meier method and tested with 
the stratified log-rank test.
The primary analysis of efficacy will be based on the intent-to-treat (ITT) analysis set, which includes all 
subjects who are randomized in the Phase 2 Portion of the study. 
Descriptive summaries of subject disposition, demographics, disease characteristics, baseline and 
pharmacodynamics biomarkers, extent of exposure to study treatment, and safety will be provided. The 
relationship of vadastuximab talirine PK and relevant pharmacodynamic endpoints, safety, or efficacy may 
be explored; these analyses, if conducted, will be descriptive.
DATE AND VEURSION: 13 April 2017, Version 03 


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3.
TABLE OF CONTENTS
1.
SIGNATUURES...........................................................................................................2
2.
SYNOPSIS..................................................................................................................4
3.
TABLE OF CONTENTS........................................................................................10
4.
LIST OF ABBUREVIATIONS AND DEFINITION OF TEURMS.........................15
5.
ETHICS....................................................................................................................18
5.1
Ethics Committee......................................................................................................18
5.2
Ethical Conduct of the Study.....................................................................................18
5.3
Subject Information and Consent..............................................................................18
6.
INVESTIGATOURS AND STUDY ADMINISTURATIVE STURUCTUURE...........19
7.
INTURODUCTION...................................................................................................20
7.1
Disease UReview.........................................................................................................20
7.2
Compound UReview....................................................................................................21
7.3
Clinical Study URationale............................................................................................22
8.
STUDY OBJECTIVES...........................................................................................23
8.1
Primary Study Objective...........................................................................................23
8.1.1
Phase 1 Portion..........................................................................................................23
8.1.2
Phase 2 Portion..........................................................................................................23
8.2
Secondary Study Objectives......................................................................................23
8.3
Exploratory Objectives..............................................................................................23
8.4
Endpoints...................................................................................................................24
8.4.1
Primary Endpoint.......................................................................................................24
8.4.2
Secondary Efficacy Endpoints...................................................................................24
8.4.3
Pharmacokinetic and Antitherapeutic Antibody Assessments..................................24
8.4.4
Biomarker Assessments.............................................................................................24
8.4.5
Safety Criteria............................................................................................................25
8.4.6
Quality of Life...........................................................................................................25
9.
INVESTIGATIONAL PLAN.................................................................................26
9.1
Overall Study Design and Plan..................................................................................26
9.1.1
Phase 1 Portion –Open-Label Dose Evaluation........................................................26
9.1.2
Phase 2 Portion –URandomized, Placebo-Controlled.................................................27
9.1.3
Study Stopping Criteria.............................................................................................29
9.2
Discussion of Study Design.......................................................................................29
9.3
Study Duration...........................................................................................................29
9.4
Study Population.......................................................................................................30
9.4.1
Inclusion Criteria.......................................................................................................30
9.4.2
Exclusion Criteria......................................................................................................31
9.4.3
Withdrawal and UReplacement of Subjects.................................................................32
9.4.3.1
Discontinuation of Study Drug..................................................................................32
9.4.3.2 
Subject Withdrawal From Study...............................................................................33
9.4.3.3
UReplacement of Subjects...........................................................................................33
9.5
Treatment...................................................................................................................33
9.5.1
Treatments Administered..........................................................................................33
9.5.1.1
URequired Premedication and Postmedication............................................................34


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9.5.1.2
Vadastuximab Talirine..............................................................................................34
9.5.1.2.1
Description................................................................................................................34
9.5.1.2.2
Method of Procurement.............................................................................................34
9.5.1.2.3
Dose and Administration...........................................................................................34
9.5.1.2.4
Preparation................................................................................................................35
9.5.1.2.5
Study Treatment Labeling and Packaging.................................................................35
9.5.1.2.6
Study Treatment Storage and Accountability............................................................35
9.5.1.3
Azacitidine.................................................................................................................36
9.5.1.3.1
Description................................................................................................................36
9.5.1.3.2
Method of Procurement.............................................................................................36
9.5.1.3.3
Dose and Administration...........................................................................................36
9.5.1.3.4
Preparation................................................................................................................36
9.5.1.3.5
Storage and Accountability.......................................................................................36
9.5.1.4
Management of Adverse UReactions...........................................................................37
9.5.1.4.1
Management of Infusion UReactions...........................................................................37
9.5.1.4.2
Overdose....................................................................................................................37
9.5.1.4.3
Dose Modifications....................................................................................................37
9.5.2
Blinding of Study Medication...................................................................................39
9.5.3
Prior and Concomitant Therapy................................................................................39
9.5.4
Treatment Compliance..............................................................................................40
9.5.5
Assignment to Treatment...........................................................................................40
9.6
Efficacy and Safety Variables...................................................................................40
9.6.1
Efficacy and Safety Measurements Assessed............................................................40
9.6.1.1
Efficacy Measurements.............................................................................................40
9.6.1.2
Pharmacokinetic and Antitherapeutic Antibody Assessments..................................41
9.6.1.3
Biomarker Assessments.............................................................................................41
9.6.1.4
Safety Measurements.................................................................................................41
10.
STUDY EVALUATIONS BYVISIT.....................................................................42
10.1
Screening (Day -28 to 1)...........................................................................................48
10.2
Treatment Period.......................................................................................................49
10.2.1
Phase 1 Portion..........................................................................................................49
10.2.1.1
Cycle 1.......................................................................................................................49
10.2.1.2
Cycle 2.......................................................................................................................51
10.2.1.3
Cycle 3.......................................................................................................................52
10.2.1.4
Cycles ≥4...................................................................................................................53
10.2.2
Phase 2 Portion..........................................................................................................54
10.2.2.1
Cycle 1.......................................................................................................................55
10.2.2.2
Cycle 2.......................................................................................................................56
10.2.2.3
Cycle 3.......................................................................................................................57
10.2.2.4
Cycles ≥4...................................................................................................................58
10.3
End of Treatment.......................................................................................................59
10.4
Follow-Up..................................................................................................................60
10.5
End of Study/End of Follow-up.................................................................................60
11.
METHODS OF ASSESSMENT.............................................................................61


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11.1
Medical History.........................................................................................................61
11.2
Cytogenetics and Gene Mutations.............................................................................61
11.3
Bone Marrow Examination.......................................................................................61
11.4
Pharmacokinetic and Biomarker Assessments..........................................................61
11.4.1
Pharmacokinetics.......................................................................................................61
11.4.2
Biomarker Analyses: Whole Blood...........................................................................63
11.4.3
Biomarker Analyses: Bone Marrow Aspirate............................................................64
11.5
Physical Examination, ECOG Performance Status, Weight, and Vital Signs...........65
11.6
Electrocardiograms....................................................................................................65
11.7
Clinical Laboratory Tests..........................................................................................66
11.8
Blood Samples for Antitherapeutic Antibodies.........................................................67
11.8.1
Antitherapeutic Antibodies........................................................................................67
11.9
Quality of Life Data Collection.................................................................................67
11.10
UResponse Assessment................................................................................................67
12.
SAFETY MEASUUREMENTS AND VAURIABLES..............................................68
12.1
Adverse Events..........................................................................................................68
12.1.1
Definitions.................................................................................................................68
12.1.2
Procedures for Eliciting and URecording Adverse Events..........................................70
12.1.3
UReporting Periods for Adverse Events and Serious Adverse Events.........................71
12.1.4
Adverse Events of Special Interest............................................................................71
12.1.5
Serious Adverse Events URequire Immediate UReporting............................................72
12.1.6
Sponsor Safety UReporting URequirements in the United States..................................72
13.
DATA MANAGEMENT AND STATISTICAL ANALYSIS..............................73
13.1
Data Management......................................................................................................73
13.2
Sample Size Estimation.............................................................................................73
13.3
Statistical Analysis Plan............................................................................................73
13.4
URandomization...........................................................................................................73
13.5
Analysis Populations.................................................................................................74
13.5.1
Intent-to-Treat Population.........................................................................................74
13.5.2
Safety Population.......................................................................................................74
13.5.3
DLT-Evaluable Population........................................................................................74
13.5.4
Modified Intent-to-Treat Population..........................................................................74
13.5.5 
Per-Protocol Population.............................................................................................74
13.6
Statistical Methods....................................................................................................74
13.6.1
Missing Data..............................................................................................................74
13.6.2
Demographic and Baseline Data...............................................................................74
13.6.3
Subject Disposition....................................................................................................75
13.6.4
Efficacy......................................................................................................................75
13.6.4.1
UResponse to Treatment..............................................................................................75
13.6.4.2
Secondary Efficacy Endpoints...................................................................................75
13.6.5
Quality of Life...........................................................................................................76
13.6.6
Pharmacokinetics, Immunogenicity, and Biomarkers...............................................76
13.6.7 
Safety.........................................................................................................................76
13.6.8
Additional Data.........................................................................................................77


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13.6.9
Interim Analysis........................................................................................................77
13.6.10
Independent Data Monitoring Committee.................................................................77
14.
MONITOURING PUROCEDUURES (QUALITY ASSUURANCE)............................79
14.1
URoutine Monitoring...................................................................................................79
14.2
Inspections and Auditing Procedures........................................................................79
15.
STUDY MANAGEMENT AND MATEURIALS....................................................80
15.1
Electronic Case UReport Forms...................................................................................80
15.2
Data Collection..........................................................................................................80
15.3
Source Documents Maintenance...............................................................................81
15.4
URecord Maintenance..................................................................................................81
15.5
Confidentiality...........................................................................................................82
16.
ADMINISTURATION PUROCEDUURES..................................................................83
16.1
URegulatory Approval.................................................................................................83
16.2
Protocol Amendments...............................................................................................83
16.3
Protocol Adherence and Deviations..........................................................................83
16.4
Study Documentation, Privacy, and URecords URetention............................................84
16.5
Publication Policy......................................................................................................84
16.6
Clinical Study UReport................................................................................................84
16.7
Contractual and Financial Details..............................................................................84
16.8
Insurance, Indemnity, and Compensation.................................................................84
16.9
Discontinuation of the Study.....................................................................................85
16.10
Study Center File Management.................................................................................85
17.
UREFEURENCE LIST................................................................................................87
18.
APPENDICES..........................................................................................................89
18.1
Appendix 1: Declaration of Helsinki.........................................................................89
18.2
Appendix 2: Elements of Informed Consent.............................................................95
18.3
Appendix 3: Eastern Cooperative Oncology Group Performance Status..................96
18.4
Appendix 4: Common Terminology Criteria for Adverse Events (CTCAE; v 4.03)97
18.5
Appendix 5: URisk Factor Classification for Myelodysplastic Syndromes.................98
18.5.1
The International Prognostic ScoringSystem...........................................................98
18.5.2
The World Health Organization (WHO) Classification System...............................99
18.6
Appendix 6: UResponse Assessment –International Working Group UResponse 
Criteria.....................................................................................................................100
18.7
Appendix 7: European Organization for UResearch and Treatment of Cancer (EOURTC) 
Core Module (QLQ-C30)........................................................................................102
18.8
Appendix 8: Summary of Amendment 1.................................................................103
18.9
Appendix 9: Summary of Changes in Version 3.....................................................110


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LIST OF TABLES
Table1:
Treatment Arms....................................................................................................28
Table2:
Dose Modifications for Vadastuximab Talirine-Associated Toxicity..................38
Table3:
URecommended Scheduled Modifications for Azacitidine in Patients with 
<5% Blasts and Incomplete Hematologic URecovery at Day 42
a..........................39
Table4:
Study Schedule.....................................................................................................43
Table5:
Schedule of Pharmacokinetic, Immunogenicity, and Biomarker Assessments 
–Phase 1 Portion..................................................................................................45
Table6:
Schedule of Pharmacokinetic, Immunogenicity, and Biomarker Assessments 
–Phase 2 Portion..................................................................................................47
LIST OF FIGUURES
Figure1:
Study Schematic –Phase 1 Portion......................................................................27
Figure2:
Study Schematic –Phase 2 Portion......................................................................28


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4.
LIST OF ABBUREVIATIONS AND DEFINITION OF TEURMS
Term
Definition
ADC
Antibody-drug conjugate
AE
Adverse event 
Allo-HCT
Allogeneic hematopoietic stem cell transplant
ALT
Alanine aminotransferase (serum glutamic-pyruvic transaminase)
AML
Acute myeloid leukemia 
ANA
Antinuclear antibodies 
ANC
Absolute neutrophil count
ANCA
Anti-neutrophil cytoplasmic antibodies 
anti-dsDNA
Anti-double-stranded DNA 
ASCO
American Society of Clinical Oncology 
AST
Aspartate aminotransferase (serum glutamic-oxaloacetic 
transaminase)
ATA
Antitherapeutic antibody
CBC
Complete blood count 
CFUR
Code of Federal URegulations
CUR
Complete response
CURO
Clinical research organization
CURP
C-reactive protein
CTCAE
Common Terminology Criteria for Adverse Events
DFS
Disease-free survival
DLT
Dose-limiting toxicity
DOUR
Duration of response 
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCURF
Electronic Case UReport Form
ELISA
Enzyme-linked immunosorbent assays 
EOT
End of treatment
FAB
French-American-British 
FDA
Food and Drug Administration
GCP
Good Clinical Practice
-hCG
Beta human chorionic gonadotropin 
HI
Hematologic improvement
HIV
Human immunodeficiency virus 
HLA
Human leukocyte antigen 
HMA
Hypomethylating agent
ICH
International Council for Harmonisation
IDMC
Independent Data Monitoring Committee 


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Ig
Immunoglobulin
IND
Investigational New Drug
INN
International Nonproprietary Name
IPSS
International Prognostic Scoring System 
IURB
Institutional UReview Board
IST
Immunosuppressive therapy 
ITT
Intent-to-treat 
IUD
Intrauterine device 
IUS
Intrauterine hormone-releasing system
IV
Intravenous(ly)
IWG
International Working Group 
IXURS
Interactive voice and web recognition system 
LDH
Lactate dehydrogenase 
MDS
Myelodysplastic syndromes
MDSC
Myeloid-derived suppressor cells 
MedDURA
Medical Dictionary for URegulatory Activities
mITT
Modified intent-to-treat 
MTD
Maximum tolerated dose
NCI
National Cancer Institute
OURUR 
Overall response rate
OS
Overall survival
PBD
Pyrrolobenzodiazepine 
PBMC
Peripheral blood mononuclear cell
PD
Progressive disease 
PFS
Progression-free survival
PICC
Peripherally-inserted central catheter 
PK
Pharmacokinetic(s)
PNH
Paroxysmal Nocturnal Hemoglobinuria 
PUR
Partial response
PURO
Patient reported outcomes
QLQ
Quality of Life Questionnaire 
QoL
Quality of life 
URA
URefractory anemia 
URAEB
URefractory anemia with excess blasts 
URAEB-T
URefractory anemia with excess blasts in transformation 
URF
URheumatoid factor 
SAE
Serious adverse event
SAP
Statistical analysis plan


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SC
Subcutaneous(ly)
SD
Stable disease
SMC
Safety Monitoring Committee 
SMPC
Summary of product characteristics 
SOP
Standard Operating Procedure
SOS/VOD
Sinusoidal obstruction syndrome/veno-occlusive disease 
Study drug
Azacitidine with or without vadastuximab talirine
TEAE
Treatment-emergent AE 
ULN
Upper limit of normal
US
United States
USP
United States Pharmacopeia
USPI
United States prescribing information 
WBC
White blood cell 
WFI
Water for Injection 
WHO
World Health Organization


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5.
ETHICS
5.1Ethics Committee
This study will be conducted in compliance with Institutional UReview Board (IURB) and 
International Council for Harmonisation (ICH) Good Clinical Practice (GCP) Guidelines -
including Title 21 Part 56 of the United States (US) Code of Federal URegulations (CFUR) 
relating to IURBs and GCP as described in the US Food and Drug Administration (FDA) CFUR 
(21 CFUR § 50, 56, 312) -in accordance with applicable ICH regulations regarding clinical 
safety data management (E2A, E2B[UR3]), European Community directives 2001/20, 
2001/83, 2003/94 and 2005/28 as enacted into local law, and with ICH regulations regarding 
scientific integrity (E4, E8, E9, and E10). In addition this study will adhere to all local 
regulatory requirements and requirements for data protection.
Before initiating a trial/study, the Investigator/institution must have written and dated 
approval/favorable opinion from the IURB for the study protocol/amendment(s), written 
informed consent form, any consent form updates, subject recruitment procedures (eg, 
advertisements), and any written information to be provided to subjects and a statement from 
the IURB that they comply with GCP requirements. The IURB approval must identify the 
protocol version as well as the documents reviewed.
5.2Ethical Conduct of the Study
This study will be conducted in accordance with the Note for Guidance on GCP (ICH 
Harmonized Tripartite Guideline E6 (UR1); FDA CFUR [21 CFUR § 50, 56, 312]), Declaration of 
Helsinki (Fortaleza, Brazil, October 2013; Appendix 18.1), and all applicable regulatory 
requirements.
5.3Subject Information and Consent
The Investigator will explain the benefits and risks of participation in the study to each 
subject and obtain written informed consent. Written informed consent must be obtained 
prior to the subject entering the study and before initiation of any study-related procedure 
(including administration of study drug). 
The Sponsor will provide a sample informed consent form, based on the elements of 
informed consent in Appendix18.2. The final, version dated form must be agreed to by the 
Sponsor and the IURB and will contain all elements in the sample form, in language readily 
understood by the subject. Each subject’s original consent form, personally signed and dated 
by the subject and by the person who conducted the informed consent discussion, will be 
retained by the Investigator.The Investigator will supply all enrolled subjects with a copy of 
their signed informed consent.
The consent form may need to be revised during the study should important new information 
become available that may be relevant to the safety of the subject. In this instance approval 
should always be given by the IURB. Subjects on treatment should be informed of the changes 
and reconsented if the consent was updated for safety reasons. This is documented in the 
same way as previously described.




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7.
INTURODUCTION
7.1Disease UReview
The myelodysplastic syndromes (MDS) represent a group of heterogeneous hematopoietic 
disorders derived from an abnormal multipotent progenitor cell.  They are characterized by 
ineffective hematopoiesis, bone marrow failure, peripheral blood cytopenias, and reduced 
survival. MDS may be classified as indolent or aggressive (lower-or higher-risk), depending 
on life expectancy and likelihood of progression to acute myeloid leukemia (AML). The 
annual age-adjusted incidence of MDS is approximately 4.5 per 100,000 in the US. MDS is 
associated with age, and the incidence of MDS for Americans ≥50 years of age is 
approximately 15.5 per 100,000 per year. [1] 
Prognosis in MDS depends on the number of bone marrow blasts, cytogenetic abnormalities, 
and the amount of peripheral blood cytopenias. These risk factors are scored in the 
International Prognostic Scoring System (IPSS) as percent bone marrow blasts (<5% =0, 
5%-10% =0.5, and 11%-20% =1.5), karyotype (good [normal, -Y, del(5q), del(20q)] =0; 
intermediate [other abnormalities] =0.5, and poor [≥3 abnormalities] =1.0), and cytopenias (0 
or 1 =0 and 2 or 3 =0.5). Patientsare assigned scores based on the sum of risk factor scores, 
and prognosis is defined as Low (score =0), Intermediate-1 (score =0.5-1.0), Intermediate-2 
(score =1.5-2.0), and High (score ≥2.5) risk. These scores have been shown to predict 
survival and riskof progression to AML. [2; Appendix18.5.1] MDS can also be classified 
according to the World Health Organization (WHO) system using morphologic, 
cytochemical, and immunophenotypic features of the neoplastic cells, [Appendix18.5.2] an 
update to the older French-American-British (FAB) classification.
For patients with Low or Intermediate-1 risk MDS, standard treatment is usually supportive 
care; symptomatic anemia is treated with growth factors as appropriate (patients with del(5q) 
and symptomatic anemia are generally treated with lenalidomide). Among patients who are 
intolerant or fail to respond to treatment with erythropoiesis-stimulating agents, those with 
low serum erythropoietin levels (<500mU/mL)may be candidates for immunosuppressive 
therapy (IST) with antithymocyte globulin/cyclosporine. Those not candidates for IST and 
those who are intolerant of or fail to respond to IST are generally treated with 
hypomethylating agents (HMAs; azacitidine or decitabine); HMA treatment generally 
continues for at least 4-6cycles with maintenance treatment until disease progression. [3]
For patients with Intermediate-2 or High risk MDS, allogeneic hematopoietic stem cell 
transplant (allo-HCT) is the preferred treatment for patients who are candidates and have a 
donor stem cell source available. However, the majority of higher-risk MDS patients are not 
eligible for allo-HCT due to age, comorbidities, or donor availability. For such patients who 
are not candidates for allo-HCT, treatment with HMAsas described above is appropriate. In 
this setting, azacitidine is the preferred agent, as only azacitidine has demonstrated an 
improvement in overall survival (OS) when compared to standard of care in a randomized 
controlled trial. [4] There is no standard treatment for patients who do not respond to or 
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Azacitidine (VIDAZA®) is a nucleoside metabolic inhibitor that is indicated for the treatment 
of subjects with certain FAB MDS subtypes. [15] Azacitidine is a pyrimidine nucleoside 
analog of cytidine. It is believed to exert its anti-neoplastic effects by causing 
hypomethylation of DNA and direct cytotoxicity on abnormal hematopoietic cells in the bone 
marrow. Azacitidine is indicated for refractory anemia (URA) or URA with ringed sideroblasts 
(if accompanied by neutropenia or thrombocytopenia or requiring transfusions), URA with 
excess blasts (URAEB), URA with excess blasts in transformation (URAEB-T), and chronic 
myelomonocytic leukemia MDS subtypes.Azacitidine is administered at a dose of 75 mg/m2
subcutaneously (SC) or intravenously (IV), daily for 7 days every 28 days. [15] At some 
institutions, azacitidine is administered on a 5 days on/2 days off/2 days on schedule, rather 
than for 7 consecutive days. [3, 16–18]
7.3Clinical Study URationale
Though HMAs are part of the standard treatment protocols for MDS, the benefits are limited. 
In subjects with Intermediate-2 or High risk MDS, median OS with azacitidine was 21 to 
24months. [19, 20] Decitabine has been shown to produce durable responses, but an 
improvement in OS has not been demonstrated. [21] Improved treatment options are needed 
for Intermediate-2 and High risk MDS, particularly for subjects not eligible for allo-HCT. By 
targeting CD33, combining vadastuximab talirine with azacitidine may add significant 
activity in allo-HCT-ineligible subjects compared to treatment with azacitidine alone. 
Vadastuximab talirine (10 mcg/kg) has been administered with azacitidine at standard doses 
(75 mg/m
2per day for 7 consecutive days) to subjects with AML without unacceptable 
toxicity in Study SGN33A-001, suggesting that the combination may also have an acceptable 
safety profile in subjects with MDS. 
The study will assess the safety of vadastuximab talirine in combination with azacitidine in a 
dose-escalation Phase 1 Portion of the study and its efficacy in a double-blind Phase 2 
Portion at the dose identified in phase 1. The safety of this drug combination will be 
monitored in an ongoing process as part of the dose-escalation portion of this study by an 
SMC, and safety and toxicity will be monitored during the double-blind portion by an IDMC. 


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8.
STUDY OBJECTIVES 
8.1Primary Study Objective
8.1.1 Phase 1 Portion
To determine therecommended vadastuximab talirine (SGN-CD33A) dose in 
combination with azacitidine.
8.1.2 Phase 2 Portion
To compare the overall response rate (OURUR = complete response + partial response 
[CUR+PUR]) between treatment arms.
8.2 Secondary Study Objectives
To evaluate the safety of the combination of vadastuximab talirine and azacitidine 
(Phase 1 and Phase 2 Portions)
To compare the CUR rate between treatment arms (Phase 2 Portion)
To compare the hematologic improvement (HI) rate between treatment arms (Phase 2 
Portion)
Tocompare the duration of response (DOUR) between treatment arms (Phase 2 
Portion)
To compare progression-free survival (PFS) between treatment arms (Phase 2 
Portion)
To compare the rate of transformation to AML between treatment arms (Phase 2 
Portion)
To compare the OS between treatment arms (Phase 2 Portion)
8.3Exploratory Objectives
To assess the pharmacokinetics (PK) and pharmacodynamics of vadastuximab talirine 
(Phase 1 and Phase 2 Portions)
To assess the incidence of antitherapeutic antibodies (ATAs) against vadastuximab 
talirine (Phase 1 and Phase 2 Portions)
To assess exploratory biomarkers of clinical activity of vadastuximab talirine in 
combination with azacitidine (Phase 1 and Phase 2 Portions)
To assess quality of life (QoL; Phase 2 Portion)


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8.4Endpoints
8.4.1 Primary Endpoint
The primary endpoint of the Phase 1 Portion of the study is to determine the recommended 
dose for the Phase 2 Portion, based upon the maximum tolerated dose (MTD).
The primary efficacy endpoint of the Phase 2 Portion of the study is theOURUR, defined as the 
proportion of subjects who achieve any category of CUR (CUR and Marrow CUR) or PUR based on 
the 2006 International Working Group (IWG) criteria for MDS. [22] 
8.4.2 Secondary Efficacy Endpoints
Secondary efficacy endpoints of the Phase 2 Portion of the study are the following: 
CUR rate
HI rate
DOUR
PFS
URate of transformation to AML
OS
8.4.3 Pharmacokinetic and Antitherapeutic Antibody Assessments
Estimates of selected PK parameters for plasma vadastuximab talirine and released 
SGD-1882
Incidence of ATA
8.4.4 Biomarker Assessments
Biomarker assessments may include 
CD33 expression level
Abundance of MDSC
Characterization of leukocyte subpopulations in peripheral blood (peripheral blood 
mononuclear cells; PBMCs)
Variation in sequence of CD33 and genes commonly mutated in MDS and 
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Soluble CD33
Abundance of a variety of cytokines
Testing for Paroxysmal Nocturnal Hemoglobinuria (PNH)and human leukocyte 
antigen (HLA)-DUR15 
8.4.5 Safety Criteria 
Safety assessments will consist of the surveillance of AEs, laboratory test measures, physical 
examination findings, and concomitant medication records. 
8.4.6 Quality of Life 
Quality of life will be assessed with the Quality of Life Questionnaire (QLQ)-C30 patient 
reported outcomes (PURO) tool at protocol-defined time points. 


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9.
INVESTIGATIONAL PLAN
9.1Overall Study Design and Plan
This is a phase 1/2 study to evaluate the combination of vadastuximab talirine (SGN-
CD33A) and azacitidine in subjects with previously untreated IPSS Intermediate-2 or High 
risk MDS. In the Phase 1 Portion of the trial, escalating doses of vadastuximab talirine will 
be evaluated in combination with azacitidine, and 1 dose will be selected for the randomized, 
double-blind, placebo-controlled Phase 2 Portion of the study, which is designed to compare 
the OURUR between the 2study arms.
9.1.1 Phase 1 Portion –Open-Label Dose Evaluation 
Cohorts of 6 dose-limiting toxicity (DLT)-evaluable subjects will be enrolled in an open-
label fashion to receive vadastuximab talirine in combination with azacitidine in 28-day 
cycles, starting at 5mcg/kg vadastuximab talirine. The DLT-evaluable population will 
include all Phase 1 subjects who have completed atleast Cycle 1 of treatment (Cycle 1 of 
treatment is completed when the patient receives the first dose of azacitidine on Day 1 of 
Cycle 2) ordiscontinued study treatment because of AEs, or for a safety-related reason 
before having had the opportunity to receive the first dose of azacitidine on Day 1 of Cycle 2. 
In the Phase 1 Portion of the study, DLTs will be defined as posttreatment grade 4 
neutropenia or grade 4 thrombocytopenia lasting >42 days from the start of therapy, in the 
absence of evidence of active MDS, or any grade 3 or higher non-hematologic toxicity that is 
clearly NOT resulting from underlying MDS or azacitidine, with the exception of:
a. Grade 3 allergic reaction, fatigue, asthenia, anorexia, or constipation
b. Grade 3 nausea, vomiting, or diarrhea not requiring tube feeding or total parenteral 
nutrition or hospitalization 
c. Febrile neutropenia (which resolves with appropriate treatment or marrow recovery), 
infection, bleeding, or other expected direct complications of cytopenias due to active 
MDS
If 2 or more subjects in a 6-subject cohort have DLTs, that dose level will be considered to 
have exceeded the MTD. If 5mcg/kg vadastuximab talirine in combination with azacitidine 
is considered tolerable (≤1 of 6 subjects experiences a DLT), a cohort of 6 DLT-evaluable 
subjects will receive 10 mcg/kg vadastuximab talirine and azacitidine. If 10mcg/kg 
vadastuximab talirine in combination with azacitidine is considered tolerable, a cohort of 
6DLT-evaluable subjects will receive 15 mcg/kg, and if 15mcg/kg vadastuximab talirine in 
combination with azacitidine is considered tolerable, a cohort of 6DLT-evaluable subjects 
will receive 20 mcg/kg. If 5 mcg/kg vadastuximab talirine in combination with azacitidine is 
not considered tolerable (>1 of 6 subjects experiences a DLT), a cohort of 6DLT-evaluable 
subjects will receive 3 mcg/kg vadastuximab talirine and azacitidine. The dose-escalation 
plan is presented in Figure1.


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Figure1:
Study Schematic –Phase 1 Portion
Enroll 6
≤1DLT
Enroll 6
≤1DLT
Enroll 6
≤1DLT
Enroll 6
≤1DLT
5 mcg/kg
10 mcg/kg
15 mcg/kg
20 mcg/kg
>1DLT
>1DLT
>1DLT
>1DLT
Enroll 6
5 mcg/kg 
=MTD
10 mcg/kg 
=MTD
15 mcg/kg 
=MTD
3 mcg/kg
>1DLT
≤1DLT
20 mcg/kg
=MTD
End
3 mcg/kg
=MTD
DLT = dose-limiting toxicity; MTD = maximum tolerated dose.
Azacitidine will be given on 7 days per cycle, either on the first 7 days or 5 days on/2 days 
off/2 days on; vadastuximab talirine will be given after azacitidine on the last day of 
azacitidine administration in each cycle. UResponse assessments (bone marrow examination 
and complete blood count [CBC]) will be conducted on Day 22-29 of even-numbered cycles 
until CUR, then every 4 cycles thereafter. Subjects may continue on study treatment until 
disease progression, relapse, or unacceptable toxicity. After discontinuation of study 
treatment, subjects who have not experienced progression or relapse will continue to be 
assessed for response every 4 months through 24 months after the end of treatment (EOT) or 
until initiation of another anticancer treatment, progression, or relapse, whichever comes 
first. All subjects will be contacted for survival status every 2 months after EOT in follow-up 
until death or study closure, whichever comes first. Safety will be monitored through the 
surveillance of AEs, laboratory test measures, physical examination findings, and 
concomitant medication records. An additional bone marrow examination will be conducted 
for research purposes for subjects in the Phase 1 Portion of the study only. 
After 6 DLT-evaluable subjects have had the opportunity to complete at least Cycle 1 
(Cycle1 of treatment is completed when the patient receives the first dose of azacitidine on 
Day 1 of Cycle 2) of treatment in each planned dose cohort, the data will be aggregated and 
analyzed by an SMC (Section13.6.9). Based on the evaluation of the data, including the 
incidence of DLT in each cohort, the SMC may recommend the dose of vadastuximab 
talirine for the Phase 2 Portion of the study at the time of the evaluation. If additional safety 
information is required to recommend a phase 2 dose, the SMC could recommend enrollment 
of up to 12 additional treated subjects to continue to evaluate the safetyof the combination at 
vadastuximab talirine dose(s) of 3, 5, 10, or 20 mcg/kg. Subsequently, upon completion of 
dose escalation, up to 12 more expansion patients may be enrolled (maximum of 24 
expansion patients total), at any dose level not previously shown to exceed the MTD, to 
further characterize safety, PK, and activity.
9.1.2 Phase 2 Portion –URandomized, Placebo-Controlled 
Subjects will be randomized in a 1:1 manner to one of the study arms described in Table1. 
URandomization will be stratified by Eastern Cooperative Oncology Group (ECOG) 
performance status (0 vs 1 or 2) and IPSS score (Intermediate-2 vs High risk). 


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Table1:
Treatment Arms 
Treatment Arm
Study Treatment 
Experimental Comparator
Open-Label Study 
Treatment
Azacitidine 75 mg/m2SC or IV (at the Investigator’s 
discretion) for 7 days
X
X
Blinded Study 
Treatment
Vadastuximab talirine (SGN-CD33A) every 4 weeks (after 
azacitidine on the last day of azacitidine administration) via 
IV push at SMC-recommended dose
X
Placebo every 4 weeks (after azacitidine on the last day of 
azacitidine administration) via IV push 
X
IV = intravenous; SC = subcutaneous; SMC = Safety Monitoring Committee.
Subjects will receive vadastuximab talirine in combination with azacitidine in 28-day cycles, 
starting at the dose level of vadastuximab talirine determined in phase 1. UResponse 
assessments (bone marrow examination and CBC) will be conducted once between Day 22 
and Day 29 of even-numbered cycles until CUR, then every 4 cycles thereafter. Subjects may 
continue on study treatment until disease progression, relapse, or unacceptable toxicity
. After 
discontinuation of study treatment,subjects who have not had progression or relapse will 
continue to be assessed for response every 4 months through 24 months after EOT or until 
initiation of another anticancer treatment, progression, or relapse, whichever comes first. All 
subjects will becontacted for survival status every 2 months after EOT in follow-up until 
death or study closure, whichever comes first. Safety will be monitored through the 
surveillance of AEs, laboratory test measures, physical examination findings, and 
concomitant medication records. An IDMC (Section13.6.10) will also periodically assess the 
ongoing safety data and make recommendations to either continue evaluating the 
combination or to stop the study due to toxicity concerns. Figure2is a study schematic for 
the Phase 2 Portion.
Figure2:
Study Schematic –Phase 2 Portion
Screening
URandomization
AZA +SGN33A
URepeated 4-Week Cycles
(Disease assessment even-
numbered cycles until CUR, then 
every 4 cycles)
Discontinuationa
Long-term
Follow-up
(Disease progression
b
and survival)
AZA + Placebo
URepeated 4-Week Cycles
(Disease assessment even-
numbered cycles until CUR, then 
every 4 cycles)
AZA = azacitidine; CUR = complete response.
a
Subjects may continue to receive repeated cycles of treatment until disease progression, relapse, unacceptable toxicity, 
or other discontinuation criteria are met.
b
For subjects who discontinue without having experienced disease progression follow-up will include disease assessment 
(CBC and bone marrow) every 4 months for 24 months or until disease progression. Subjects will be followed every 
2months for survival until death or the end of the study.
Unblinding a subject’s treatment assignment will be limited to emergency circumstances 
where knowledge of the treatment assignment would affect decisions regarding the 
management of the subject. In the event of such an emergency circumstance, a formal 
unblinding procedure will be followed to allow the Investigator to immediately access a 


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subject’s treatment assignment. Information on study treatment assignment should not be 
distributed to any other personnel involved in the clinical trial. 
9.1.3 Study Stopping Criteria
The SMC (Phase 1 Portion) or the IDMC (Phase 2 Portion) will provide recommendations to 
the Sponsor if either of the following criteria are met:
●
 
 
 
 
 
 
 
 
The Sponsor will pause enrollment and notify the FDA and other health authorities, as 
applicable, if the stopping criteria are met. 
9.2 Discussion of Study Design
The Phase 1 Portion of this study is a dose-escalation design to balance subject safety and 
speed of accrual while minimizing the number of subjects exposed to subtherapeutic doses. 
[23] This is a standard design in clinical oncology development.
The Phase 2 Portion is a randomized, double-blind study. URandomization reduces the risk of 
bias in treatment allocation, and the double-blind methodology reduces the risk of bias in 
treatment or assessment. 
The safety and efficacy assessments in both portions are standard and well accepted 
measures in clinical oncology.
9.3Study Duration
Study treatment consists of repeated 4-week cycles of combination treatment. Subjects may 
continue to receive treatment until they experience disease progression, relapse, or 
unacceptable toxicity.
The estimated duration of study treatment through final primary analysis is approximately 
51months from enrollment of the first subject to completion of the last subject. All subjects 
will be contacted for survival status every 2 months after EOT in follow-up until death or 
study closure, whichever comes first. 


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9.4Study Population
9.4.1Inclusion Criteria
Subjects cannot be enrolled before all inclusion criteria (including test results) are confirmed. 
Eligible subjects must meet the following criteria: 
1. Subjects with cytologically/histologically confirmed MDS according to the WHO 
2008 classification, that is determined to be Intermediate-2 (1.5-2-points) or High risk 
(≥2.5 points) according to the IPSS risk category, with ≥5% and <20% bone marrow 
blasts.
2. Previously untreated for MDS with the exception of transfusions, hematopoietic 
growth factors, or IST.
3. Age ≥18 years.
4. Eligible for therapy with azacitidine.
5. Life expectancy of at least 12 weeks.
6. ECOG performance status ≤2.
7. The following baseline laboratory data:
a. white blood cell (WBC) count <20,000/mcL; pre-study use of hydroxyurea to 
control WBC is acceptable up to 24 hours prior to first doseof study 
treatment.
b. direct bilirubin ≤2 x upper limit of normal (ULN) and/or total serum bilirubin 
≤1.5 x ULN (or total serum bilirubin ≤3 x ULN for subjects with Gilbert’s 
disease).
c. serum creatinine ≤2.5 x ULN and creatinine clearance ≥30 mL/min 
(calculated using the Cockcroft-Gault formula; Section11.7).
d. alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 
≤3xULN.
8. Females of childbearing potential must have a negative serum or urine beta human 
chorionic gonadotropin (β-hCG)pregnancy test result within 7 days prior to the first 
dose of study treatment. Females of non-childbearing potential are those who are 
postmenopausal greater than 1 year or who have had a bilateral tubal ligation or 
hysterectomy.
9. Females of childbearing potential and males who have partners of childbearing 
potential must agree to use 2 effective contraception methods during the study and for 
6 months following the last dose of study drug. 


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Acceptable methods of contraception include: hormonal (birth control pills, 
injections, implants), intrauterine device (IUD), intrauterine hormone-releasing 
system (IUS), vasectomy (for males), barrier methods (male and female condoms, 
diaphragms, and spermicides), and complete abstinence. Complete abstinence is 
acceptable when this is in line with the preferred and usual lifestyle of the patient. 
(Periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation 
methods] and withdrawal are not acceptable methods of contraception.) 
10.Subjects must provide writteninformed consent. 
9.4.2 Exclusion Criteria
If any of the following apply, the subject MUST NOTenter the study:
1. UReceived prior treatment for MDS with lenalidomide or HMAs. 
2. History of one of the following myeloproliferative neoplasms: essential 
thrombocythemia, polycythemia vera, and primary myelofibrosis.
3. Second malignancy currently requiring active therapy (except for hormonal/anti-
hormonal treatment, eg, prostate or breast cancer).
4. Central nervous system leukemia based on imaging or documented positive cytology 
in cerebral spinal fluid.
5. Any uncontrolled grade 3 or higher (per National Cancer Institute [NCI; US] 
Common Terminology Criteria for Adverse Events [CTCAE], Version 4.03) viral, 
bacterial, or fungal infection within 14 days prior to the first dose of study treatment. 
Antimicrobial prophylaxis or ongoing treatment of resolving/controlled infection is 
permitted.
6. Known to be positive for hepatitis B by surface antigen expression. Known to have 
active hepatitis C infection (positive by polymerase chain reaction or on antiviral 
therapy for hepatitis C within the last 6 months).
7. Known to be positive for human immunodeficiency virus (HIV).
8. Documented history of a cerebral vascular event (stroke or transient ischemic attack), 
unstable angina, or myocardial infarction within 6 months prior to their first dose of 
study drug, or refractory congestive heart failure unresponsive to medical treatment.
9. Therapy with the following agents within the specified timeframe prior to first study 
treatment:
a. systemic anti-neoplastic or investigational agents within prior 14 days.


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b. hematopoietic growth factors within 7 days (erythropoietin, granulocyte 
colony stimulating factor, granulocyte-macrophage colony stimulating factor, 
or thrombopoietin receptor agonists).
10.Known hypersensitivity to any excipient contained in the drug formulation of any 
study treatment.
11.Prior allo-HCT, for any indication.
12.Hypocellular MDS, defined as bone marrow cellularity <30% in subjects ≤60years 
old or <20% cellularity in subjects >60 years old.
13.Candidates for allogeneic stem cell transplant at the time of screening.
14.History of clinically significant liver disease (e.g. liver cirrhosis) or ongoing alcohol 
abuse.
9.4.3 Withdrawal and UReplacement of Subjects
In accordance with the Declaration of Helsinki (Appendix18.1) and applicable regulations, a 
subject has the right to discontinue treatment or withdraw from the study at any time and for 
any reason without prejudice to his or her future medical care by the physician or at the 
institution.
9.4.3.1Discontinuation of Study Drug
Subjects may continue on study treatment until disease progression, relapse, or unacceptable 
toxicity. After discontinuation of study treatment, subjects who have not experienced 
progression or relapse will continue to be assessed for response every 4 months through 
24months after EOT or until initiation of another anticancer treatment, progression, or 
relapse, whichever comes first. All subjects will be contacted for survival status every 
2months after EOT in follow-up until death or study closure, whichever comes first. 
A subject’s treatment with study drug may be discontinued for any of the following reasons:
Progressive disease (PD) or relapse after remission
AE
Investigator decision
Subject decision, non-AE
Study termination by Sponsor
Other, non-AE


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The reason for treatment discontinuation will be recorded in the clinical records and the 
electronic Case UReport Form (eCURF). Allsubjects who discontinue treatment will undergo an 
EOT visit (see Section10.3). These subjects will continue to be followed for survival and 
disease status (see Section10.4) unless they withdraw from the study (see Section9.4.3.2). 
For replacement of withdrawn/discontinued subjects, see Section9.4.3.3.
9.4.3.2Subject Withdrawal From Study
Any subject may be discontinued from the study for any of the following reasons:
Subject withdrawal of consent
Study termination by Sponsor
Lost to follow-up
Death
Other
Subjects who withdraw from the study will not be further contacted. 
9.4.3.3UReplacement of Subjects
During the Phase 1 Portion, sufficient DLT-evaluable subjectswill be enrolled in each cohort 
for determination of the DLT (6 DLT-evaluable subjects per cohort in the absence of DLTs). 
During the Phase 2 Portion, subjects who discontinue from treatment or the study will not be 
replaced.
9.5Treatment
9.5.1 Treatments Administered
The Investigator must ensure that the investigational product will be used only in accordance 
with the protocol. 
Phase 1 Portion
During the Phase 1 Portion of the study, vadastuximab talirine (SGN-CD33A) will be 
administered every 4 weeks (after azacitidine on the last day of azacitidine administration) 
via IV push at the assigned dose level (3 to 20 mcg/kg), based on the dose evaluation cohort.
Subjects will also receive azacitidine 75 mg/m2SC or IV (at the Investigator’s discretion) for 
7 days (7consecutive days or 5 days on/2 days off/2 days on), beginning on Day 1 of 
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Phase 2 Portion
During the Phase 2 Portion of the study, subjects will be randomized to receive either 
vadastuximab talirine (SGN-CD33A) administered every 4 weeks (after azacitidine on the 
last day of azacitidine administration) via IV push at the dose determined in the Phase 1 
Portion or placebo every 4weeks (after azacitidine on the last day of azacitidine 
administration) via IV push.
All subjects will alsoreceive azacitidine 75 mg/m
2SC or IV (at the Investigator’s discretion) 
for 7 days (7 consecutive days or 5 days on/2 days off/2 days on), beginning on Day 1 of 
repeated 4-week cycles.
9.5.1.1URequired Premedication and Postmedication
Subjects receiving azacitidine should be premedicated for the prevention of nausea and 
vomiting according to institutional practice. 
Prophylaxis/treatment of hematologic toxicity and infection may be administered according 
to institutional practice.
9.5.1.2Vadastuximab Talirine 
Detailedinformation describing the preparation, administration, and storage of vadastuximab 
talirine is located in the Pharmacy Binder.
9.5.1.2.1 Description
Vadastuximab talirine is a sterile, preservative-free, lyophilized cake or powder, supplied in 
single-use amber vials. See the Pharmacy Binder for further information.
9.5.1.2.2 Method of Procurement
Vadastuximab talirine and matching placebo will be provided by the Sponsor.
9.5.1.2.3 Dose and Administration
Administration of SGN-CD33A will be via IV push. It is recommended that SGN-CD33Abe 
administered via central venous access port (eg, 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. Due to potential for severe tissue damage, monitor the injection site closely for redness, 
swelling, pain, infection during and at any time after administration. Advise patients to report 
redness or discomfort promptly at the time of administration or after infusion. Follow 
institutional guidelines for the administration of chemotherapy and take precautions to 
prevent extravasation per institutional standards and as described by Schulmeister. [25]
Depending on the lot of study treatment supplied, a sterile 0.2-mcmfilter may be required for 
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(including the filter and any associated tubing or closed-delivery injection devices) must be 
flushed with at least 20 mL of saline. 
Vadastuximab talirine will be administered in repeated 4-week cycles after azacitidine on the 
last day of azacitidine treatment, via IV push. 
During the Phase 1 Portion of the study, the dose level will be determined according to the 
dose-escalation schedule. 
During the Phase 2 Portion of the study, the dose level will be the dose level selected by the 
SMC based on the phase 1 data. Subjects in the Phase 2 Portion of the study will receive 
either vadastuximab talirine or matching placebo.
Dosing is based on subject weight. Doses will be adjusted for subjects who have a ≥10% 
change in weight from baseline. An exception to weight-based dosing is made for subjects 
weighing greater than 100 kg; doses will be based on 100 kg for these individuals.URefer 
to the Pharmacy Binder for further details.
9.5.1.2.4 Preparation
Vadastuximab talirine vials are provided via single-use containers. Any partially used vials 
or diluted dosing solutions should be discarded using appropriate institutional drug disposal 
procedures.
Vadastuximab talirine drug product is reconstituted with sterile Water for Injection (WFI), 
United States Pharmacopeia (USP) or equivalent, for IV administration. The reconstituted 
vadastuximab talirine drug product is a clear to slightly opalescent, colorless to light yellow 
solution. Depending on the dose level, the reconstituted solution is either used directly, or 
subsequently diluted in sterile 0.9% Sodium Chloride for Injection, USP or equivalent, for IV 
administration.
Detailed drug preparation instructions are provided in the Pharmacy Binder.
9.5.1.2.5 Study Treatment Labeling and Packaging
Vadastuximab talirine is the International Nonproprietary Name (INN) assigned to 
SGN-CD33A. Drug product vials may be labeled as SGN-CD33A or as vadastuximab 
talirine; the 2 names can be used interchangeably.
9.5.1.2.6 Study Treatment Storage and Accountability
It is forbidden to use investigational drug material for purposes other than as defined in this 
protocol.
Study Treatment Storage
Vials containing vadastuximab talirine must be stored under refrigeration at 2-8°C, protected 
from light (both sunlight and artificial light).


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The chemical and physical stability of the reconstituted drug product has been demonstrated 
for 24 hours at 2-8°C, protected from light. However, vadastuximab talirinedrug product 
does not contain preservatives; therefore, from a microbiological standpoint, opened and 
reconstituted vials should be used immediately. If not used immediately, the in-use storage of 
the reconstituted product should not be longer than 24 hours under refrigeration at 2-8°C. If 
dilution is needed, the reconstituted drug product should be diluted in 0.9% Sodium Chloride 
Injection, USP, or equivalent, at the time of use. The prepared dosing solution (reconstituted 
drug product or drug product dilution) should be used within 4 hours after exposing to 
ambient temperature and light conditions.
Study Treatment Accountability
Drug accountability instructions are provided in the Pharmacy Binder.
9.5.1.3Azacitidine
Azacitidine is marketed in the US as VIDAZA®by Celgene Corporation Summit, NJ USA. 
Please refer to the approved US prescribing information (USPI) for detailed information.
9.5.1.3.1 Description
Azacitidine is a pyrimidine nucleoside analog of cytidine.
9.5.1.3.2 Method of Procurement
Commercially available azacitidine will be provided by the study sites from their usual 
suppliers.
9.5.1.3.3 Dose and Administration
The starting dose for the first treatment cycle for all subjects is 75mg/m2SC or IV (at the 
Investigator’s discretion), 7 days per cycle, either on the first 7 days or5 days on/2 days off/
2days on.
9.5.1.3.4 Preparation
Azacitidine will be prepared for SC or IV administration according to the USPI and local 
standard of care. 
9.5.1.3.5 Storage and Accountability
Azacitidine must be stored, distributed, and disposed of according to institutional practice 
and the USPI.


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9.5.1.4Management of Adverse UReactions
9.5.1.4.1
Management of Infusion UReactions
Infusions should be administered at a site properly equipped and staffed to manage 
anaphylaxis should it occur. All supportive measures consistent with optimal subject care 
should be given throughout the study according to institutional standards. Supportive 
measures may include extending the infusion time and/or administering medications for 
infusion-related reactions. 
9.5.1.4.2 Overdose
In the event of an overdose ≥10%,the site should notify the sponsor as soon as they are 
aware of the overdose.
9.5.1.4.3 Dose Modifications
Common toxicities including myelosuppression, nausea, gastrointestinal toxicity, fatigue, 
pyrexia, headache, weight decrease, dyspnea, rash, and stomatitis should be managed 
according to institutional standards or accepted guidelines (eg, American Society of Clinical 
Oncology [ASCO] guidelines for the use of WBC growth factors [26]). Growth factor 
support may be administered as needed according toinstitutional standard of care. 
Vadastuximab Talirine
Table2describes guidelines for dose modifications of vadastuximab talirine (Phase 1 
Portion) or blinded study treatment (Phase 2 Portion)for toxicity. 
Dose delays of any study treatment are permitted. If dosing is delayed for azacitidine, 
vadastuximab talirine (Phase 1 Portion), or blinded study treatment (Phase 2 Portion), both 
study treatments should be held and resumed together on the same schedule except when one 
agent is omitted during a cycle due to toxicity. 
For patients who achieve a response to therapy, dose decreases, delays, or dose re-escalation 
(to original dose level) are permitted at the discretion of the medical monitor and site 
Investigator. Following achievement of marrow blast clearance to <5% (ie, a CUR or marrow 
CUR), patients originally treated with a dose higher than 5mcg/kg of study drug will receive 
azacitidine with vadastuximab talirine (Phase 1 Portion) or blinded study treatment (Phase 2 
Portion) as continuation therapy at the maintenance dose of 5mcg/kg in subsequent cycles.
Azacitidine, vadastuximab talirine (Phase 1 Portion), or blinded study drug (Phase 2 Portion) 
may be permanently discontinued in the event of unacceptable related toxicity. Subjects will 
not be considered off study treatment until both study treatments are discontinued. 
If subjects become candidates for stem cell transplant after enrollment, vadastuximab talirine 
must be discontinued at least 30 days prior to initiation of preparative regimen for stem cell 
transplant.


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Table2:
Dose Modifications for Vadastuximab Talirine-Associated Toxicity 
Category
Event
Action
Hematologic toxicity with 
marrow blast count <5%
a
≥ Grade 3 
neutropenia or 
thrombocytopenia 
Cycles of treatment may be delayed up to 14 days
buntil 
hematologic recovery is observed. 
Adequate hematologic recovery is defined as 
neutropenia and thrombocytopeniaimproved to
<grade3 (unsupported),
OUR
ANC / platelets ≥ [(NADIUR COUNTc) + (BASELINE 
COUNTd–NADIUR COUNT)x 0.50] 
If hematologic recovery as defined above has not 
occurred within 14 days of the end of the cycle (by Day 
42), omit vadastuximab talirine (Phase 1) or blinded 
study treatment (Phase 2) from the next cycle, and 
initiate next dose of azacitidine based on marrow 
cellularity as defined in Table3.
Hematologic toxicity with 
marrow blasts ≥5%b 
≥ Grade 3 
neutropenia or 
thrombocytopenia 
Treatment may continue without dose modification.
Clinically significant 
non-hematologic toxicity
or asymptomatic non-
hematologic laboratory 
abnormality (with the 
exception of hepatic 
toxicity)
≥ Grade 3 event 
Treatment delay of up to 14 days is permitted until 
resolution of toxicity to < grade 3. 
Laboratory evidence of
hepatic toxicity (elevation 
in ALT, AST, or total 
bilirubin)
≥ Grade 3 event
Treatment delay of up to 14 days is required until 
resolution of toxicity to ≤ grade 1 or baseline. If toxicity 
has not resolved within 14 days, permanently 
discontinue vadastuximab talirine (Phase 1) or blinded 
study treatment (Phase 2)
ALT = alanine aminotransferase;ANC = absolute neutrophil count; AST = aspartate aminotransferase.
a
If cytopenias above grade 3 (e.g.,ANC <1000/mm3or platelets <50 x 109/L) are present at Day 28 of a cycle in which 
no response assessment is required, an ‘unscheduled’ bone marrow biopsy is required within 14 days of the scheduled 
end of the cycle (eg, between Day 28 and Day 42). If the bone marrow cellularity is ≤10%, vadastuximab talirine or 
blinded study treatment will be permanently discontinued. If marrow cellularity is >10%, follow guidance as above. 
b Delays of >14 days may be permitted with approval of the medical monitor.
c
Nadir Count = the lowest count reached during the treatment cycle.
d
Baseline Count = counts prior to Cycle 1 of study treatment.
Azacitidine
Dose modifications to azacitidine, including permanent discontinuation due to toxicity, are at 
the discretion of the treating physician and should adhere to the USPI, the summary of 
product characteristics (SMPC), or institutional guidelines/standards. URecommended 
schedule modifications for azacitidine in patients with delayed count recovery and <5% 
blasts are provided in Table3. 


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Table3: 
URecommended Scheduled Modifications for Azacitidine in Patients with 
<5% Blasts and Incomplete Hematologic URecovery at Day 42a
Bone Marrow 
Cellularity:
>30%
15-30%
<15%
Timing of Next 
Cycle 
Next cycle may 
begin
Delay next cycle until 
ANC and platelets ≥
[(NADIUR COUNT) + 
(BASELINE COUNT –
NADIUR COUNT)x 0.50]
Delay next cycle until ANC and 
platelets ≥[(NADIUR COUNT) + 
(BASELINE COUNT –NADIUR 
COUNT)x 0.75]
a If vadastuximab talirine (Phase 1) or blinded study drug (Phase 2) was omitted during the previous cycle, consider dose 
reduction of azacitidine to 50% upon initiation of next cycle. 
9.5.2 Blinding of Study Medication
The Phase 1 Portion of this study is an open-label study.
The Phase 2 Portion will be double-blinded. Subjects will receive vadastuximab talirine or 
matching placebo at the volume equivalent dose level determined in the Phase 1 Portion. The 
subject and all personnel involved with the conduct and the interpretation of the study, 
including the investigators, study center personnel, and the Seattle Genetics, Inc., PURA 
Health Sciences, or designee staff, will be blinded to the medication allocation. 
URandomization data will be assigned via a centralized interactive voice and web recognition 
system (IXURS) and kept strictly confidential and accessible only to authorized persons per 
Seattle Genetics, Inc. (or designee’s) Standard Operating Procedures (SOPs) until the time of 
unblinding.
A randomization number will be assigned to each subject by the IXURS after eligibility is 
determined. At the initiation of the study, the study center will receive instructions for 
unblinding a subject using the IXURS. In the event that an emergency unblinding is required, 
authorized/approved randomization system users will have the ability to retrieve subject 
treatment group assignment through the randomization system. Unblinding a subject should 
only be done in emergency situations for reasons of subject safety. The Investigator/study 
center should make every attempt to contact the Seattle Genetics, Inc. or designee’s medical 
monitor before breaking the blind. When the Investigator contacts the IXURS, the system will 
guide the Investigator to access the emergency unblinding option. When the blinding code is 
broken, the reason must be fully documented in the source documentation.
9.5.3 Prior and Concomitant Therapy
Subjects may not receive other investigational drugs, immunosuppressive medications, 
radiotherapy, systemic anti-neoplastic therapy, or allogeneic stem cell transplant during the 
study treatment period.
Any other treatment (not explicitly excluded) considered necessary for the subject’s welfare 
may be given at the discretion of the Investigator. Administration of concomitant 
medications must be reported in the appropriate section of the eCURF along with dates of 
administration and reasons for use. 


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Prophylactic antiemetics should be administered according to institutional standards.
The use of transfusions, platelet and/or colony stimulating factors per institutional practice is 
permitted. In addition, the ASCO guideline for the use of WBC growth factors is 
recommended for the management of neutropenia and febrile neutropenia. [26]
All subjects who discontinue the study medication should be offered alternative treatment if 
applicable. Treatment should be given according to normal clinical practice, after a 
termination visit (see Section10.2.2).
9.5.4 Treatment Compliance
Vadastuximab talirine or matching placebo and azacitidine will be administered by qualified 
study site staff, and administration information will be recorded in the eCURF.
9.5.5 Assignment to Treatment
During the Phase 1 Portion, subjects will be assigned sequentially to the dose level open at 
the time of enrollment.
During the Phase 2 Portion of the study, after eligibility is determined and within 1 business 
day of the planned first dose of study treatment, subjects will be randomized to treatment by 
an IXURS. Subjects will be stratified at randomization by ECOG performance score (0 vs 1 or 
2) and IPSS risk category (Intermediate-2 vs High risk).
9.6 Efficacy and Safety Variables
9.6.1 Efficacy and Safety Measurements Assessed
9.6.1.1Efficacy Measurements
Primary Efficacy Criteria:
The primary efficacy endpoint of this study is OURUR.
Subjects will undergo routine laboratory tests (CBCs) and bone marrow examinations. 
UResponse status will be assessed according to the IWG UResponse Criteria in Myelodysplasia. 
[22] Detailed response definitions are presented in Appendix18.6.
Secondary Efficacy Criteria:
Secondary efficacy endpoints will be the following:
Complete response (CUR) rate
Hematologic improvement (HI) rate
Duration of response (DOUR)


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Progression-free survival (PFS)
URate of transformation to AML
Overall survival (OS)
See Section13.6.4for definitions.
9.6.1.2Pharmacokinetic and Antitherapeutic Antibody Assessments
Blood samples for PK and ATA assessment will be collected at the time points outlined in 
Table5and Table6(below). Sensitive, qualified assays will be used to measure 
concentrations of ADC (vadastuximab talirine) and SGD-1882 in plasma and ATAs in 
serum. URemaining PK samples will be archived for possible analysis of vadastuximab 
talirine-related species. The assays will include enzyme-linked immunosorbent assays 
(ELISA) and liquid chromatography/tandem mass spectrometry assays, as well as other 
assays if further characterization is required. A qualified electrochemiluminescence assay 
will be used to assess ATA.
9.6.1.3Biomarker Assessments
Peripheral blood and bone marrow aspirates will be collected at the time points outlined in 
Table5and Table6(below). Biomarker assessments may include CD33 expression level, 
abundance of MDSC, characterization of leukocyte subpopulations in PBMCs, variation in 
sequence of CD33 and genes commonly mutated in MDS and hematologic malignancies, 
soluble CD33, abundance of a variety of cytokines, and testing for PNH and HLA-DUR15 at 
protocol-specified time points. Methods of analysis may include flow cytometry, ELISA, 
DNA, and URNA sequencing.
9.6.1.4Safety Measurements
Safety assessments will consist of the surveillance of AEs, laboratory test measures, physical 
examination findings, and concomitant medication records. 


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10.
STUDY EVALUATIONS BYVISIT
A full schedule of study procedures for the screening and treatment periods is provided in 
Table4, and schedules of PK, immunogenicity, and biomarker assessments are given in 
Table5and Table6.


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Table4:
Study Schedule 
Visit Window
Baseline/Screening
Enrollment/
URandomizationa
Each Cycle
EOTb
Long-term 
F/U
D1 
D2-6
D7
D15 
D22-29
Within 28D 
prior to 
study drug
Within 7D 
prior to 
study drug
Within 7D 
prior to 
study drug
±1D
1D
30–37 days 
post last dose ±2 wks
Baseline and 
Safety 
Assessments
Informed consent
X
Eligibility documentation submitted 
to Sponsor prior to study start
Inclusion/exclusion
X
Medical/MDS history
X
Physical examination
X
X
Height
X
Weight
X
X
Vital signs
Xu
Pregnancy test (serum or urine) for 
women of childbearing potential only
X
X
Electrocardiogram 
X
ECOG performance status
X
X
X
Serum chemistry including ferritin
X
X
Xc
X
CBC with differential
X
X
Xc
Xd
X
Urinalysise 
X
Xf
Xc
X
Inflammatory serologies
g
X
Xh
X
Specialty autoimmune serologiesi
X
Xj
X
Concomitant medications and 
adverse eventst
Collect any related to 
study protocol procedures
Collect from predose through 30 days post last dose or EOT visit, 
whichever is later
Treatment
Administra-
tion
Phase 1: vadastuximab talirine k
Phase 2: blinded study treatment k
Xl
Azacitidinek
X 
X 
Xl
QoL
PURO questionnaire 
Xm
X
PK/ATA 
Blood samples for PK
See Table5(Phase 1 Portion) and Table6(Phase 2 Portion)
Blood samples for ATA
Biomarkers
Cytogenetics and gene mutations
n
X
Whole blood for biomarker analysis
See Table5(Phase 1 Portion) and Table6(Phase 2 Portion)
             Bone marrow for biomarker analysis
o
UResponse 
Assessments
Bone marrow examinationp
X
Xd
Xr
Xr
Survival status
Xs
AE = adverse event; ANA = antinuclear antibodies; ANCA = anti-neutrophil cytoplasmic antibodies; anti-dsDNA =anti-double-stranded DNA;ATA = antitherapeutic antibody; 
CBC = complete blood count; CUR = complete response; CURP = C-reactive protein; D = day; ECOG = Eastern Cooperative Oncology Group; EOT = end of treatment; F/U = 
follow-up; Ig = immunoglobulin; MDS = myelodysplastic syndrome; PK = pharmacokinetics; PURO = patient reported outcomes; QoL = quality of life; URF = rheumatoid factor.
Please refer to footnotes on following page.


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a 
During the Phase 2 Portion, randomization must be within 1 business day before Cycle 1 Day 1.
b
EOT evaluations should be obtained before the initiation of non-protocol therapy. If EOT evaluations are completed before 30 days following the last study treatment, conduct 
a phone screen 30–37 days following the subject’s last study treatment to ensure that no changes in AE profile have occurred.
c
Cycles 1 through 4 only.
d
Day 22-29 in even-numbered cycles until CUR, then every 4 cycles thereafter. If cytopenias above grade 3 (eg ANC <1000/mm
3or platelets <50 x 109/L) are present at Day 28 
of a cycle in which no response assessment is required, an ‘unscheduled’ bone marrow biopsy is required within 14 days of thescheduled end of the cycle (eg, between 
Day28 and Day 42) to assess marrow cellularity and blast count, in order to determine if dose / schedule modifications are required in the next cycle.. 
e
Includes urine dipstick or microscopic analysis, as well as spot urine protein and creatinine.
f
Even-numbered cycles only. 
g
Includes clinical laboratory testing for CURP, C3, and C4.
h
Cycles 2 and 4 only.
i Includes clinical laboratory testing for ANCA, anti-dsDNA, quantitative immunoglobulins [IgM, IgG, IgA], URF, ANA, and Direct Coomb’s].
j
Cycle 4 only.
k Alternative schedule of treatment administration permitted: azacitidine 5 days on/2 days off/2 days on and vadastuximab talirine or placebo given on Day 9.
l
Day 9 if alternate azacitidine schedule administered.
m
Cycles 1, 2,and even-numbered cycles (Cycles 4, 6, 8, etc) thereafter.
n
Locally assessed according to institutional standard. 
o
Portion of bone marrow sample obtained at baseline or for response assessment.
p Bone marrow examination should be based on a bone marrowbiopsy; however, if marrow cannot be biopsied, but aspiration is successful, the aspirate may be used to 
determine blast count. For subjects requiring a marrow evaluation to assess cellularity due to cytopenias, a biopsy is required.
q
Only required if not conducted within 4 weeks prior to EOT.
r If study treatment discontinued prior to disease progression or relapse, obtain every 4 months through 24 months after EOT oruntil initiation of another anticancer treatment, 
progression, or relapse.
s
Contact subject for survival status every 2 months after EOT until death or study closure. Collection of subsequent anticancer treatment information.
t
See Sections10.4and12.1.4for follow-up of adverse events of special interest.
u
Beforeand within 30 minutes after vadastuximab talirine (Phase 1 Portion), or blinded study drug (Phase 2 Portion)administration.


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Table5:
Schedule of Pharmacokinetic, Immunogenicity, and Biomarker Assessments –Phase 1 Portion
Whole Blood
Bone Marrow Aspirate
Cycle
Day
Time
Window
PK
ATA
PNH & 
HLA-
DUR15
sCD33, 
Cytokines 
& UResearch
MDSC
CD33 
Expression PBMC MDSC
CD33 
Expression
Mutation 
Profiling
Baseline/Screening
Within 28 d 
prior to study 
drug
X
Xe
Xe
Xe
Within 7 d 
prior to study 
drug
X
1
1
Pre-azacitidine
within 24 hr
X
X 
X 
X
7 or
9
Pre-vadastuximab talirine
within 24 hr
X
X 
X 
X
Xi
Xi
End of vadastuximab 
talirine administration
within 15 min 
postdose
X
2 hr
15 min
X
6 hr
2 hr
X
8b
24 hr
4 hr
X
10c
72 hr
4 hr
X
X 
X
15d
192 hr
4 hr
X 
X
28
Day 22-29
2
1
Pre-azacitidine dose
within 24 hr
X
X 
X 
X 
X
7 or
9a
Pre-vadastuximab talirine
within 8 hr
X
End of vadastuximab 
talirine administration
within 15 min 
postdose
X
2 hr
15 min
X
8b
24 hr
4 hr
X
10c
72 hr
4 hr
X
28
Day 22-29
Xe
Xe
3
1
Pre-azacitidine
within 24 hr
X
7 or
9a
End of vadastuximab 
talirine administration
within 15 min 
postdose
X
4+
1
Pre-azacitidine
within 24 hr
Xh
Xf
Xf
Xf
Xf
7 or
9a
End of vadastuximab 
talirine administration
within 15 min 
postdose
Xh
28
Day 22-29
Xe,f
Xe,f
End of treatment
30–37 d 
post last dose
X
X 
X 
X 
X 
Xe,g
Xe,g
Xe,g
ATA = antitherapeutic antibody; CUR = complete response; d = days; EOT = end of treatment; HLA = human leukocyte antigen; MDSC= myeloid-derived suppressor cells; PBMC = 
peripheral blood mononuclear cells; PK = pharmacokinetics; PNH = Paroxysmal Nocturnal Hemoglobinuria; sCD33 = soluble CD33.


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a 
Day 9 if vadastuximab talirine is given on Day 9.
b
Day 10 if vadastuximab talirine is given on Day 9.
c
Day 12 if vadastuximab talirine is given on Day 9.
d
Day 17 if vadastuximab talirine is given on Day 9.
e Portion of bone marrow sample obtained at baseline or for response assessment, including at progression.
f
Even-numbered cycles until CUR, then every 4 cycles thereafter.
g Only required if not conducted within 4 weeks prior to EOT.
h
Cycle 4 and every 4 cycles thereafter.
i
Cycle 1, Day 7 or 9 bone marrow samples may be up to 48 hours predose.


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Table6:
Schedule of Pharmacokinetic, Immunogenicity, and Biomarker Assessments –Phase 2 Portion
Whole Blood
Bone Marrow Aspirate
Cycle
Day
Time
Window
PK
ATA
PNH & 
HLA-
DUR15
sCD33, 
cytokines & 
research
MDSC
CD33 
expression PBMC
MDSC
CD33 
expression
Mutation 
Profiling
Baseline/Screening
Within 28 d 
prior to study 
drug
X
Xe
Xe
Xe
Within 7 d 
prior to study 
drug
All
1
Pre-azacitidine dose
within 24 hr
Xb
Xi
Xi
Xi
Xi
7 or
9a,c
Pre dose blinded study 
drug
within 24/8 hr
Xd
Xh
Xh
Xh
Xh
End of blinded study drug 
administration
within 15 min 
postdose
Xb
28
Day 22-29
Xe,f
Xe,f
Xe,f
End of treatment
30–37 d 
post last dose
X
X
X 
X 
X 
Xe,g
Xe,g
Xe,g
ATA = antitherapeutic antibody; CUR = complete response; d = days; EOT = end of treatment; HLA = human leukocyte antigen; MDSC= myeloid-derived suppressor cells; PBMC = 
peripheral blood mononuclear cells; PK = pharmacokinetics; PNH = Paroxysmal Nocturnal Hemoglobinuria.
a
Cycle 1 Day 7c predose window is 24 hours prior to blinded study treatment administration.
b
URequired in Cycle 1-4 and every 4 cycles thereafter.
c
Day 9 if blinded study treatment given on Day 9.
d
Cycles 1-2 only; within 24 hours pre-infusion in Cycle 1 and within 8 hours pre-infusion in Cycle 2.
e Portion of bone marrow sample obtained at baseline or for response assessment, including at progression.
f
Even-numbered cycles until CUR, then every 4 cycles thereafter.
g Only required if not conducted within 4 weeks prior to EOT.
h
Cycle 1 and even-numbered cycles until CUR, then every 4 cycles.
i
Cycle 1 only.


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10.1Screening (Day -28 to 1)
The following procedures will be performed within 28 days before beginning treatment:
Informed consent
Study eligibility per inclusion/exclusion criteria
Medical history, including MDS history (Section11.1)
Cytogenetics and gene mutations (Section11.2)
Bone marrow examination (Section 11.3)
Biomarker assessments (Section 11.4)
o Whole blood (PNH and HLA-DUR15) 
o Bone marrow (MDSC, CD33 expression, and mutation profiling)
The following procedures will be performed within 7 days before beginning treatment:
Physical examination, ECOG performance status, weight, and height (Section11.5)
Electrocardiogram (ECG; Section11.6)
Serum or urine pregnancy test (women of childbearing potential only)
Clinical laboratory tests (CBC with differential, serum chemistry including ferritin, and 
urinalysis; Section11.7)
Serology laboratory tests (inflammatory serologies and special autoimmune serologies; 
Section11.7)
Subjects Phase 1 Portion only: Biomarker assessments (Section 11.4)
o Whole blood (PBMCs).
From the time of informed consent through the day prior to study Day 1, only study protocol-
related AEs should be recorded, as well as any concomitant medications given for the treatment 
of these AEs. 
For Phase 2 Portion only: Within one business day of the planned start of treatment with 
azacitidine, the study site will contact the IXURS as directed in the study manual. Contact 
information for the IXURS is provided in the study manual.


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10.2Treatment Period
All subjects will receive treatment in repeated 28-day cycles of azacitidine (75mg/m2SC or IV 
for 7 consecutive days or 5 days on/2 days off/2 days on) and vadastuximab talirine (after 
azacitidine on the last day of azacitidine treatment; Section9.5.1). In addition, procedures will be 
performed during the treatment period as indicated separately for the Phase 1 Portion 
(Section10.2.1) and the Phase 2 Portion (Section10.2.2), below.
10.2.1Phase 1 Portion
10.2.1.1Cycle 1
Day 1, pretreatment:
o Biomarker assessments (Section 11.4)
Whole blood (sCD33 -cytokines and research; MDSC; and CD33 expression)
o ECOG performance status and weight (Section11.5)
o Clinical laboratory tests (CBC with differential and serum chemistry including 
ferritin; Section11.7)
o PURO questionnaire (Section11.9)
o Blood samples for ATAs (within 24 hours before beginning the azacitidine infusion; 
Section11.8)
Days 1 to 6 (if azacitidine is administered on 7 consecutive days) or Days 1 to 5, and 8 (if 
administered 5 days on/2 days off/2 days on): Administer azacitidine according to the 
selected treatment schedule (Section9.5.1.3)
Day 7 (if azacitidine is administered on 7 consecutive days) or Day 9 (if administered 
5days on/2days off/2days on), pretreatment: 
o PK sample collection (within 24 hours before beginning the vadastuximab talirine 
infusion (Phase 1 Portion; Section11.4.1)
o Biomarker assessments (Section 11.4)
Whole blood (sCD33 -cytokines and research; MDSC; and CD33 expression)
Bone marrow (MDSC and CD33 expression; within 48 hours before beginning 
the vadastuximab talirine infusion)
o Vital signs


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o After completion of pretreatment procedures, administer azacitidine (Section9.5.1.3) 
followed by vadastuximab talirine (Section9.5.1.2) 
Days 7 to 15 (if azacitidine is administered on 7 consecutive days) or Days 9 to 17 (if 
administered 5 days on/2 days off/2 days on), posttreatment: 
o Vital signs (Day 7 or 9 only; within 30minutes after completing the vadastuximab 
talirine infusion)
o PK sample collection at the following time points (Section11.4.1)
At the end of the vadastuximab talirine infusion (+15 minutes; Day7 or Day9)
2 hours (±15 minutes) after the end of the vadastuximab talirine infusion (Day7 
or Day9)
6 hours (±2 hours) after the end of the vadastuximab talirine infusion (Day7 or 
Day9)
24 hours (±4 hours) after the end of the vadastuximab talirine infusion (Day8 or 
Day10)
72 hours (±4 hours) after the end of the vadastuximab talirine infusion (Day10 or 
Day12)
o Whole blood (MDSC and CD33 expression)
72 hours (±4 hours) after the end of the vadastuximab talirine infusion (Day10 or 
12)
Day 15 (±1 day): 
o Clinical laboratory tests (CBC with differential, serum chemistry including ferritin, 
and urinalysis; Section11.7) (±1 day)
o Whole blood (MDSC and CD33 expression; Section 11.4)
192 hours (±4 hours) after the end of the vadastuximab talirine infusion (Day10 
or 12)
Day 28 (±7days): 
o Bone marrow biopsy to assess bone marrow cellularity. Cycle 1 marrow biopsy 
may be omitted if either a) patient has recovered counts to less than grade 3 
cytopenias, ie, absolute neutrophil count (ANC) >1000/mcL AND platelet count 
>50,000/mcL, without transfusion support, by Day 28 of Cycle 1 or b) there is 
evidence in the peripheral blood of active MDS, eg, circulating blasts. 


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Note: 
A. If the marrow is not hypocellular (total marrow cellularity ≥10%), the patient 
may proceed to Cycle 2 per dose modification guidance, depending on marrow 
blast percentage / remission status. 
B. If the marrow is hypocellular (total marrow cellularity <10%), Cycle 2 should be 
delayed until count recovery (defined in Cycle 1 as thrombocytopenia and 
neutropenia improving to less than CTCAE grade 4, or by the following formula: 
[(NADIUR COUNT) + (BASELINE COUNT –NADIUR COUNT) x 0.75]. If 
neutrophil count or platelet count have not recovered to less than Grade 4 by Day 
42, a repeat marrow should be performed within a week. If the marrow is 
hypocellular at Day 42, then the subject will have experienced a DLT 
(posttreatment grade 4 neutropenia or grade4 thrombocytopenia lasting >42 
days from the start of therapy in the absence of evidence of active MDS); if 
marrow cellularity has recovered to ≥10%, and ongoing cytopenia(s) are 
attributed to active MDS, then Cycle 2 may be initiated.
10.2.1.2Cycle 2
Day 1 (±1 day), pretreatment:
o Biomarker assessments (Section 11.4)
Whole blood (sCD33 -cytokines and research; MDSC; CD33 expression; and 
PBMCs)
o ECOG performance status and weight (Section11.5)
o PURO questionnaire (Section11.9)
o Clinical laboratory tests (CBC with differential, serum chemistry including ferritin, 
and urinalysis; Section11.7)
o Blood samples for ATAs (within 24 hours before beginning the azacitidine infusion; 
Section11.8)
Days 1 to 6 (if azacitidine is administered on 7 consecutive days) or Days 1 to 5, and 8 (if 
administered 5 days on/2 days off/2 days on): Administer azacitidine according to the 
selected treatment schedule (Section9.5.1.3)
Day 7 (if azacitidine is administered on 7 consecutive days) or Day9 (if administered 
5days on/2 days off/2 days on), pretreatment: 
o PK sample collection (within 8 hours before beginning the vadastuximab talirine 
infusion; Section11.4.1)
o Vital signs


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o After completion of pretreatment procedures, administer azacitidine (Section9.5.1.3) 
followed by vadastuximab talirine (Section9.5.1.2)
Days 7 to 15 (if azacitidine is administered on 7 consecutive days) or Days9 to 17 (if 
administered 5 days on/2 days off/2 days on), posttreatment: 
o Vital signs (Day 7 or 9 only; within 30 minutes after completing the vadastuximab 
talirine infusion)
o PK sample collection at the following time point (Section11.4.1)
At the end of the vadastuximab talirine infusion (+15 minutes;Day7 or Day9)
2 hours (±15 minutes) after the end of the vadastuximab talirine infusion (Day7 
or Day9)
24 hours (±4 hours) after the end of the vadastuximab talirine infusion (Day8 or 
10)
72 hours (±4 hours) after the end of the vadastuximab talirineinfusion (Day10 or 
12)
Day 15 (±1 day): 
o Clinical laboratory tests (CBC with differential, serum chemistry including ferritin, 
and urinalysis; Section11.7)
Day 22 to 29: 
o Clinical laboratory tests (CBC with differential; Section11.7)
o Bone marrow examination (Section 11.3)
o Biomarker assessments (Section 11.4)
Bone marrow (MDSC and CD33 expression)
10.2.1.3Cycle3
Day 1 (±1 day), pretreatment:
o ECOG performance status and weight (Section11.5)
o Clinical laboratory tests (CBC with differential and serum chemistry including 
ferritin; Section11.7)
o Blood samples for ATAs (within 24 hours before beginning the azacitidine infusion; 
Section11.8)


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Days 1 to 6 (if azacitidine is administered on 7 consecutive days) or Days 1 to 5, 8, and 9 
(if administered 5 days on/2 days off/2 days on): Administer azacitidine according to the 
selected treatment schedule (Section9.5.1.3)
Day 7 (if azacitidine is administered on 7 consecutive days) or Day 9 (if administered 
5days on/2 days off/2 days on), pretreatment:
o Vital signs
Day 7 (if azacitidine is administered on 7 consecutive days) or Day9 (if administered 
5days on/2 days off/2 days on), posttreatment: 
o Administer azacitidine (Section9.5.1.3) followed by vadastuximab talirine 
(Section9.5.1.2)
o Vital signs(within 30 minutes after completing the vadastuximab talirine infusion)
o PK sample collection (within 15 minutes after completing the vadastuximab talirine 
infusion; Section11.4.1)
Day 15 (±1 day): 
o Clinical laboratory tests (CBC with differential, serum chemistry including ferritin, 
and urinalysis; Section11.7)
10.2.1.4Cycles ≥4 
Day 1 (±1 day), pretreatment:
o ECOG performance status and weight (Section11.5)
o Clinical laboratory tests (Section11.7)
All cycles: CBC with differential and serum chemistry including ferritin
Even-numbered cycles only: urinalysis
o Even-numbered cycles only: PURO questionnaire (Section11.9)
o Even-numbered cycles until CUR, then every 4 cycles: Biomarker assessments 
(Section11.4)
Whole blood (sCD33 -cytokines and research; MDSC; CD33 expression; and 
PBMCs)
o Cycle 4 only: Serology laboratory tests (inflammatory serologies and special 
autoimmune serologies; Section11.7)


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o Cycle 4, then every 4 cycles: Blood samples for ATAs (within 24 hours before 
beginning the azacitidine infusion; Section11.8)
Days 1 to 6 (if azacitidine is administered on 7 consecutive days) or Days 1 to 5, and 8 (if 
administered 5 days on/2 days off/2 days on): Administer azacitidine according to the 
selected treatment schedule (Section9.5.1.3)
Day 7 (if azacitidine is administered on 7 consecutive days) or Day 9 (if administered 
5days on/2 days off/2 days on), pretreatment:
o Vital signs
Day 7 (if azacitidine is administered on 7 consecutive days) or Day 9 (if administered 
5days on/2 days off/2 days on), posttreatment: 
o Administer azacitidine (Section9.5.1.3) followed by vadastuximab talirine 
(Section9.5.1.2)
o Vital signs(within 30 minutes after completing the vadastuximab talirine infusion)
o Cycle 4, then every 4 cycles: PK sample collection (within 15 minutes after 
completing the vadastuximab talirine infusion; Section11.4.1)
Day 15 (±1 day): 
o Cycle 4 only: Clinical laboratory tests (CBC with differential, serum chemistry 
including ferritin, and urinalysis; Section11.7)
Day 22 to 29: Even-numbered cycles until CUR, then every 4 cycles: 
o Clinical laboratory tests (CBC with differential; Section11.7)
o Biomarker assessments (Section 11.4)
Bone marrow (MDSC and CD33 expression)
o Bone marrow examination (Section 11.3)
Any AEs (Section12.1) and serious adverse events (SAEs; Section12.1.1), reported or observed, 
will be reported on the eCURF, and SAEs will be reported as indicated in Section12.1.5. Any 
changes in concomitant medications will be recorded at each visit or as they are reported. 
10.2.2Phase 2 Portion
The subject will receive treatment in repeated 28-day cycles of azacitidine (75mg/m2SC or IV 
for 7 consecutive days or 5 days on/2 days off/2 days on) and/or blinded study medication 
(vadastuximab talirine or placebo; Section9.5.1). In addition, procedures will be performed as 
indicated below.


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10.2.2.1Cycle 1
Day 1, pretreatment:
o Biomarker assessments (Section 11.4)
Whole blood (sCD33 -cytokines and research; MDSC; CD33 expression; and 
PBMCs)
o ECOG performance status and weight (Section11.5)
o Clinical laboratory tests (CBC with differential and serum chemistry including 
ferritin; Section11.7)
o PURO questionnaire (Section11.9)
o Blood samples for ATAs (within 24 hours before beginning the azacitidine infusion; 
Section11.8)
Days 1 to 6 (if azacitidine is administered on 7 consecutive days) or Days 1 to 5,and 8 (if 
administered 5 days on/2 days off/2 days on): Administer azacitidine according to the 
selected treatment schedule (Section9.5.1.3)
Day 7 (if azacitidine is administered on 7 consecutive days) or Day 9 (if administered 
5days on/2days off/2days on), pretreatment: 
o PK sample collection (within 8 hours before beginning the blinded study medication) 
(Section11.4.1)
o Biomarker assessments (Section 11.4)
Whole blood (sCD33 -cytokines and research; MDSC; CD33 expression; and 
PBMCs)
o Vital signs
o After completion of pretreatment procedures, administer azacitidine (Section9.5.1.3) 
followed by blinded study medication (Section9.5.1.2)
o Vital signs(within 30 minutes after completing the blinded study medication 
infusion)
o PK sample collection (within 15 minutes after completing the blinded study 
medication infusion; Section11.4.1)
Day 15 (±1 day): 


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o Clinical laboratory tests (CBC with differential, serum chemistry including ferritin, 
and urinalysis; Section11.7)
10.2.2.2Cycle 2
Day 1 (±1 day), pretreatment:
o ECOG performance status and weight (Section11.5)
o PURO questionnaire (Section11.9)
o Clinical laboratory tests (CBC with differential, serum chemistry including ferritin, 
and urinalysis; Section11.7)
o Serology laboratory tests (inflammatory serologies; Section11.7)
o Blood samples for ATAs (within 24 hours before beginning the azacitidine infusion; 
Section11.8)
Days 1 to 6 (if azacitidine is administered on 7 consecutive days) or Days 1 to 5, and 8 (if 
administered 5 days on/2 days off/2 days on): Administer azacitidine according to the 
selected treatment schedule (Section9.5.1.3)
Day 7 (if azacitidine is administered on 7 consecutive days) or Day9 (if administered 
5days on/2 days off/2 days on), pretreatment: 
o PK sample collection (within 8 hours before beginning the blinded study medication 
infusion; Section11.4.1)
o Whole blood (sCD33 -cytokines and research; MDSC; CD33 expression; and 
PBMCs)
o Vital signs
o After completion of pretreatment procedures, administer azacitidine (Section9.5.1.3) 
followed by blinded study medication (Section9.5.1.2)
o Vital signs(within 30 minutes after completing the blinded study medication 
infusion)
o PK sample collection (within 15 minutes after completing the blinded study 
medication infusion; Section11.4.1)
Day 15 (±1 day): 
o Clinical laboratory tests (CBC with differential, serum chemistry including ferritin, 
and urinalysis; Section11.7)


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Day 22 to 29: 
o Clinical laboratory tests (CBC with differential; Section11.7)
o Bone marrow examination (Section 11.3)
o Biomarker assessments (Section 11.4)
Bone marrow (MDSC, CD33 expression, and mutation profiling)
10.2.2.3Cycle 3
Day 1 (±1 day), pretreatment:
o ECOG performance status and weight (Section11.5)
o Clinical laboratory tests (CBC with differential and serum chemistry including 
ferritin; Section11.7)
o Blood samples for ATAs (within 24 hours before beginning the azacitidine infusion; 
Section11.8)
Days 1 to 6 (if azacitidine is administered on 7 consecutive days) or Days 1 to 5, and 8 (if 
administered 5 days on/2 days off/2 days on): Administer azacitidine according to the 
selected treatment schedule (Section9.5.1.3)
Day 7 (if azacitidine is administered on 7 consecutive days) or Day 9 (if administered 
5days on/2 days off/2 days on), pretreatment:
o Vital signs
Day 7 (if azacitidine is administered on 7 consecutive days) or Day9 (if administered 
5days on/2 days off/2 days on), posttreatment: 
o Administer azacitidine (Section9.5.1.3) followed by blinded study medication 
(Section9.5.1.2)
o Vital signs(within 30 minutes after completing the blinded study medication 
infusion)
o PK sample collection (within 15 minutes after completing the blinded study 
medication infusion; Section11.4.1)
Day 15 (±1 day): 
o Clinical laboratory tests (CBC with differential, serum chemistry including ferritin, 
and urinalysis; Section11.7)


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10.2.2.4Cycles ≥4 
Day 1 (±1 day), pretreatment:
o ECOG performance status and weight (Section11.5)
o Even-numbered cycles only: PURO questionnaire (Section11.9)
o Clinical laboratory tests (Section11.7)
All cycles: CBC with differential and serum chemistry including ferritin
Even-numbered cycles only: urinalysis
o Even-numbered cycles until CUR, then every 4 cycles: Biomarker assessments 
(Section11.4)
Whole blood (sCD33 -cytokines and research; MDSC; CD33 expression; and 
PBMCs)
o Cycle 4 only: Serology laboratory tests (inflammatory serologies and special 
autoimmune serologies; Section11.7)
o Cycle 4, then every 4 cycles: Blood samples for ATAs (within 24 hours before 
beginning the azacitidine infusion; Section11.8)
Days 1 to 6 (if azacitidine is administered on 7 consecutive days) or Days 1 to 5, and 8 (if 
administered 5 days on/2 days off/2 days on): Administer azacitidine according to the 
selected treatment schedule (Section9.5.1.3)
Day 7 (if azacitidine is administered on 7 consecutive days) or Day 9 (if administered 
5days on/2 days off/2 days on), pretreatment:
o Vital signs
Day 7 (if azacitidine is administered on 7 consecutive days) or Day9 (if administered 
5days on/2 days off/2 days on), posttreatment: 
o Administer azacitidine (Section9.5.1.3) followed by blinded study medication 
(Section9.5.1.2)
o Vital signs(within 30 minutes after completing the blinded study medication 
infusion)
o Cycle 4, then every 4 cycles: PK sample collection (within 15 minutes after 
completing the blinded study medication infusion; Section11.4.1)


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Day 15 (±1 day): 
o Cycle 4 only: Clinical laboratory tests (CBC with differential, serum chemistry 
including ferritin, and urinalysis; Section11.7)
Day 22 to 29: Even-numbered cycles until CUR, then every 4 cycles: 
o Clinical laboratory tests (CBC with differential; Section11.7)
o Biomarker assessments (Section 11.4)
Bone marrow (MDSC and CD33 expression)
o Bone marrow examination (Section 11.3)
Any AEs (Section12.1) and SAEs (Section12.1.1), reported or observed, will be reported on the 
eCURF, and SAEs will be reported as indicated in Section12.1.5. Any changes in concomitant 
medications will be recorded at each visit or as they are reported. 
10.3End of Treatment
For all subjects in both portions of the study, an EOT visit will be performed 30 to 37 days after 
the last dose of study treatment (vadastuximab talirine or placebo and/or azacitidine). At the 
EOT visit, the following assessments/procedures will be performed:
Physical examination and ECOG performance status (Section11.5)
Serum or urine pregnancy test (women of childbearing potential only)
Clinical laboratory tests (CBC with differential, serum chemistry including ferritin, 
urinalysis; Section11.7)
Serology laboratory tests (inflammatory serologies and special autoimmune serologies; 
Section11.7)
PURO questionnaire (Section11.9)
Bone marrow examination (Section 11.3)
Blood samples for ATAs (Section11.8)
Biomarker assessments (Section 11.4)
o Whole blood (sCD33 -cytokines and research;MDSC; CD33 expression; and 
PBMCs)
o Bone marrow (MDSC; CD33 expression; and mutation profiling) –not required if a 
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Any AEs (Section12.1) and SAEs (Section12.1.1), reported or observed, will be reported on the 
eCURF, and SAEs will be reported as indicated in Section12.1.5. End-of-treatment evaluations 
should be obtained before the initiation of non-protocol therapy. If the EOT visit occurs less than 
30days after the last treatment with any study treatment, the subject will be contacted by 
telephone 30 to 37 days after the last study treatment to assess any AEs or changes in 
concomitant medications that may have occurred since the EOT visit.
10.4Follow-Up
If study treatment is discontinued prior to disease progression or relapse, bone marrow samples 
will be obtained from assessments conducted every 4 months through 24 months after EOT or 
until initiation of another anticancer treatment, progression, or relapse.
Events of sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) that occur within 
180 days of the last dose of vadastuximab talirine or blinded study drug will be reported to the 
Sponsor, regardless of causality. Patients who undergo subsequent allo-SCT within 180 days of 
the last dose of vadastuximab talirine or blinded study drug inthe absence of relapse and 
additional therapy will be followed for SOS/VOD for 100 days post-transplant.
Subjects will be contacted for survival information and collection of subsequent anticancer 
treatment information approximately every 2 months until death or study completion.
If subjects become candidates for stem cell transplant after enrollment, initiation of preparative 
regimen for stem cell transplant should not be performed until at least 30 days after the last dose 
of vadastuximab talirine.It isrecommended to avoid transplant conditioning regimens with 
higher risk of SOS/VOD, including total-body irradiation and multiple alkylating agents.[27, 28] 
An association of SOS/VOD in patients with pre-exposure to vadastuximab talirine has not been 
established.
10.5 End of Study/End of Follow-up
The date the subject met criteria for study discontinuation and the reason for study 
discontinuation will be collected. 


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11.
METHODS OF ASSESSMENT
11.1Medical History
A full medical history, including demographic information and history of MDS and 
comorbidities, will be performed at screening on the eCURF. Any AEs (Section12.1) occurring 
after screening and before the first dose of study drug will be included as medical history.
11.2Cytogenetics and Gene Mutations 
Cytogenetics and mutation status at baseline will be assessed locally according to institutional 
standard and recorded on the eCURF. Additional samples will be assessed for mutation profiling 
(Section11.4).
11.3Bone Marrow Examination 
Bone marrow examinations for disease assessment at baseline, on treatment, and during follow-
up will be performed according to local standards and recorded on the eCURF. After EOT, bone 
marrow examinations for disease assessment should be performed every 4months through 24 
months after EOT or until initiation of another anticancer treatment, progression, or relapse. 
Bone marrow examination should be based on a bone marrow biopsy; however, if marrow 
cannot be biopsied,but aspiration is successful, the aspiratemay be used to determine blast 
count.
In addition to response assessment time points, a bone marrow biopsywill be performed between 
Day28 and Day 42 of any cycle in which the patient has not achieved hematologic recovery (as 
defined in Table2). This biopsy is to determine the blast count and marrow cellularity, in order 
to determine if dose modification / dose delay is required in the subsequent cycle (Table2and 
Table3). This biopsy to assess cellularity is not required if counts have recovered (ie, ANC 
>1000/mm3AND platelet count >50,000/mm3, without transfusion support, by Day 28 of the 
cycle) or if there are circulating blasts in the peripheral blood (as evidence of active MDS).
11.4Pharmacokinetic and Biomarker Assessments 
11.4.1Pharmacokinetics
Plasma samples will be collected for assessment of ADC (vadastuximab talirine) and SGD-1882. 
Pharmacokinetic sample collection procedures are detailed in the laboratory manual. 
Full-profile PK sample collection will be performed for subjects enrolled in the Phase 1 Portion 
of the study. In the Phase 1 Portion, samples will be collected at the following time points:
Cycle1
o Day 1: (within 24 hours before azacitidine administration)
o Day 7 or Day9 (last day of azacitidine dosing):


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Within 24 hours before vadastuximab talirine administration
At the end of vadastuximab talirine administration (within 15 minutes postdose)
2 hours (±15minutes) after the end of vadastuximab talirine administration
6 hours (±2hours) after the end of vadastuximab talirine administration
24 hours (±4hours) after the end of vadastuximab talirine administration (Day8 
or 10)
72 hours (±4hours) after the end of vadastuximab talirine administration (Day10 
or 12)
Cycle 2
o Day 7 or Day9 (last day of azacitidine dosing):
Within 8 hours before vadastuximab talirine administration
At the end of vadastuximab talirine administration (within 15 minutes postdose)
2 hours (±15minutes) after the end of vadastuximab talirine administration
24 hours (±4hours) after the end of vadastuximab talirine administration (Day8 
or 10)
72 hours (±4hours) after the end of vadastuximab talirine administration (Day10 
or 12)
Cycle 3
o Day 7 or Day9 (last day of azacitidine dosing):
At the end of vadastuximab talirine administration (within 15 minutes postdose)
Cycle 4, then every 4 cycles
o Day 7 or Day9 (last day of azacitidine dosing):
At the end of vadastuximab talirine administration (within 15 minutes postdose)
In the Phase 2 Portion, PK samples will be collected at the following time points:
Cycle 1
o Day 7 or Day9 (last day of azacitidine dosing):


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Within 24 hours before vadastuximab talirine/placebo administration
At the end of vadastuximab talirine/placebo administration (within 15 minutes 
postdose)
Cycle 2
o Day 7 or Day9 (last day of azacitidine dosing):
Within 8 hours before vadastuximab talirine/placebo administration
At the end of vadastuximab talirine/placebo administration (within 15 minutes 
postdose)
Cycles 3 and 4, then every 4 cycles
o Day 7 or Day9 (last day of azacitidine dosing):
At the end of vadastuximab talirine/placebo administration (within 15 minutes 
postdose)
11.4.2Biomarker Analyses: Whole Blood
Whole blood samples will be collected for assessment of biomarkers. Antitherapeutic antibody 
sample collection procedures are detailed in the laboratory manual. 
During the Phase 1 Portion of the study, samples will be collected at the following time points:
Baseline/Screening
o Within 28 days before Day 1 (PNH and HLA-DUR15)
o Within 7 days before Day 1 (PBMCs): Both baseline/screening samples may be 
collected at the same time if it is within 7 days before Day 1.
Cycle 1
o Day 1: Within 24 hours before azacitidine administration (sCD33 cytokines and 
research; MDSC; CD33 expression)
o Day 7 or Day9 (last day of azacitidine dosing): Within 24 hours before vadastuximab 
talirine administration (sCD33 cytokines and research; MDSC; CD33 expression)
o Day10 or 12: 72 hours (±4hours) after the end of vadastuximab talirine 
administration (MDSC; CD33 expression)
o Day15 or 17: 192 hours (±4hours) after the end of vadastuximab talirine 
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Cycle 2
o Day 1: Within 24 hours before azacitidine administration (sCD33 cytokines and 
research; MDSC; CD33 expression; PBMCs)
Cycle 4 and even-numbered cycles until CUR, then every 4 cycles
o Day 1: Within 24 hours before azacitidine administration (sCD33 cytokines and 
research; MDSC; CD33 expression; PBMCs)
At the EOT visit (30 to 37 days after the last dose of study drug; sCD33 cytokines and 
research; MDSC; CD33 expression; PBMCs)
During the Phase 2 Portion of the study, samples will be collected at the following time points:
Baseline/Screening: Within 28 days before Day 1 (PNH and HLA-DUR15)
Cycle 1
o Day 1: Within 24 hours before azacitidine administration (sCD33 cytokines and 
research; MDSC; CD33 expression; and PBMCs)
o Day 7 or Day9 (last day of azacitidine dosing): Within 8 hours before vadastuximab 
talirine/placebo administration (sCD33 cytokines and research; MDSC; CD33 
expression; and PBMCs)
Cycle 2 and even-numbered cycles thereafter (Cycles 4, 6, 8, etc) until CUR, then every 4 
cycles
o Day 7 or Day9 (last day of azacitidine dosing): Within 8 hours before vadastuximab 
talirine/placebo administration (sCD33 cytokines and research; MDSC; CD33 
expression; and PBMCs)
At the EOT visit (30 to 37 days after the last dose of study drug; sCD33 cytokines and 
research; MDSC; CD33 expression; PBMCs)
11.4.3Biomarker Analyses: Bone Marrow Aspirate
A portion of the bone marrow samples (aspirate) collected for disease assessment at baseline, for 
response assessment, and at the time of progression will be preserved for biomarker analyses. If 
baseline sample is collected prior to consent, a separate bone marrow aspirate will be collected 
for biomarker analyses. Sample collection and preparation procedures are detailed in the 
laboratory manual. 
During the Phase 1 Portion of the study, samples will be collected at the following time points:
Baseline/Screening (within 28 days before Day 1; MDSC; CD33 expression; mutation 
profiling)


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Cycle 1
o Day 7 or Day9: Within 24 hours before vadastuximab talirine administration 
(MDSC; CD33 expression)
Cycle 2 and even-numbered cycles thereafter until CUR, then every 4cycles
o Day 22-29 (MDSC; CD33 expression)
At the EOT visit (30 to 37 days after the last dose of study drug; MDSC; CD33 
expression; mutation profiling). An EOT sample is not required if a sample was collected 
within the previous 4 weeks.
During the Phase 2 Portion of the study, samples will be collected at the following time points:
Baseline/Screening: Within 28 days before Day 1 (MDSC; CD33 expression; mutation 
profiling)
Cycle 2 and even-numbered cycles thereafter until CUR, then every 4 cycles
o Day 22-29 (MDSC; CD33 expression; mutation profiling)
At the EOT visit (30 to 37 days after the last dose of study drug; MDSC; CD33 
expression; mutation profiling). An EOT sample is not required if a sample was collected 
within the previous 4 weeks.
11.5Physical Examination,ECOG Performance Status, Weight, and Vital Signs
Physical examinations will be performed within 7 days before starting treatment and will include 
examination of the following: head, ears, eyes, nose, throat, neck, skin, cardiovascular system, 
respiratory system, abdominal system, and nervous system. Postscreening physical examinations 
may be focused, at the discretion of the Investigator, to identify changes from baseline. 
ECOG performance status (Appendix 18.3) will be assessed at the time points indicated in 
Table4and recorded on the eCURF.
Body weight (kg) and height (cm) will be determined within 7 days before starting treatment to 
assess body surface area (to be recorded in the eCURF).
Vital signs (including temperature, heart rate, respiratory rate, and blood pressure) will be 
assessed at the timepoints indicated in Table4and recorded on the eCURF.
11.6Electrocardiograms
ECG recordings will be obtained within 7 days before starting treatment. A copy of all ECGs 
will be retained on site.


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For the purposes of screening, the Investigator or a designee will evaluate whether the ECG is 
normal or abnormal and whether it is clinically acceptable for inclusion, if abnormal.
ECGs may be repeated for quality reasons, and additional ECGs may be collected by the 
Investigator for safety reasons. Any posttreatment clinically relevant abnormal ECG findings 
will be reported as AEs.
11.7Clinical Laboratory Tests
For all women of childbearing potential, serum or urine pregnancy tests will be performed 
locally at screening and at EOT.
Screening laboratory assessments to determine eligibility will be performed locally by certified 
laboratories.
Postscreening, all protocol-required laboratory assessments will be performed by the central 
laboratory to evaluate safety at the times indicated in Table4. Additional local laboratory testing 
may be performed for evaluating safety and making clinical decisions. 
The following parameters will be determined by the central laboratory:
Hematology:WBC count with 5-part differential (neutrophils, lymphocytes, monocytes, 
eosinophils, and basophils), red blood cell count, platelet count, and hemoglobin/hematocrit.
Clinical chemistry:Albumin, alkaline phosphatase, ALT, AST, blood urea nitrogen, calcium, 
creatinine, chloride, ferritin, lactate dehydrogenase (LDH), phosphorus, potassium, sodium, total 
bilirubin, uric acid, lipase, and amylase.
Creatinine clearancewill be calculated using the Cockcroft-Gault [24] formula:
Male subjects
Creatinine clearance (mL/min) 
=
[140 –Age (years)] × body weight (kg)
72 × serum creatinine
Female subjects
Creatinine clearance (mL/min) =
0.85 ×
[140 –Age (years)] × body weight (kg)
72 × serum creatinine
Urinalysis:Urine dipstick or microscopic analysis, as well as spot urine protein and creatinine 
will be performed locally as indicated in Table4. 
Inflammatory serologies:C-reactive protein (CURP), C3, and C4.
Specialty autoimmune serologies:Anti-neutrophil cytoplasmic antibodies (ANCA), 
anti-double-stranded DNA (anti-dsDNA), quantitative immunoglobulins (IgM, IgG, IgA), 
rheumatoid factor (URF), antinuclear antibodies (ANA), and Direct Coomb’s.
Additional laboratory assessments, as necessary for subject management, may be performed by 
certified local laboratories. Documentation of certification will be filed with study 
documentation.


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Central laboratory results will not be provided to the study sites. Additional and repeat laboratory 
safety testing may be performed at the discretion of the Investigator. 
11.8Blood Samples for AntitherapeuticAntibodies
11.8.1Antitherapeutic Antibodies
Serum samples will be collected for assessment of ATAs. Antitherapeutic antibody sample 
collection procedures are detailed in the laboratory manual. 
Sample collection for ATAs will be performed for all subjects enrolled in both phases of the 
study before treatment with vadastuximab talirine/placebo (on Day 7 or Day9) in Cycles 1-4 and 
in every 4 cycles thereafter. The sample collection window is within 24 hours pretreatment in 
Cycle 1 and within 8 hours pretreatment for other cycles.
11.9Quality of Life Data Collection 
Quality of life will be assessed by using the PURO tool QLQ-C30. The QLQ-C30 is a validated 
QoL/PURO tool [29and Appendix18.7] and will be assessed pretreatment on Day 1 of Cycles 1 
and 2 and even-numbered cycles thereafter (ie, Cycles 4, 6,8, etc) and at EOT. The subject will 
be instructed to fill out the questionnaires to the best of his/her abilities, and the study staff will 
be responsible for confirming that the subject has completed the questionnaires.
11.10UResponse Assessment
UResponse willbe assessed according to the 2006 IWG criteria [22] as outlined in 
Section13.6.4.1and Appendix18.6. Disease assessments (blood and bone marrow) will be 
performed at the end of each even-numbered cycle (Day 22-29) until CUR, then every 4 cycles 
thereafter (Table4) according to local practice. 


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12.
SAFETY MEASUUREMENTS AND VAURIABLES
12.1Adverse Events 
12.1.1Definitions 
Adverse Events
According to the ICH E2A guideline Definitions and Standards for Expedited UReporting, and 21 
CFUR 312.32, Investigational New Drug (IND) Safety UReporting, an AE is any untoward medical 
occurrence in a subject or clinical investigational subject administered a medicinal product and 
which does not necessarily have a causal relationship with this treatment.
The following information should be considered when determining whether or not to record a 
test result, medical condition, or other incident on the Adverse Events and Pre-existing 
Conditions eCURF:
• From the time of informed consent through the day prior to study Day 1, only study 
protocol-related AEs should be recorded. 
• All medical conditions present or ongoing predose on study Day 1 should be recorded. 
• All AEs (regardless of relationship to study drug) should be recorded from study Day1 
(during and postdose) through the end of the safety reporting period (see Section 12.1.3). 
Complications that occur in association with any procedure (eg, biopsy) should be 
recorded as AEs whether or not the procedure was protocol mandated. 
• Changes in medical conditions and AEs, including changes in severity, frequency, or 
character, during the safety reporting period should be recorded.
• In general, an abnormal laboratory value should not be recorded as an AE unless it is 
associated with clinical signs or symptoms, requires an intervention, results in an SAE, or 
results in study termination or interruption/discontinuation of study treatment. When 
recording an AE resulting from a laboratory abnormality, the resulting medical condition 
rather than the abnormality itself should be recorded (eg, record “anemia” rather than 
“low hemoglobin”).


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Serious Adverse Events
An AE should be classified as an SAE if it meets one of the following criteria:
Fatal:
AE resulted in death.
Life threatening:
The AE placed the patient at immediate risk of death. This classification does not 
apply to an AE that hypothetically might cause death if it were more severe.
Hospitalization:
The AE required or prolonged an existing inpatient hospitalization. Hospitalizations 
for elective medical or surgical procedures or treatments planned before the signing of 
informed consent in the study or routine check-ups are not serious AEs by this 
criterion. Admission to a palliative unit or hospice care facility is not considered to be 
a hospitalization. Hospitalizations or prolonged hospitalizations for scheduled therapy 
of the underlying cancer or study target disease need not be captured as SAEs.
Disabling/ 
incapacitating:
UResulted 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 AEdid 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 infectiousagent.
Adverse Event Severity 
AE severity should be graded using the NCI CTCAE, version 4.03 (Appendix18.4). These 
criteria are provided in the study manual.
AE severity and seriousness are assessed independently. ‘Severity’ characterizes the intensity of 
an AE. ‘Serious’ is a regulatory definition and serves as a guide to the Sponsor for defining 
regulatory reporting obligations (see definition for SAEs).
URelationship of the Adverse Event to Study Treatment
The relationship of each AE to each study drug (vadastuximab talirine or azacitidine) should be 
evaluated by the Investigator using the following criteria:
URelated:
There is evidence to suggest a causal relationship between the drug and the AE, such 
as:
• An event that is uncommon and known to be strongly associated with drug 
exposure (eg, angioedema, hepatic injury, Stevens-Johnson Syndrome)
• An event that is not commonly associated with drug exposure, but is 
otherwise uncommon in the population exposed to the drug (eg, tendon 
rupture)
Unrelated:
Another cause of the AE is more plausible (eg,due to underlying disease or occurs 
commonly in the study population), or a temporal sequence cannot be established with 
the onset of the AE and administration of the study treatment, or a causal relationship 
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12.1.2Procedures for Eliciting and URecording Adverse Events
Investigator and study personnel will report all AEs and SAEs, whether elicited during subject 
questioning, discovered during physical examination, laboratory testing, and/or other means by 
recording them on the eCURF 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.
URecording Adverse Events
The following information should be recorded on the Adverse Events and Pre-existing 
Conditions eCURF:
Description including onset and resolution dates
Whether it met serious criteria
Severity
URelationship to study treatment or other causality
Outcome
Diagnosis vs Signs or Symptoms
In general, the use of a unifying diagnosis is preferred to the listing of individual symptoms. 
Grouping of symptoms into a diagnosis should only be done if each component sign and/or 
symptom is a medically confirmed component of a diagnosis as evidenced by standard medical 
textbooks. If any aspect of a sign or symptom does not fit into a classic pattern of the diagnosis, 
report the individual symptom as a separate AE.
Important exceptions for this study are adverse reactions associated with the infusion of study 
drug. For infusion-related reactions, do not use the NCI CTCAE terms of ‘cytokine release 
syndrome,’ ‘acute infusion reaction,’ or ‘allergic or hypersensitivity reaction.’ Instead, record 
each sign or symptom as an individual AE. If multiple signs or symptoms occur with a given 
infusion-related event, each sign or symptom should be recorded separately with its level of 
severity.
URecording Serious Adverse Events
For SAEs, record the primary event on both the eCURF and an SAE form; events occurring 
secondary to the primaryevent should be described on the SAE form in the narrative description 
of the case.
The following should be considered when recording SAEs:
• Death is an outcome of an event. The event that resulted in the death should be recorded 
and reported on both an SAE form and eCURF.
• 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 


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procedure should be captured in the narrative as part of theaction taken in response to the 
illness.
Progression of the Underlying Cancer
Do not use the term ‘disease progression’ when reporting an AE because it is too general. 
Instead, report the specific disease (clinical) manifestation of the progression (eg,‘malignant 
pleural effusion’, ‘spinal bone metastases’, ‘lymphadenopathy from underlying non-Hodgkin 
lymphoma’, ‘brain metastases’).
Pregnancy
Notification to Drug Safety: Complete a Pregnancy UReport 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 subject. Only report 
pregnancies that occur in a male subject’s partner if the estimated date of conception is after the 
male subject’s first study drug dose. Fax or email the Sponsor’s Drug Safety Department within 
48 hours of becoming aware of a pregnancy.
All pregnancies will be monitored for the full duration; all perinatal and neonatal outcomes 
should be reported. Infants should be followed for a minimum of 8 weeks.
Collection of data on the eCURF: All pregnancies (as described above) that occur within 30days 
of the last dose of study drug(s) will also be recorded on the Adverse Events and Pre-existing 
Conditions eCURF.
Abortion, whether accidental, therapeutic, or spontaneous, should be reported as an SAE. 
Congenital anomalies or birth defects, as defined by the ‘serious’ criterion above (see definitions 
Section 12.1.1) should be reported as SAEs.
12.1.3UReporting Periods for Adverse Events and Serious Adverse Events
The safety reporting period for all AEs and SAEs is from study Day 1 (predose) through 30days 
after the last dose of study treatment (vadastuximab talirine or azacitidine). However, all study 
protocol-related AEs are to be collected from the time of informed consent. 
All SAEs that occur after the end of safety reporting period (ie, more than 30 days after the last 
dose of study treatment) and are considered treatment-related in the opinion of the Investigator 
should also be reported to the Sponsor.
SAEs will be followed until significant changes return to baseline, the event stabilizes 
(recovering/resolving) or is no longer considered clinically significant by the Investigator, or the 
subject dies or withdraws consent, or study closure. All non-serious AEs will be followed 
through the safety reporting period. 
12.1.4Adverse 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 


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Disease Adverse Event Information Form” for all of these events. All reported adverse events of 
special interest will be subject to expedited reporting according to safety reporting requirements. 
Events of SOS/VOD that occur within 180 days of the last dose of vadastuximab talirine or 
blinded study drug will be reported to the Sponsor, regardless of causality. Patients who undergo 
subsequent allo-SCT within 180 days of the last dose of vadastuximab talirine or blinded study 
drug in the absence of relapse and additional therapy will be followed for SOS/VOD for 
100days post-transplant.
12.1.5Serious Adverse Events URequire Immediate UReporting
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:
Subject number 
Date of event onset
Description of the event
Study treatment, if known
The completed SAE form and SAE Fax Cover Sheet are tobe faxed to the Sponsor’s Drug 
Safety Department at (425) 527-4308 ordrug.safety@seagen.comwithin 24 hours. 
URelevant follow-up information is to be submitted to the Sponsor as soon as it becomes 
available.
12.1.6Sponsor Safety UReporting URequirements in the United States
According to the final rule amending the IND safety reporting requirements under 21 CFUR 
312.32 and the FDA’s final guidance Safety UReporting URequirements for INDs and BA/BE 
Studies (December 2012),endpoints that assess disease-related mortality or major morbidity, as 
well other SAEs that are not study endpoints, but are known consequences of the underlying 
disease or condition that are anticipated to occur in the study population, should not be reported 
to the FDA as individual IND safety reports.
In this study, 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 Seattle 
Genetics’ Drug Safety Department. If, upon review, an SAE is occurring at a higher rate than 
that which would be expected for the study population, then an IND safety report for the SAE 
will be submitted to the FDA.
These safety reporting requirements apply only to the process by which the Sponsor reports 
SAEs to the FDA. Investigators are required to report all SAEs, including anticipated SAEs, to 
the Sponsor. In addition, the Sponsor will report all SAEs to international authorities as required 
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13.
DATA MANAGEMENT AND STATISTICAL ANALYSIS
The data management and statistical analysis of this study will be performed by an external 
clinical research organization(CURO) PURA HealthSciences.
13.1Data Management
An eCURF will be used for the current study, and a data management plan will be prepared by the 
CURO PURA Health Sciences. 
Previous and concomitant medications will be coded using the latest available WHO Drug 
UReference Dictionary.Coexistent diseases and AEs will be coded using the Medical Dictionary 
for URegulatory Activities (MedDURA).
When the database has been declared to be complete and accurate, the database will be locked. 
Any changes to the database after that time can only be made by written agreement between 
Seattle Genetics, Inc., and the PURA Health Sciences project team.
13.2Sample Size Estimation
Phase 1 Portion (minimum of 6 subjects per cohort): Six subjects are adequate to appropriately 
assess the safety profiles and DLT rates of differing dose levels of vadastuximab talirine in 
combination with azacitidine. If the true incidence rate of DLT is 10%, the probability of 
considering a dose level tolerable (ie, ≤1 of 6 subjects experiences a DLT) will be 88.6%. If the 
true incidence rate of DLT is 50%, the probability of considering a dose level tolerable will be 
10.9%.
Phase 2 Portion (106 subjects): A sample size of 106 subjects will provide 85% power to detect a 
treatment difference in OURUR, assuming an OURUR of 30% for azacitidine alone vs 55% for the 
combination of vadastuximab talirine with azacitidine, at a 2-sided 0.1 alpha level.
13.3Statistical Analysis Plan
A Statistical Analysis Plan (SAP) will be written and finalized prior to any lock of the study 
database. The SAP will provide a detailed description of the statistical methods and expand on 
the details provided in the protocol. Additional analyses may be added. Table, listing, and figure 
shells will also be provided.
13.4URandomization
During the Phase 2 Portion of the study, subjects will be randomized in a 1:1 manner to receive 
azacitidine with or without vadastuximab talirine, stratified by ECOG performance score (0 vs 1 
or 2) and IPSS score (Intermediate-2 vs High risk). URandomization will be performed by an 
IXURS.


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13.5Analysis Populations
13.5.1Intent-to-Treat Population
The intent-to-treat (ITT) population will include all subjects who are randomized in the Phase 2 
Portion of the study. Subjects will be grouped according to their randomized treatment group 
assignment regardless of the treatment they actually received.
13.5.2Safety Population
The safety population will include all subjects who are enrolled and received at least 1 dose of 
study treatment (vadastuximab talirine or azacitidine) in both portions of the study.
13.5.3DLT-Evaluable Population 
The DLT-evaluable population will include all Phase 1 subjects who have completed at least 
Cycle 1 of treatment (Cycle 1 of treatment is completed when the patient receives the first dose 
of azacitidine on Day 1 of Cycle 2) ordiscontinued study treatment because of AEs or for a 
safety-related reason before having had the opportunity to receive the first dose of azacitidine on 
Day 1 of Cycle 2. Subjects in the DLT-evaluable population will be grouped by assigned dose 
level. 
13.5.4Modified Intent-to-Treat Population
The modified intent-to-treat (mITT) population will include all ITT subjects who received at 
least 1 dose of study medication (azacitidine or vadastuximab talirine).
13.5.5Per-Protocol Population
A per-protocol population may be defined in the SAP.
13.6Statistical Methods
13.6.1Missing Data
Missing data will not be imputed, with the exception of missing or partial dates; imputation rules 
for missing or partial dates will be specified in the SAP.
Time-to-event data will be censored as outlined in Section13.6.4.2. All other missing data will 
be treated as missing.
13.6.2Demographic and Baseline Data
Demographic and baseline data will be summarized descriptively by phase and treatment arm or 
dose level. For continuous variables, descriptive statistics will include the mean, standard 
deviation (or standard error), median, range, and interquartile range.For categorical variables, 
descriptive statistics will include the number and percent. All demographic and baseline data will 
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13.6.3Subject Disposition
The number and percent of subjects who discontinue treatment and withdraw from study and the 
reasons for discontinuation or withdrawal will be summarized. Disposition by the number of 
cycles of treatment will be summarized by phase and treatment arm or dose level.
13.6.4Efficacy
The primary endpoint of the Phase 2 Portion is OURUR, and the study will be unblinded for analysis 
of OURUR after all subjects have completed 6 cycles of therapy or have discontinued treatment for 
any reason before completing 6 cycles. Data collection for the secondary efficacy endpoints and 
the safety and other endpoints will continue inan unblinded or partially blinded fashion until all 
subjects have discontinued study treatment.
13.6.4.1UResponse to Treatment
Subjects will be assigned a response status based on assessments at each visit as indicated in 
Table4. The primary efficacy endpoint of the study is OURUR, defined as the proportion of subjects 
who achieve any category of CUR (CUR and Marrow CUR) or PUR based on the 2006 IWG criteria for 
MDS [22] that are summarized in Appendix18.6. OURUR will be analyzed based on the phase 2 
ITT population. OURUR will be assessed during the on treatment period until EOT. 
The OURUR will be summarized by treatment group and the corresponding 90% confidence 
intervals will be calculated. The treatment difference in OURUR will be tested using a Cochran-
Mantel-Haenszel test for the Phase 2 Portion of the study. 
OURUR will be summarized descriptively by dose for the subjects in the Phase 1 Portion of the 
study who qualified for the safety population.
13.6.4.2Secondary Efficacy Endpoints
Time-to-event variables (DOUR, PFS, and OS) will be summarized descriptively using the 
Kaplan-Meier estimate. Additional details will be provided in the SAP. Secondary endpoints will 
be assessed in the ITT population (except as indicated below). 
CUR URate: UResponse (CUR/Marrow CUR, PUR, OURUR [CUR/Marrow CUR+PUR], HI rate, stable disease 
[SD], and PD) will be summarized descriptively by treatment arm. CUR rate will be summarized 
with 90% confidence intervals. URate of transformation to AML will also be summarized. 
DOUR(for PUR/CUR and CUR): DOUR is defined as the time from first observation of response 
(PUR+CUR/Marrow CUR or CUR/Marrow CUR) to disease progression/relapse or death from any cause, 
whichever occurs first. Durations will be assessed in the ITT population with a PUR or CUR and 
calculated separately for subjects with CUR/Marrow CUR and those with PUR+CUR/Marrow CUR 
combined. For subjects with a remission without subsequent disease progression/relapse or death 
on study, DOUR will be censored at the time of the last disease assessment demonstrating a lack of 
disease progression/relapse. Subjects who receive another anti-neoplastic therapy in the absence 
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malignancy, EXCEPT that subjectswho receive stem cell transplant in remission will continue to 
be followed for progression.
Progression-free Survival: PFS is defined as the time from first dose of study medication to first 
documentation of disease progression/relapse, or to death due to any cause, whichever occurs 
first. For subjects without disease progression/relapse or death on study, PFS will be censored at 
the time of the last on-study disease assessment demonstrating a lack of disease progression/
relapse. If more than one date of progression is available, the earliest date will be used to 
determine PFS. Subjects who receive another anti-neoplastic therapy in the absence of 
documented progression will be censored at the time of receiving off-protocol therapy for 
malignancy, EXCEPTthat subjects who receive stem cell transplant in remission will continue to 
be followed for progression.
Overall Survival: OS is defined as the time from first dose of study medication to death due to 
any cause. For subjects not known to have died at theend of the study, OS will be censored at 
the time the subject was last known to be alive (including follow-up data).
Efficacy endpoints will be summarized descriptively by dose for the subjects in the Phase 1 
Portion of the study who qualified for the safety population.
13.6.5Quality of Life 
Data from the QLQ-C30 will be scored as recommended by the European Organization for 
UResearch and Treatment of Cancer (see Appendix18.7) and summarized descriptively.
13.6.6Pharmacokinetics, Immunogenicity, and Biomarkers
Estimates of selected PK parameters (vadastuximab talirine ADC and SGD-1882), incidence of 
ATA to vadastuximab talirine, and biomarker data (in whole blood and bone marrow, as outlined 
in Section11.4.2and Section11.4.3) will be summarized by phase and treatment arm or dose 
level. 
13.6.7Safety
Safety data will be summarized for the safety population separately for the Phase 1 and Phase 2 
Portions by treatment arm or dose level. 
Exposure to treatment will be summarized separately for vadastuximab and azacitidine. 
Summaries will include the duration of treatment, number of doses received, number of cycles 
received, number of doses interrupted and the reasons for dose interruption, the number of
subjects with dose decreases for toxicity, the cumulative dose, and the relative dose intensity.
All AEs reported after initiation of treatment and pre-existing conditions that worsen after 
initiation of treatment will be considered treatment-emergent AEs(TEAEs). All AEs will be 
coded by system organ class, MedDURA preferred term, and severity grade using NCI CTCAE 
(v4.03; Appendix 18.4). All recorded AEs will be included in the data listings.


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The number and percent of subjects reporting all TEAEs, treatment-related AEs, SAEs, and 
deaths; TEAEs according to worst CTCAE grade; and AEs leading to treatment discontinuation 
will be summarized by preferred term and, where appropriate, system organ class. Deaths, SAEs, 
and AEs leading to treatment discontinuation will also be listed.
Adverse events that were considered DLTs will be listed and summarized by dose level for the 
DLT-evaluable population.
Summary statistics for actual values and for change from baseline will be tabulated as 
appropriate for laboratory results by scheduled visit. Where appropriate, laboratory results will 
be graded according to CTCAE 4.03, and shift tables from baseline to worst observed 
posttreatment grade will be presented. 
All medications received during the treatment period will be considered as concomitant 
medications and will be coded by WHO medical dictionary and summarized. 
13.6.8Additional Data
Additional summaries may bedefined in the SAP.
13.6.9Interim Analysis
No formal interim analyses for efficacy are planned for this study. During the Phase 1 Portion, 
the SMC will monitor safety in an ongoing fashion. The SMC will comprise medical experts 
from Seattle Genetics or their designee and a group of the investigators involved in the Phase 1 
Portion. Exploratory or other analyses of the open-label phase 1 data may be performed.
During the Phase 2 Portion, an IDMC will periodically assess the ongoing safety data and make 
recommendations to either continue evaluating the combination or to halt due to toxicity 
concerns. 
13.6.10Independent Data Monitoring Committee
The IDMC will consist of individuals external to Seattle Genetics, Inc. and PURA Health 
Sciences, chosen for their expertise in oncology. Members of the IDMC will include, at a 
minimum, physicians and appropriate statistical representation. The primary role of this IDMC 
will be to monitor safety data. 
The IDMC will review unblinded safety data after the first 20 subjects in the Phase 2 Portion 
have completed 2cycles of therapy and then every 6 months thereafter and as needed. The 
IDMC may recommend changes to the protocol. In addition, the IDMC will communicate major 
safety concerns and recommendations regarding study modificationor termination to Seattle 
Genetics, Inc. senior management at any time during the conduct of the study. 
The safety analysis will evaluate the overall safety of the treatment regimens including, but not 
limited to, the following parameters:
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Incidence of grade ≥3 febrile neutropenia
Type, incidence, and severity of laboratory abnormalities
Incidence and severity of infusion-related and hypersensitivity reactions.
Additional details of the safety reviews will be provided in the IDMC charter.


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


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15.
STUDY MANAGEMENT AND MATEURIALS
15.1Electronic Case UReport Forms
An eCURF will be used to store and transmit subject information. The file structure and format for 
the eCURF will be provided by the Sponsor or their representative and should be handled in 
accordance with the instructions provided.
The eCURF must be reviewed, electronically signed, and dated bythe Investigator.
Access to the eCURF will be strictly password protected and limited to personnel directly 
participating in the study. Data should be entered into the eCURF completely by examining 
personnel or the study coordinator. The eCURF must be completed as soon as possible after any 
subject evaluation or communication. If data are to be changed due to erroneous input or other 
reason, an electronic audit trail will track these changes. The eCURFs and computers that store 
them must be accessible to studymonitors and other regulatory auditors.
15.2Data Collection
During each study visit, a physician participating in the study will maintain medical records to 
document all significant observations. At a minimum, these notes will contain:
The date of the visit and the corresponding day or visit in the study schedule (eg, 
screening, Cycle 1, Day 1, etc.)
General condition and status remarks by the subject, including any significant medical 
findings. The severity, frequency, duration, and resolution of any reportedAE, and the 
Investigator
's assessment as to whether or not the reported AE is study drug-related
Changes in concomitant medications or dosages
A general reference to the procedures completed
The signature or initials of all physicians making an entry in the medical record (progress 
notes)
In addition, any contact with the subject via telephone or other means that provides significant 
clinical information will also be documented in the medical record (progress notes), as described 
above. 
Information from the medical records (progress notes) and other source documents will be 
promptly transcribed to the appropriate section of the eCURF.
Changes to information in the medical record (progress notes), eCURF, and other source 
documents will be initialed and datedon the day the change is made by the Investigator or 
designee. If the reason for the change is not apparent, a brief explanation for the change will be 
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15.3Source Documents Maintenance
Source documents contain the results of original observations and activities of a clinical 
investigation. Source documents include, but are not limited to, medical records (progress notes), 
computer printouts, screening logs, and recorded data from automated instruments. 
All source documents fromthis study will be maintained by the Investigator and made available 
for inspection by authorized persons. The original signed informed consent for each subject shall 
be filed with records kept by the Investigator, and a copy shall be given to the subject.
15.4URecord Maintenance
All data derived from the study will remain the property of Seattle Genetics, Inc.
URecords must be retained in accordance with the current ICH Guidelines on GCP. All essential 
study documents including records of subjects, source documents, eCURFs, and study drug 
inventory must be kept on file.
US FDA regulations (21 CFUR 312.62[c]) require that records and documents pertaining to the 
conduct of this study and the distribution of investigational drug, including eCURFs, consent 
forms, laboratory test results, and medical inventory records, must be retained by the Principal 
Investigator for 2 years after marketing application approval. If no application is filed, these 
records must be kept for 2 years after the investigation is discontinued and the US FDA and the 
applicable national and local health authorities are notified. The Sponsor or their representative 
will notify the Principal Investigator of these events.
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region, or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational products. However, essential 
documents may be retained for a longer period if required by the applicable regulatory 
requirements or by agreement with the Sponsor. The Sponsor is responsible for informing the 
Investigator when these documents need no longer be retained.
The Investigator will not dispose of any records relevant to this study without written permission 
from the Sponsor and will provide the Sponsor the opportunity to collect such records. The 
Investigator shall take responsibility for maintaining adequate and accurate source documents of 
all observations and data generated during this study. Such documentation is subject to 
inspection by the Sponsor, its representatives, and regulatory authorities.
If an Investigator moves, withdraws from an investigation, or retires, the responsibility for 
maintaining the records may be transferred to another person who will accept responsibility. 
Notice of transfer must be made to and agreed on by the Sponsor.


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


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16.
ADMINISTURATION PUROCEDUURES
16.1URegulatory Approval
Seattle Genetics, Inc., or their appointed agents, will be responsible for ensuring that appropriate 
regulatory authority approvals are obtained, according to local country requirements.
16.2Protocol Amendments
In accordance with ICH Topic E6 (UR1) Guideline for GCP, the Investigator should not 
implement any deviation from or changes to the protocol without agreement by the Sponsor and 
documented approval from the IURB of a protocol amendment, except where necessary to 
eliminate an immediate hazard(s) to study subjects, or when the change(s) involves only 
logistical or administrative aspects of the study (eg, change in monitor[s] or changeof telephone 
number[s]).
Any change to the protocol must be handled as a protocol amendment. Any potential amendment 
must be approved by the Sponsor. A written amendment must be submitted to the appropriate 
regulatory authorities and to the IURB assuming this responsibility. The Investigator must await 
IURB approval of protocol amendments before implementing the changes, except where necessary 
to eliminate apparent immediate hazard to subjects. In these cases, the IURB must be notified 
within 5 days of the change.
All amendments to the protocol must be approved in writing by both the appropriate regulatory 
authorities and the IURB, except for administrative amendments, which require notification but 
not written approval. Once approved, the protocol amendment will be distributed to all recipients 
of the original protocol, with instructions to append the amendment to the protocol.
If, in the judgment of the local IURB, the Investigator and/or Sponsor, the protocol amendment 
alters the study design, procedures and/or increases the potential risk to the subject, the currently 
approved written informed consent form will require modification. The modified informed 
consent form must also be reviewed and approved by the Sponsor, appropriate regulatory 
authorities, and theIURB. In such cases, repeat informed consent must be obtained from subjects 
enrolled in the study before participation continues.
16.3Protocol Adherence and Deviations
The protocol must be read thoroughly, and the instructions must be followed. However, 
exceptions will be made in emergency situations when the protection, safety, and well-being of 
the subject requires immediate intervention based on the judgment of the Investigator or a 
responsible, appropriately trained, and credentialed professional(s) designated by the Investigator 
as a sub-Investigator
.
In the event of an important protocol deviation due to an emergency, accident, or error, the 
Investigator or designee must contact the medical monitor at the earliest possible time by 
telephone. This allows for an early joint decision to be made as to whether or not the subject 
should continue study treatment. The Investigator, the Sponsor, and the medical monitor will 
document this decision.


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16.4Study Documentation, Privacy, and URecords URetention
Government agency regulations and directives require that all study documentation pertaining to 
the conduct of a clinical trial must be retained by the Investigator until notified by the Sponsor in 
writing that retention is no longer necessary.
To protect the safety of participants in the study and to ensure accurate, complete, and reliable 
data, the Investigator will keep records of laboratory tests, clinical notes, and patient medical 
records in the patient files as original source documents for the study. If requested, the 
Investigator will provide the Sponsor, its licensees and collaborators, applicable regulatory 
agencies, and the applicable IURB with direct access to original source documents or certified 
copies.
URecords containing patient medical information must be handled in accordance with the 
requirements of the Health Information Portability and Accountability Act (HIPAA) Privacy 
URule and be consistent with the terms of the patient Authorization contained in the informed 
consent document for the study (the Authorization). Care should be taken to ensure that such 
records are not shared with any person or for any purpose not contemplated by the Authorization. 
Furthermore, case report forms and other documents to be transferred to the Sponsor should be 
completed in strict accordance with the instructions provided by the Sponsor, including the 
instructions regarding the coding of patient identities.
In compliance with local and/or regional regulations, this trial may be registered and trial results 
may be posted on public registries, such as ClinicalTrials.gov.
16.5Publication Policy
The details of the processes of producing and reviewing publications and presentations based on 
the data from this study will be described in the Clinical Trial Agreement between Seattle 
Genetics, Inc., and the institution of the Investigator.
16.6Clinical Study UReport
A final clinical study report will be prepared according to the ICH guideline on Structure and 
Contents of Clinical Study UReports. A final clinical study report will be prepared regardless of 
whether the study is completed or prematurely terminated. 
16.7Contractual and Financial Details
The Investigator (and/or, as appropriate, the hospital administrative representative) and the 
Sponsor will sign a clinical study agreement prior to the start of the study, outlining overall 
Sponsor and Investigator responsibilities in relation to the study. The contract should describe 
whether costs for pharmacy, laboratory, and other protocol-required services are being paid 
directly or indirectly. 
16.8Insurance, Indemnity, and Compensation
Seattle Genetics, Inc. undertakes to maintain an appropriate clinical study insurance policy.


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Deviations from the study protocol -especially the prescription of a dose other than that 
scheduled in the study protocol, other modes of administration, other indications, and longer 
treatment periods-are not permitted and shall not be covered by the statutory subject insurance 
scheme.
16.9Discontinuation of the Study
This study may be terminated by the Sponsor. The study may also be terminated prematurely at 
any time when agreed to by both the Investigator and the Sponsor as being in the best interests of 
subjects and justified on either medical or ethical grounds. In terminating the study, Seattle 
Genetics, Inc., the CURO (PURA Health Sciences), and the Investigator will ensure that adequate 
considerationis given to the protection of the subjects’ interests.
16.10Study Center File Management
The Investigator is responsible for assuring that the Study Center File is maintained. The Study 
Center File will contain, but will not be limited to, the information listed below:
1. Investigator’s Brochure
2. Current, signed version of the protocol and any previous versions of the protocol
3. Protocol amendments (if applicable)
4. Operations manual (if applicable)
5. Current informed consent form (blank) and any previous versions of theinformed 
consent form
6. Curricula vitae of Investigator(s) and sub-Investigator (s) and photocopy of their 
respective license(s) where required by law; Original US FDA Form 1572 (for all studies 
conducted under US IND regulations), signed by all Principal Investigators. The names 
of any sub-Investigators must appear on this form. Investigators must also complete all 
regulatory documentation as required by ICH GCP and by local or national regulations
7. Documentation of IURB approval of the protocol, the informedconsent form, any protocol 
amendments, and any informed consent form revisions
8. All correspondence between the Investigator, IURB, and the Sponsor/CURO relating to 
study conduct
9. Laboratory certification(s)
10.Monitoring log
11.Study drug invoices
12.Signature list ofall staff completing eCURFs


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13.Signature list of all staff completing drug accountability summaries


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17.
UREFEURENCE LIST
1. Howlader N, Noone AM, Krapcho M, Garshell J, Miller D, Altekruse SF, Kosary CL, Yu M, 
URuhl J, Tatalovich Z, Mariotto A, Lewis DUR, Chen HS, Feuer EJ, Cronin KA (eds). SEEUR 
Cancer Statistics UReview, 1975-2012, National Cancer Institute. Bethesda, MD, 
http://seer.cancer.gov/csr/1975_2012/, based on November 2014 SEEUR data submission, 
posted to the SEEUR website, April 2015.
2. Greenberg P, Cox C, LeBeauMM, et al. International scoring system for evaluating 
prognosis in myelodysplastic syndromes. Blood. 1997;89(6):2079-2088.
3. NCCN Clinical Practice Guidelines in Oncology. Myelodysplastic Syndromes. Version 
1.2016 (28 May 2015).
4. Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al. Efficacy of azacitidine compared with that 
of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: A 
randomised, open-label, phase III study. Lancet Oncol. 2009;10(3):223-232.
5. Andrews UR, Singer J, Bernstein I. Precursors of colony forming cells in humans can be 
distinguished from colony forming cells by expression of the CD33 and CD34 antigens and 
light scatter properties. J Exp Med. 1989;169:1721-1731.
6. Jilani I, Estey E, Huh Y, et al. Differences in CD33 intensity between various myeloid 
neoplasms. Am J Clin Pathol. 2002;118:560-566.
7. Knapp W. Flow cytometric analysis of cell-surface and intracellular antigens in leukemia 
diagnosis. Cytometry. 1994;8:187-198.
8. Bernstein ID. Monoclonal antibodies to the myeloid stem cells: therapeutic implication of 
CMA-676, a humanized anti-CD33 antibody calicheamicin conjugate. Leukemia. 
2000;14:474-475.
9. Cowan AJ, Laszlo GS, Estey EH, Walter URB. Antibody-based therapy of acute myeloid 
leukemia with gemtuzumab ozogamicin. Front Biosci. 2013;18:1311-1334.
10.Walter URB, Appelbaum FUR, Estey EH, Bernstein ID. Acute myeloid leukemia stem cells and 
CD33-targeted immunotherapy. Blood. 2012;119(26):6198-6208.
11.Schlesinger M, Silverman LUR, Jiang JD, et al. Analysis of myeloid and lymphoid markers on 
the surface and in the cytoplasm of mononuclear bone marrow cells in patients with 
myelodysplastic syndrome. J Clin Lab Immunol.1996;48(4):149-166.
12.Chen X, Eksioglu EA, Zhou J, et al. Induction of myelosydplasia by myeloid-derived 
suppressor cells. J Clin Invest. 2013;123(11):4595-4611.
13.Sutherland MSK, Walter URB, Jeffrey SC, et al. SGN-CD33A: a novel CD33-targeting 
antibody-drug conjugate using a pyrrolobenzodiazepinedimer is active in models of drug-
resistant AML. Blood.2013;122(8):1455-1463.
14.Seattle Genetics, Inc. Vadastuximab Talirine (SGNCD33A) Investigator’s Brochure. 
Version3, 06 July 2015.
15.Celgene Corporation. VIDAZA (azacitidine) US Prescribing Information. January 2014.
16.Sadashiv SK, Hilton C, Khan C, et al. Efficacy and tolerability of treatment with azacitidine 
for 5 days in elderly patients with acute myeloid leukemia. Cancer Med. 
2014;3(6):1570-1578.


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17.Martin MG, Walgren URA, Procknow E, et al. A phase II study of 5-day intravenous 
azacitidine in patients with myelodysplastic syndromes. Am J Hematol. 2009;84(9):560-564. 
18.Fenaux P, Haase D, Sanz GF, et al. Myelodysplastic syndromes: ESMO Clinical Practice: 
Guidelines for diagnosis, treatment and follow-up. AnnOncol. 2014;25(Supplement 3):iii57–
iii69.
19.Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al. Efficacy of azacitidine compared with that 
of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a 
randomised, open-label, phase III study. Lancet Oncol. 2009;10(3):223-232. 
20.Silverman LUR, Demakos EP, Peterson BL, et al. URandomized controlled trial of azacitidine in 
patients with the myelodysplastic syndrome: a study of the cancer and leukemia group Br J
Clin Oncol.2002;20(10):2429-2440.
21.Kantarjian H, Issa JP, URosenfeld CS, et al. Decitabine improves patient outcomes in 
myelodysplastic syndromes: results of a phase III randomized study. Cancer. 
2006;106(8):1794-1803.
22.Cheson BD, Greenberg PL, Bennett JM, et al. Clinical application and proposal for 
modification of the International Working Group (IWG) response criteria in myelodysplasia. 
Blood. 2006;108(2):419-425.
23.Skolnik JM, Barrett JS, Jayaraman B, et al. Shortening the timeline of pediatric phase I trials: 
the URolling Six Design. J Clin Oncol. 2008;26:190-195.
24.Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. 
Nephron. 1976;16(1):31-41.
25.Schulmeister L. Preventing and managing vesicant chemotherapy extravasations. J Support 
Oncol. 2010;8(5):212-215.
26.Smith TJ, Khatcheressian J, Lyman GH, et al. 2006 Update of recommendations for the use 
of white blood cell growth factors: an evidence-based clinical practice guideline. J Clin 
Oncol. 2006;24(19):3187-3205.
27.Mohty M, Malard F, Abecassis M, et al. Sinusoidal obstruction syndrome/veno-occlusive 
disease: current situation and perspectives-a position statement from the European Society 
for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplant.2015 
Jun;50(6):781-9.
28.Dalle JH, Giralt SA. Hepatic veno-occlusive disease after hematopoietic stem cell 
transplantation: URisk factors and stratification, prophylaxis, and treatment. Biol Blood 
Marrow Transplant.2016 Mar;22(3):400-9.
29.Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for UResearch and 
Treatment of Cancer QLQ-C30: a quality of life instrument for use in international clinical 
trials in oncology. J Natl Cancer Inst. 1993;Mar 3;85(5):365-376.


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18.
APPENDICES
18.1Appendix 1: Declaration of Helsinki
WOURLD MEDICAL ASSOCIATION DECLAURATION OF HELSINKI
Ethical Principles for Medical UResearch Involving Human Subjects
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the:
29th WMA General Assembly, Tokyo, Japan, October 1975
35th WMA General Assembly, Venice, Italy, October 1983
41st WMA General Assembly, Hong Kong, September 1989
48th WMA General Assembly, Somerset West, URepublic of South Africa, October 1996
52nd WMA General Assembly,Edinburgh, Scotland, October 2000
53th WMA General Assembly, Washington 2002 (Note of Clarification on paragraph 29 added)
55th WMA General Assembly, Tokyo 2004 (Note of Clarification on Paragraph 30 added)
59th WMA General Assembly, Seoul, October 2008
64th WMA General Assembly, Fortaleza, Brazil, October 2013
A. Preamble
1.
The World Medical Association (WMA) has developed the Declaration of Helsinki as a 
statement of ethical principles for medical research involving human subjects, including 
research on identifiable human material and data.
The Declaration is intended to be read as a whole and each of its constituent paragraphs 
should be applied with consideration of all other relevant paragraphs.
2.
Consistent with the mandate of the WMA, the Declaration is addressed primarily to 
physicians. The WMA encourages others who are involved in medical research involving 
human subjects to adopt these principles. 
General Principles
3.
The Declaration of Geneva of the WMA binds the physician with the words,“The health of 
my patient will be my first consideration,” and the International Code of Medical Ethics 
declares that, “A physician shall act in the patient
's best interest when providing medical 
care.”
4.
It is the duty of the physician to promote and safeguard the health, well-being and rights of 
patients, including those who are involved in medical research. The physician
's knowledge 
and conscience are dedicated to the fulfilment of this duty.
5.
Medical progress is based on research that ultimately must include studies involving human 
subjects.
6.
The primary purpose of medical research involving human subjects is to understand the 
causes, development and effects of diseases and improve preventive, diagnostic and 
therapeutic interventions (methods, procedures and treatments). Even the best proven 


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


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17. All medical research involving human subjects must be preceded by careful assessment of 
predictable risks and burdens to the individuals and groups involved in the research in 
comparison with foreseeable benefits to them and to other individuals or groups affected by 
the condition under investigation.
         Measures to minimise the risks must be implemented. The risks must be continuously 
monitored, assessed and documented by the researcher. 
18. Physicians may not be involved in a research study involving human subjects unless they are 
confident that the risks have been adequately assessed and can be satisfactorily managed.
When the risks are found to outweigh the potential benefits or when there is conclusive proof 
of definitive outcomes, physicians must assess whether to continue, modify or immediately 
stop the study.
Vulnerable Groups and Individuals
19. Some groups and individuals are particularly vulnerable and may have an increased 
likelihood of being wronged or of incurring additional harm.
All vulnerable groups and individuals should receive specifically considered protection.
20. Medical research with a vulnerable group is only justifiedif the research is responsive to the 
health needs or priorities of this group and the research cannot be carried out in a non-
vulnerable group. In addition, this group should stand to benefit from the knowledge, 
practices or interventions that result fromthe research.
Scientific URequirements and UResearch Protocols 
21. Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant 
sources ofinformation, and adequate laboratory and, as appropriate, animal experimentation. 
The welfare of animals used for research must be respected.
22. The design and performance of each research study involving human subjects must be clearly 
described and justified in a research protocol.
The protocol should contain a statement of the ethical considerations involved and should 
indicate how the principles in this Declaration have been addressed. The protocol should 
include information regarding funding, Sponsors, institutional affiliations, potential 
conflicts of interest, incentives for subjects and information regarding provisions for 
treating and/or compensating subjects who are harmed as a consequence of participation 
in the research study.
In clinical trials, the protocol must also describe appropriate arrangements for post-trial 
provisions.
UResearch Ethics Committees


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23. The research protocol must be submitted for consideration, comment, guidance and approval 
to the concerned research ethics committee before the study begins. This committee must be 
transparent in its functioning, must be independent of the researcher, the Sponsor and any 
other undue influence and must be duly qualified. It must take into consideration the laws 
and regulations of the country or countries in which the research is to be performed as well 
as applicable international norms and standards but these must not be allowed to reduce or 
eliminate any of the protections for research subjects set forth in this Declaration. 
The committee must have the right to monitor ongoing studies. The researcher must provide 
monitoring information to the committee, especially information about any serious adverse 
events. No amendment to the protocol may be made without consideration and approval by 
the committee. After the end of the study, the researchers must submit a final report to the 
committee containing a summary of the study’s findings and conclusions. 
Privacy and Confidentiality 
24. Every precaution must be taken to protect the privacy ofresearch subjects and the 
confidentiality of their personal information.
Informed Consent 
25. Participation by individuals capable of giving informed consent as subjects in medical 
research must be voluntary. Although it may be appropriate to consult family members or 
community leaders, no individual capable of giving informed consent may be enrolled in a 
research study unless he or she freely agrees.
26. In medical research involving human subjects capable of giving informed consent, each 
potential subject must be adequately informed of the aims, methods, sources of funding, any 
possible conflicts of interest, institutional affiliations of the researcher, the anticipated 
benefits and potential risks of the study and the discomfort it may entail, post-study 
provisions and any other relevant aspects of the study. The potential subject must be 
informed of the right to refuse to participate in the study or to withdraw consent to participate 
at any time without reprisal. Special attention should be given to the specific information 
needs of individual potential subjects as well as to the methods used to deliver the 
information.
After ensuring that the potential subject has understood the information, the physician or 
another appropriately qualified individual must then seek the potential subject’s freely-given 
informed consent, preferably in writing. If the consent cannot be expressed in writing, the 
non-written consent must be formally documented and witnessed.
All medical research subjects should be giventhe option of being informed about the general 
outcome and results of the study.
27. When seeking informed consent for participation in a research study the physician must be 
particularly cautious if the potential subject is in a dependent relationship with the physician 
or may consent under duress. In such situations the informed consent must be sought by an 
appropriately qualified individual who is completely independent of this relationship.


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28. For a potential research subject who is incapable of giving informed consent, the physician 
must seek informed consent from the legally authorised representative. These individuals 
must not be included in a research study that has no likelihood of benefit for them unless it 
is intended to promote the health of the group represented by the potential subject, the 
research cannot instead be performed with persons capable of providing informed consent, 
and the research entails only minimal risk and minimal burden.
29. When a potential research subject who is deemed incapable of giving informed consent is 
able to give assent to decisions about participation in research, the physician must seek that 
assent in addition to the consent of the legally authorised representative. The potential 
subject’s dissent should berespected.
30. UResearch involving subjects who are physically or mentally incapable of giving consent, for 
example, unconscious patients, may be done only if the physical or mental condition that 
prevents giving informed consent is a necessary characteristic of the research group. In such 
circumstances the physician must seek informed consent from the legally authorised 
representative. If no such representative is available and if the research cannot be delayed, 
the study may proceed without informed consent provided that the specific reasons for 
involving subjects with a condition that renders them unable to give informed consent have 
been stated in the research protocol and the study has been approved by a research ethics 
committee. Consent to remain in the research must be obtained as soon as possible from the 
subject or a legally authorised representative.
31. The physician must fully inform the patient which aspects of their care are related to the 
research. The refusal of a patient to participate in a study or the patient’s decision to withdraw 
from the study must never adversely affect the patient-physician relationship.
32. For medical research using identifiable human material or data, such as research on material 
or data contained in biobanks or similar repositories, physicians must seek informed consent 
for its collection, storage and/or reuse. There may be exceptional situations where consent 
would be impossible or impracticable to obtain for such research. In such situations the 
research may bedone only after consideration and approval of a research ethics committee.
Use of Placebo
33. The benefits, risks, burdens and effectiveness of a new intervention must be tested against 
those of the best proven intervention(s), except in the following circumstances:
Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; 
or
Where for compelling and scientifically sound methodological reasons the use of any 
intervention less effective than the best proven one, the use of placebo, or no intervention 
is necessary to determine the efficacy or safety of an intervention 


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and the patients who receive any intervention less effective than the best proven one, 
placebo, or no intervention will not be subject to additional risks of serious or irreversible 
harm as a result of not receiving the best proven intervention. 
Extreme care must be taken to avoid abuse of this option.
Post-Trial Provisions
34. In advance of a clinical trial, Sponsors, researchers and host country governments should 
make provisions for post-trial access for all participants who still need an intervention 
identified as beneficial in the trial. This information must also be disclosed to participants 
during the informed consent process.
UResearch URegistration and Publication and Dissemination of UResults
35. Every research study involving human subjects must be registered in a publicly accessible 
database before recruitment of the first subject.
36. UResearchers, authors, Sponsors, editors and publishersall have ethical obligations with 
regard to the publication and dissemination of the results of research. UResearchers have a 
duty to make publicly available the results of their research on human subjects and are 
accountable for the completeness and accuracy of their reports. All parties should adhere to 
accepted guidelines for ethical reporting. Negative and inconclusive as well as positive 
results must be published or otherwise made publicly available. Sources of funding, 
institutional affiliations and conflicts of interest must be declared in the publication. UReports 
of research not in accordance with the principles of this Declaration should not be accepted 
for publication.
Unproven Interventions in Clinical Practice
37. In the treatment of an individual patient, where proven interventions do not exist or other 
known interventions have been ineffective, the physician, after seeking expert advice, with 
informed consent from the patient or a legally authorised representative, may use an 
unproven intervention if in the physician
's judgement it offers hope of saving life, re-
establishing health or alleviating suffering. This intervention should subsequently be made 
the object of research, designed to evaluate its safety and efficacy. In all cases, new 
information must be recorded and, where appropriate, made publicly available.


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


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


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


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18.5Appendix 5: URisk Factor Classification for Myelodysplastic Syndromes
18.5.1The International Prognostic Scoring System
In the IPSS, a score for each patient is derived based on the percent bone marrow blasts, 
mutation status, and the presence of cytopenias, as follows (a score is assigned for each row, and 
the total score is the sum of the 3 row scores):
Score Value
Prognostic Variable
0
0.5
1.0
1.5
2.0
BM blasts (%) 
<5
5-10
-
11-20 
21-30
Karyotypea
Good
Intermediate
Poor
Cytopenias 
0/1
2/3
a
Good
normal, -Y, del(5q), del(20q)
Poor
complex (≥3 abnormalities) or chromosome 7 anomalies
Intermediate
other abnormalities.
The total score is then used for risk calculation as follows:
URisk Group
Total Score
Low
0
Intermediate-1
0.5-1.0
Intermediate-2
1.5-2.0
High
≥2.5
From: Greenberg P, Cox C, LeBeau MM, et al. International Scoring System for Evaluating 
Prognosis in Myelodysplastic Syndromes. Blood. 1997;89 (6):2079-2088.


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18.5.2The World Health Organization (WHO) Classification System
Disease
Blood findings
Bone marrow findings
URefractory anemia (URA)
Anemia
Erythroid dysplasia only
No or rare blasts 
<5% blasts
<15% ringed sideroblasts
URefractory anemia with ringed sideroblasts (URAURS) 
Anemia
Erythroid dysplasia only
No blasts 
≥15% ringed sideroblasts
<5% blasts
URefractory cytopenia with multilineage dysplasia (URCMD) 
Cytopenias (bicytopenia or 
pancytopenia)
Dysplasia in ≤10% of cells in 2 or more myeloid cell lines
No or rare blasts 
<5% blasts in marrow
No Auer rods 
No Auer rods
<1 x109/L monocytes 
<15% ringed sideroblasts
URefractory cytopenia with multilineage dysplasia and ringed 
sideroblasts (URCMD-URS) 
Cytopenias (bicytopenia or 
pancytopenia)
Dysplasia in ≥10% of cells in 2 or more myeloid cell lines
No or rare blasts 
≥15% ringed sideroblasts
No Auer rods 
<5% blasts
<1 x109/L monocytes 
No Auer rods
URefractory anemia with excess blasts-1 (URAEB-1)
Cytopenias
Unilineage or multilineage dysplasia
<5% blasts 
5% to 9% blasts
No Auer rods 
No Auer rods
1 x109/L monocytes
URefractory anemia with excess blasts-2 (URAEB-2)
Cytopenias 
Unilineage or multilineage dysplasia
5% to 19% blasts
10% to 19% blasts
Auer rods ±
Auer rods ±
<1 x109/L monocytes
Myelodysplastic syndrome, unclassified (MDS-U)
Cytopenias
Unilineage dysplasia in granulocytes or megakaryocytes
No or rare blasts 
<5% blasts
No Auer rods
No Auer rods
MDS associated with isolated del(5q)
Anemia
Normal to increased megakaryocytes with hypolobated 
nuclei
<5% blasts
<5% blasts
Platelets normal or increased
No Auer rods
Isolated del(5q)
From: Vardiman JW, Harris NL, Brunning URD. The World Health Organization (WHO) classification of the myeloid neoplasms. 
Blood. 2002;100:2292-2302.


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18.6Appendix 6: UResponse Assessment –International Working Group UResponse 
Criteria 
Category
UResponse criteria (responses must last at least 4 weeks)
Complete remission Bone 
marrow: 
≤5% myeloblasts with normal maturation of all cell lines*
Persistent dysplasia will be noted*†
Peripheral blood‡
  Hgb ≥11 g/dL
  Platelets ≥100 x109/L
  Neutrophils ≥1.0 x109/L†
  Blasts 0%
Partial remission 
All CUR criteria if abnormal before treatment except:
Bone marrow blasts decreased by ≥50% over pretreatment but still >5%
Cellularity and morphology not relevant
Marrow CUR† 
Bone marrow: ≤5% myeloblasts and decrease by ≥ 50% over pretreatment†
Peripheral blood: if HI responses, they will be noted in addition to Marrow 
CUR†
Stable disease 
Failure to achieve at least PUR, but no evidence of progression for >8 weeks
Failure 
Death during treatment or disease progression characterized by worsening of 
cytopenias, increase in percentage of bone marrow blasts, or progression to a 
more advanced MDS FAB subtype than pretreatment
URelapse after CUR or PUR
At least 1 of the following:
  UReturn to pretreatment bone marrow blast percentage
  Decrement of ≥50% from maximum remission/response levels in 
  granulocytes or platelets
  UReduction in Hgb concentration by ≥1.5 g/dL or transfusion dependence
Cytogenetic response 
Complete
  Disappearance of the chromosomal abnormality without appearance of new 
  ones
Partial
  At least 50% reduction of the chromosomal abnormality
Disease progression 
For patients with:
  Less than 5% blasts: ≥50% increase in blasts to >5% blasts
  5%-10% blasts: ≥50% increase to >10% blasts
  10%-20% blasts: ≥50% increase to >20% blasts
  20%-30% blasts: ≥50% increase to >30% blasts
Any of the following:
  At least 50% decrement from maximum remission/response in granulocytes 
  or platelets
  UReduction in Hgb by ≥2 g/dL
  Transfusion dependence
Survival 
Endpoints:
  Overall: death from any cause
  Event free: failure or death from any cause
  PFS: disease progression or death from MDS
  DFS: time to relapse
  Cause-specific death: death related to MDS
See footnotes on following page


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Deletions to IWG response criteria are not 
shown.
To convert hemoglobin from grams per deciliter to grams per liter, multiply grams per deciliter by 10.
MDS indicates myelodysplastic syndromes; Hgb, hemoglobin; CUR, complete remission; HI, hematologic 
improvement; PUR, partial remission; FAB, French-American-British; PFS, progression-free survival; DFS, 
disease-free survival.
*Dysplastic changes should consider the normalrange of dysplastic changes (modification). (URamos F, 
Fernandez-Ferrero S, Suarez D, et al. Myelodysplastic syndrome: a search for minimal diagnostic criteria. Leuk 
URes. 1999;23:283-290)
†Modification to IWG response criteria.
‡In some circumstances, protocol therapy may require the initiation of further treatment (eg, consolidation, 
maintenance) before the 4-week period. Such patients can be included in the response category into which they 
fit at the time the therapy is started. Transient cytopenias during repeated chemotherapy courses should not be 
considered as interrupting durability of response, as long as they recover to the improved counts of the previous 
course.
From: Cheson BD, Greenberg PL, Bennett JM, et al. Clinical application and proposal for
modification of the International Working Group (IWG) response criteria in myelodysplasia. 
Blood. 2006; 108(2):419-425.


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18.7Appendix 7: European Organization for UResearch and Treatment of Cancer 
(EOURTC) Core Module (QLQ-C30) 
EOURTC website: http://groups.eortc.be/qol/(Accessed August 31, 2015) 
The subject should be instructed to fill out the questionnaires to the best of his/her abilities. 
The study staff will be responsible for confirming that the subject has completed the 
questionnaires.
UReferences for the EOURTC QLQ-C30 are as follows:
EOURTC QLQ C30 (Version 3):
Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for UResearch and 
Treatment of Cancer QLQ-C30: a quality of life instrument for use in international clinical 
trials in oncology. J Natl Cancer Inst. 1993 Mar 3;85(5):365 376.
For details of the scoring procedure for the EOURTC QLQ-C30:
Fayers PM, Aaronson NK, Bjordal K, Groenvold M, Curran D, and Bottomley A, on behalf 
of the EOURTC Quality of Life Group. The EOURTC QLQ-C30 Scoring Manual (3rd Edition). 
Brussels, Belgium: European Organisation for UResearch and Treatment of Cancer; 2001.


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18.8Appendix 8: Summary of Amendment 1
URATIONALE:
The protocol was amended to 
To update the definitionof the DLT-evaluable population to be those phase 1 patients 
who completed at least Cycle 1 of treatment or discontinued study treatment because 
of AEs or for a safety-related reason before having had the opportunity to receive 
Day1 of Cycle 2; Cycle 1 of treatment is completed when the patient receives the 
first dose of azacitidine on Day 1 of Cycle 2. Patients will not have to receive their 
second dose of vadastuximab talirine to be considered DLT evaluable
To rename the efficacy-evaluable population asthe “modified intent-to-treat (mITT)” 
population
Specify certain hematological toxicities that are expected and should not be counted 
as DLTs
Exclude patients with prior allo-HCT and those with hypocellular MDS
More clearly define the entry criteria with regard to bilirubin, specifying values for 
both direct bilirubin (≤2x ULN) and total serum bilirubin (≤1.5x ULN)
Allow more flexibility in the IV azacitidine administration by removing the 
requirement that it be administered by IV push
Update the dose reduction recommendations to be more specific for MDS
Modify the description of the bone marrow examination to indicate that biopsy is the 
preferred method of examination.
To add a bone marrow biopsy on Cycle 1, Day 28 (+/-1 week), in the Phase 1 Portion 
of the study, to assess marrow cellularity in order to distinguish cytopenia due to 
active MDS from cytopenia due to drug-induced myelosuppression
Clarify that urinalysis only requires dipstick or microscopy in addition to spot urine 
protein and creatinine
URemove erythrocyte sedimentation rate from the list of required inflammatory 
serologies. 
Update SAE reporting guidance to be consistent with current standards and expected 
events in MDS
URemove neuropathy as an AE of special interest
URemove the requirement for HbA1c at screening; this is not necessary based on 
accumulating clinical experience with vadastuximab talirine
To allow serum or urine pregnancy testing 
Change the description of the analysis summaries to match current planning in the 
statistical analysis plan
Make minor editorial corrections and clarifications


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SUMMAURY OF CHANGES:
Note: Editorial and formatting changes are not included below.
Section: Synopsis, Study Design and Methodology, page 5; 9.1.1, Phase 1 Portion –Open-
Label Dose Evaluation, page 28; 13.5.3, DLT-Evaluable Population, page 75
UReplace:
DLTevaluable subjects are those who complete 2 cycles or discontinue treatment due to 
study treatmentrelated toxicity before having had the opportunity to receive treatment in 
Cycle 2. 
With:
The DLT-evaluable population will include all Phase 1 subjects who have completed at 
least Cycle 1 of treatment (Cycle 1 of treatment is completed when the patient receives 
the first dose of azacitidine on Day 1 of Cycle 2) ordiscontinued study treatment because 
of AEs or for a safety-related reason before having had the opportunity to receivethe 
first dose of azacitidine onDay 1 of Cycle 2.
Section: Synopsis, Study Design and Methodology, page 5; 9.1.1, Phase 1 Portion –Open-
Label Dose Evaluation, page28
UReplace:
In the Phase 1 Portion of the study,DLTs will be defined as any hematologic toxicity that 
delays Cycle 2 by >14 days or any grade 3 or 4 nonhematologic toxicity considered to be 
related to study treatment. 
With:
In the Phase 1 Portion of the study, DLTs will be defined as posttreatment grade 4 
neutropenia or grade 4 thrombocytopenia lasting >42 days from the start of therapy, in 
the absence of evidence of active MDS, or any grade 3 or higher non-hematologic 
toxicity that is clearly NOT resulting from underlying MDS and is considered related to 
study treatment, with the exception of:
a. Grade 3 allergic reaction, fatigue, asthenia, anorexia, or constipation
b. Grade 3 nausea, vomiting, or diarrhea not requiring tube feeding or total 
parenteral nutrition or hospitalization 
c. Febrile neutropenia (which resolves with appropriate treatment or marrow 
recovery), infection, bleeding, or other expected direct complications of 
cytopenias due to active MDS
Change:
After 6 DLT-evaluable subjects have had the opportunity to complete at least Cycle 1
(Cycle1 of treatment is completed when the patient receives the first dose of azacitidine 
on Day 1 of Cycle 2)2cyclesof treatment 


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Section: Synopsis, Study Design and Methodology, page 5; Synopsis, Study treatments, 
page7 (2 places); Table 1, page 30; 9.5.1, Treatments Administered, page 35 (2 places)
Delete (in reference to azacitidine only):
IV push
Section: Synopsis, Study Population and Main Criteria for Inclusion/Exclusion, page 6-7; 
9.4, Study Population,page 32-33
UReplace (Inclusion Criterion 7):
b. serum bilirubin ≤1.5 x upper limit of normal (ULN) or ≤3 x ULN for subjects with 
Gilbert’s disease.
With:
b. direct bilirubin ≤2x upper limit of normal (ULN) and/or total serum bilirubin 
≤1.5x ULN (or total serum bilirubin ≤3x ULN for subjects with Gilbert’s disease).
Add (Exclusion Criteria 11 and 12):
11.Prior allogeneic hematopoietic stem cell transplant, for any indication.
12.Hypocellular MDS, defined as bone marrow cellularity <30% in subjects 
≤60years old or <20% cellularity in subjects > 60 years old.
Section: Synopsis, Analysis Methods, page 9; 13.6.4.1, UResponse to Treatment, page 76
Change:
The OURUR will be summarized by treatment group and the corresponding 95%90%
confidence intervals will be calculated. 
Section: 6. Investigators and Study Administrative Structure, page 21
Add:
Central clinical laboratory services will be provided by a central laboratory (refer to the 
study manual) for protocol-required hematology and serum chemistry tests; central 
laboratory results will not be provided to the Investigator. Additional analyses …
Section: Table 2:
URecommended dose modifications for vadastuximab talirine-
associated toxicity, page 40
UReplace:
Hematologic toxicity in the absence of blasts (CUR)
With:
Hematologic toxicity in the absence ofactive MDS
UReplace (footnote a):
a Blasts are at least 5% in bone marrow by morphology, circulating blasts are present, 
or there is evidence of extramedullary leukemia


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With:
a Blasts are at least 5% in bone marrow by morphology, circulating blasts are present, 
or there is persisting myelodysplasia contributing to cytopenias
Section: Table 3:
Study Schedule, page 45-46
Add (table body):
Pregnancy test (serum orurine) for women of childbearing potential only
Add (to footnote d):
d Day 22-28 in even-numbered cycles until CUR, then every 4 cycles thereafter. In the 
Phase 1 Portion only, an additional bone marrow biopsy will be performed on 
Cycle 1, Day 28 (±7 days) to assess bone marrow cellularity. Cycle 1 bone 
marrow biopsy may be omitted if either a) patient has recovered counts to less 
than grade 4 cytopenias, ie, absolute neutrophil count (ANC) >500/mcL AND 
platelet count >25,000/mcL, without transfusion support, by Day 28 of Cycle 1 or 
b) there is evidence in the peripheral blood of active MDS, eg, circulating blasts. 
Change (footnote e):
e Includes urine dipstick andormicroscopic analysis, as well as spot urine protein and 
creatinine.
Delete (footnote g):
g Includes clinical laboratory testing for ESUR,CURP, C3, and C4.
Change (footnote p):
p A bone marrow aspirate is sufficient; however, if marrow cannot be aspirated, a 
biopsy may be conducted.
To:
p Bone marrow examination should be based on a bone marrow biopsy; however, 
if marrow cannot be biopsied, but aspiration is successful, the aspirate may be 
used to determine blast count. For subjects in the Phase 1 Portion, at Cycle 1 
Day 28, a biopsy is required.
Section: 10.1, Screening (Day -28 to 1), page 50; 10.3, End of Treatment, page 60
Add:
• Serum orurine pregnancy test (women of childbearing potential only)
Section: 10.2.1, Phase 1 Portion, Cycle 1, page 52-53
Add:
Day 28 (±7days): 
o Bone marrow biopsy to assess bone marrow cellularity. Cycle 1 marrow 
biopsy may be omitted if either a) patient has recovered counts to less 
than grade 4 cytopenias, ie, absolute neutrophil count (ANC) >500/mcL
AND platelet count >25,000/mcL, without transfusion support, by Day 28 


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of Cycle 1 or b) there is evidence in the peripheral blood of active MDS, 
eg, circulating blasts. 
Note: 
A. If the marrow is not hypocellular (total marrow cellularity ≥10%), the 
patient may proceed to Cycle 2. 
B. If the marrow is hypocellular (total marrow cellularity <10%), Cycle 2 
should be delayed until count recovery (defined as thrombocytopenia and 
neutropenia improving to less than CTCAE grade 4: ANC >500/mcLand 
platelet count >25,000/mcL). If neutrophil count or platelet count have not 
recovered to less than Grade 4 by Day 42,a repeat marrow should be 
performed within a week. If the marrow is hypocellular at Day 42, then the 
subject will have experienced a DLT (posttreatment grade 4 neutropenia or 
grade4 thrombocytopenia lasting >42 days from the start of therapy in the 
absence of evidence of active MDS); if marrow cellularity has recovered to 
≥10%, and ongoing cytopenia(s) are attributed to active MDS, then Cycle 2 
may be initiated.
Section: 11.3, Bone Marrow Examination, page 62
Change: 
Bone marrow examinations for diseaseassessment at baseline, on treatment, and during 
follow-up will be performed according to local standards and recorded on the eCURF. 
After the end of treatment, bone marrow examinations for disease assessment should be 
performed every 4 months through 24 months after EOT or until initiation of another 
anticancer treatment, progression, or relapse. Bone marrow examination maybe based on 
a bone marrow aspirate; however, if marrow cannot be aspirated, a biopsymay be 
conducted.
To: 
Bone marrow examinations for disease assessment at baseline, on treatment, and during 
follow-up will be performed according to local standards and recorded on the eCURF. 
After the end of treatment, bone marrow examinations for disease assessment should be 
performed every 4 months through 24 months after EOT or until initiation of another 
anticancer treatment, progression, or relapse. Bone marrow examination should be based 
on a bone marrowbiopsy; however, if marrow cannot bebiopsied, but aspiration is 
successful, the aspirate may beused to determine blast count.
Add:
In the Phase 1 Portion only, an additional bone marrow biopsy will be performed on 
Day 28 of Cycle 1 (±7 days). This biopsy is to determine the presence of active MDS 
in order to determine if any observed cytopenias qualify as DLTs. The Cycle 1 
biopsy is not required if there are no cytopenias that need to be assessed (ie, ANC 
>500/mcL AND platelet count >25,000/mcL, without transfusion support, by Day 28 
of Cycle 1) or if there is other evidence of active MDS (eg, circulating blasts in the 
peripheral blood).


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Section: 11.7, Clinical Laboratory Tests, page 67
Add:
For all women of childbearing potential,serum or urine pregnancy tests will be 
performed locally at screening and at EOT.
Delete:
Clinical chemistry:Albumin, alkaline phosphatase, ALT, AST, blood urea nitrogen, 
calcium, creatinine, chloride, ferritin, lactate dehydrogenase (LDH), phosphorus, 
potassium, sodium, total bilirubin, uric acid, lipase, andamylase, and hemoglobin A1c 
(at screening only).
Add:
Urinalysis: Urine dipstick or microscopic analysis, as well as spot urine protein and 
creatinine will be performed locally as indicated in Table 3. 
Delete:
Inflammatory serologies: Erythrocyte sedimentation rate (ESUR),C-reactive protein 
(CURP), C3, and C4.
Add:
Central laboratory results will not be provided to the study sites.
Section: 12.1.3, UReporting Periods for Adverse Events and Serious Adverse Events, page 72
Delete:
…Ongoing nonserious AEs of interest (including, but not limited to, neuropathy) may be
followed until resolution, return to baseline, or study closure.
Section: 12.1.5, Sponsor Safety UReporting URequirements in the United States, page 73
Change:
In this study, the SAEs that do not require individual IND safety reports are disease 
progression events. 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…
Section: 13.5.4, Modified Intent-to-Treat, page 75
Change (section title):
13.5.4
EfficacyEvaluableModified Intent-to-Treat Population 
Change:
The efficacyevaluablemodified intent-to-treat (mITT) population will include all ITT 
subjects who received at least 1dose of study medication (azacitidine or vadastuximab 
talirine). 


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Section: 13.6.3, Subject Disposition, page 76
Add:
The number and percent of subjects who discontinue treatment and withdrawfrom 
studyand the reasons for discontinuation or withdrawalwill be summarized. 
Section: 13.6.4.2, Secondary Efficacy Endpoints, page 76
Change:
CUR rate will be summarized with 95%90%confidence intervals. 
Section: 13.6.8, Additional Data, page 78
Delete:
All data collected on the eCURFs will be included in data listings.
Section: Global
UReplace:
Version 01, Date 24 September 2015
With:
Version 02, Date 18 May 2016


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18.9Appendix 9: Summary of Changes in Version 3
URATIONALE:
The protocol was amended to 
Clarify the DLT definition (excluding AEs clearly related to azacitidine, and 
removing the requirement of attribution as related to studytreatment from DLT 
definition)
Exclude subjects who are candidates for stem cell transplant from the study and to 
explicitly require a minimum of 30 days between the last dose of vadastuximab 
talirine and stem cell transplant for those subjects who become candidates during the 
study
Add hepatic SAEs (including sinusoidal obstruction syndrome/veno-occlusive disease 
[SOS/VOD]) as adverse events of special interest
Add requirements for action by the Independent Data Monitoring Committee (IDMC) 
to make recommendations based on the occurrence of SOS/VOD
To exclude subjects with a history of cirrhosis or current alcohol abuse
Toupdate the dose modifications recommendations based on accumulating clinical 
experience
To provide guidance on dose / schedule modifications for patients without adequate 
hematologic recovery at the end of a cycle, based on count recovery from nadir, 
marrow responsestatus, and marrow cellularity
To add vital signs assessments before and after each infusion of vadastuximab talirine 
(Phase 1 Portion) or blinded study treatment (Phase 2 Portion)
To update the protocol to make clarifications regarding the useof bone marrow 
aspirates, as was previously communicated in an administrative letter
To correct an error in the schedule of events: Collection of weight at Day 1 of each 
cycle (as was described in the protocol text) had been omitted
To expand the window for bone marrow examination from “Day 22 to 28” to 
“Day22 to 29” for Investigator convenience
Update the names of the study medical monitors
Make minor editorial corrections and clarifications
SUMMAURY OF CHANGES:
Note: Editorial and formatting changes arenot included below.
Section: Cover Page, page 1; 6, Investigators and Study Administrative Structure, page 21
Updatethe names and contact information for the Medical Monitors:
UReplace




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Section: Synopsis, Study Design and Methodology, page 5; 9.1, Overall Study Design and 
Plan, page 28; Table 4, page 45; Table 5, page 47; Table 6, page 49; 10.2, Treatment Period, 
pp51-60; 11.4.3, Biomarker Analyses: Bone Marrow Aspirate, page 65
Change:
Day 22 to 28OUR Days 22-28
To:
Day 22 to 29OUR Days 22-29
Section: Synopsis, Number of Subjects, page 8
Change:
Approximately 130subjects; approximately 24 (estimated as 4 cohorts of 6 subjects each) 
in phase 1 and approximately 106 in phase 2
To:
Approximately 142subjects; up to 36in phase 1 and approximately 106 in phase 2
Section: 6, Investigators and Study Administrative Structure, subsection Monitoring and 
Evaluation Committee(s), page 21
Add:
Conditions requiring IDMC action are provided inSection 13.6.10.
Section: 9.1.3, Study Stopping Criteria, page 31 (new section)
Add:
9.1.3 Study Stopping Criteria
The SMC (Phase 1 Portion) or the IDMC (Phase 2 Portion) will provide 
recommendations to the Sponsor if either of the following criteria aremet:
•
If 5 or more cases of sinusoidal obstruction syndrome/veno-occlusive disease 
(SOS/VOD) are observed in the interventional (ie, experimental) arm, and the 
SOS/VOD incidence rate on the interventional arm is >20% of the patients who 
undergo allo-HCT,and (in the Phase 2 Portion) the rate on the interventional 
arm is 2 or more fold greater than the rate on the control arm, as determined 
by the adjudication committee.
•
If 3 or more cases of severe SOS/VOD are observed in the interventional arm, 
and thesevere SOS/VOD incidence rate on the interventional arm is >10% of 
the patients who undergo allo-HCT, and (in the Phase 2 Portion) the rate on the 
interventional arm is 2 or more fold greater than the rate on the control arm, as 
determined by the adjudication committee.
The Sponsor will pause enrollment and notify the FDA and other global health 
authorities, as applicable, if the stopping criteria are met.
Section: 9.5.1.4.2, Overdose, page 39 (new section)
Add:
9.5.1.4.2 Overdose


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In the event of an overdose ≥10%, the site should notify the sponsor as soon as they 
are aware of the overdose.
Section: 9.5.1.4.23, Dose Modifications, subsection Vadastuximab Talirine, page 39-40
UReplace:
Vadastuximab Talirine
Dose delays of any study treatment are permitted. If dosing is delayed for azacitidine, 
vadastuximab talirine (Phase 1 Portion), or blinded study treatment (Phase 2 Portion), 
both study treatments should be held and resumed together on the same schedule. 
Dose reduction of vadastuximab talirine (Phase 1 Portion) or blinded study treatment 
(Phase 2 Portion) is permitted if a second dose delay is required. The dose will be 
decreased to the next lower level on the doseescalation schedule (eg, for a subject 
enrolled at the 10 mcg/kg dose level, the reduced dose will be 5 mcg/kg). Elimination of 
up to 2 cycles of vadastuximab talirine or placebo is permitted. 
Dose modifications to azacitidine are at the discretion of the treating physician and 
should adhere to the USPI or SMPC, or institutional guidelines/standards. 
Azacitidine, vadastuximab talirine, or placebo may be permanently discontinued in the 
event of unacceptable related toxicity. Subjects will not be considered off study treatment 
until both study treatments are discontinued.
Table 2 describes the guidelines for dose modifications of vadastuximab talirine (Phase 1 
Portion) or blinded study treatment (Phase 2 Portion).
With:
Vadastuximab Talirine
Table 2 describes guidelines for dose modifications of vadastuximab talirine (Phase 
1 Portion) or blinded study treatment (Phase 2 Portion) for toxicity. 
Dose delays of any study treatment are permitted. If dosing is delayed for azacitidine, 
vadastuximab talirine (Phase 1 Portion), or blinded study treatment (Phase 2 Portion), 
both study treatments should be held and resumed together on the same schedule except 
when one agent is omitted during a cycle due to toxicity. 
For patients who have achieved a response to therapy, dose decreases, delays, or 
dose re-escalation (to original dose level) are permitted at the discretion of the 
medical monitor and site Investigator. Following achievement of marrow blast 
clearance to <5% (ie, a CUR or marrow CUR), patients originally treated with a dose 
higher than 5 mcg/kg of study drug will receive azacitidine with vadastuximab 
talirine (Phase 1 Portion) or blinded study treatment (Phase 2 Portion) as 
continuation therapy at the maintenance dose of 5 mcg/kg in subsequent cycles. 
Azacitidine, vadastuximab talirine(Phase 1 portion), or blinded study drug (Phase 2 
portion) may be permanently discontinued in the event of unacceptable related toxicity. 
Subjects will not be considered off study treatment until both study treatments are 
discontinued.
If subjects become candidates for stem cell transplant after enrollment, 
vadastuximab talirine must be discontinued at least 30 days prior to stem cell 
transplant.


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Section: Table 2, page 40
UReplace:
Table 2:
URecommendedDose Modifications for Vadastuximab Talirine-Associated 
Toxicity
Category
Event
Action
Hematologic toxicity in the 
absence of active MDS
≥ Grade 3 
neutropenia or 
thrombocytopenia 
Cycles of treatment may be delayed up to 28daysb
until hematologic recovery is observed. Adequate 
hematologic recovery is defined as ANC < grade 3, and 
rising and/or platelets< grade 3 (unsupported). 
Dose reduction of vadastuximab talirine/blinded study 
treatment is permitted if a second dose delay is 
required. The dose will be decreased to the next lower 
level on the doseescalation schedule. Elimination of 
up to 2cycles of vadastuximab talirine or placebo is
permitted. 
Hematologic toxicity with 
marrow blasts ≥ 5%b 
persistent diseasea
≥ Grade 3 
neutropenia or 
thrombocytopenia 
Treatment may continue without dose modification 
Clinically significant 
non-hematologic toxicity 
or asymptomatic non-
hematologic laboratory 
abnormality
≥ Grade 3 event 
Treatment delay of up to 28days is permittedbuntil 
resolution of toxicity to < grade 3. 
ANC = absolute neutrophil count; MDS = myelodysplastic syndrome.
a Blasts are at least 5% in bone marrow by morphology, circulating blasts are present, or there is persisting 
myelodysplasia contributing to cytopenias 
b
Delays of >28days may be permitted with approval of the medical monitor


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With:
Table 2:
Dose Modifications for Vadastuximab Talirine-Associated Toxicity
Category
Event
Action
Hematologic toxicity with 
marrow blast count 
<5%a
≥ Grade 3 
neutropenia or 
thrombocytopenia 
Cycles of treatment may be delayed up to 2814daysb
until hematologic recovery is observed. 
Adequate hematologic recovery is defined as 
neutropenia and thrombocytopenia improved to 
<grade3 (unsupported),
OUR
ANC / platelets ≥ [(NADIUR COUNTc) + 
[(BASELINE COUNT
d–NADIUR COUNT) x 0.50]
If hematologic recovery as defined above has not 
occurred within 14 days of the end of the cycle (by 
Day 42), omit vadastuximab talirine (Phase 1) or 
blinded study treatment (Phase 2) from the next 
cycle, and initiate next dose of azacitidine based on 
marrow cellularity as defined in Table 3.
Hematologic toxicity with 
marrow blasts ≥ 5%b
≥ Grade 3 
neutropenia or 
thrombocytopenia 
Treatment may continue without dose modification until 
Cycle 5. At Cycle 5and beyond, follow action as 
defined above in hematologic toxicity in the absence of 
blasts.
Clinically significant 
non-hematologic toxicity 
or asymptomatic non-
hematologic laboratory 
abnormality(with the 
exception of hepatic 
toxicity)
≥ Grade 3 event 
Treatment delay of up to 14days is permitted until 
resolution of toxicity to < grade 3. 
Laboratory evidence of 
hepatic toxicity 
(elevation in ALT, AST, 
or total bilirubin)
≥ Grade 3 event
Treatment delay of up to 14 days is required until 
resolution of toxicity to ≤ Grade 1 or baseline. If 
toxicity has not resolved within 14 days, permanently 
discontinue vadastuximab talirine (Phase 1) or 
blinded study treatment (Phase 2)
ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate aminotransferase.
a
If cytopenias above grade 3 (eg, ANC <1000/mm
3or platelets <50 x 109/L) are present at Day 28 of a cycle in 
which no response assessment is required, an ‘unscheduled’ bone marrow biopsy is required within 14 days of 
the scheduled end of the cycle (eg, between Day 28 and Day 42). If the bone marrow cellularity is ≤10%, 
vadastuximab talirine or blinded study treatment will be permanently discontinued. If marrow cellularity is 
>10%, follow guidance as above. 
b
Delays of >14days may be permitted with approval of the medical monitor
c
Nadir Count = the lowest count reached during the treatment cycle
d
Baseline Count = counts prior to Cycle 1 of study treatment
Section: 9.5.1.4.2, Dose Modifications, subsection Azacitidine, page 39-40
UReplace:
Dose modification of azacitidine due to toxicity is allowed per institutional standards and 
according to the USPI at the discretion of the Investigator, including discontinuation of 
treatment.
With:
Dose modifications to azacitidine, including permanent discontinuation due to 
toxicity, are at the discretion of the treating physician and should adhere to the 
USPI or SMPC, or institutional guidelines/standards. URecommended schedule 


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modifications for azacitidine in patients with delayed count recovery and <5% 
blasts are provided in Table 3.
Section: Table 3, page 41 (new table)
Add:
Table3: URecommended Scheduled Modifications for Azacitidine in Patients with <5% 
Blasts and Incomplete Hematologic URecovery at Day 42a
Bone Marrow 
Cellularity:
>30%
15-30%
<15%
Timing of Next 
Cycle 
Next cycle may 
begin
Delay next cycle until 
ANC and platelets ≥
[(NADIUR COUNT) + 
[(BASELINE COUNT –
NADIUR COUNT) x 0.50]
Delay next cycle until ANC and 
platelets ≥[(NADIUR COUNT) 
+ [(BASELINE COUNT –
NADIUR COUNT) x 0.75]
a
If vadastuximab talirine (Phase 1) or blinded study drug (Phase 2) was omitted during the previous cycle, 
consider dose reduction of azacitidine to 50% upon initiation of next cycle. 
Section: 9.5.3Prior and Concomitant Therapy, page 41
Change:
Subjects may not receive other investigational drugs, immunosuppressive medications, 
radiotherapy, orsystemic anti-neoplastic therapy, or allogeneic stem cell transplant
during the study treatment period.
Section: 10, Study Evaluations by Visit, page 44
Change:
…and a schedule of followup assessments is provided in Table 4.
To:
…and schedules of PK, immunogenicity, and biomarker assessments are given in 
Table 5 and Table 6.
Section: Table 4 (renumbered), page 45
Separate height and weight into 2 separate rows, with height indicated within 7 days prior 
to study drug and weight indicated within 7 days prior to study drug and at Day 1 of each 
cycle. 
Change (footnote d):
Day 22-2829in even-numbered cycles until CUR, then every 4 cycles thereafter. In the 
Phase 1 Portion only, an additional bone marrow biopsy will be performed on Cycle 1, 
Day 28 (±7 days) to assess bone marrow cellularity. Cycle 1 bone marrow biopsy may be 
omitted if either a) patient has recovered counts to less than grade 4 cytopenias, ie, 
absolute neutrophil count (ANC) >500/mcL AND platelet count >25,000/mcL, without 
transfusion support, by Day 28 of Cycle 1 or b) there is evidence in the peripheral blood 


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of activeMDS, eg, circulating blasts.If cytopenias above grade 3 (eg ANC 
<1000/mm3 or platelets <50 x 109/L) are present at Day 28 of a cycle in which no 
response assessment is required, an ‘unscheduled’ bone marrow biopsy is required 
within 14 days of the scheduled end of the cycle (eg, between Day 28 and Day 42) to 
assess marrow cellularity and blast count, in order to determine if dose / schedule 
modifications are required in the next cycle.
Change (footnote p):
For subjectsin the Phase 1 Portion, at Cycle 1 Day 28, a biopsy is required requiring a 
marrow evaluation to assess cellularity due to cytopenias, a biopsy is required.
Add:
New row, indicating vital signs assessment on Day 7 of each cycle, with footnote 
indicator u.
Add(footnote u):
u Before and within 30 minutes after vadastuximab talirine (Phase 1 portion)or 
blinded study drug (Phase 2 portion) administration.
Section: 10.2.1.1, Cycle 1, page 51; 10.2.1.2, Cycle 2, page 53; 10.2.1.3, Cycle 3, page 54;
10.2.1.4, Cycles≥4, page 55;10.2.2.1, Cycle 1, page 56;10.2.2.2, Cycle 2, page 57;10.2.2.3, 
Cycle 3, page 59;10.2.2.4, Cycles≥4, page 59 (as a new sub-bullet for Day 7 or 9 
pretreatment activities)
Vital signs
Section: 10.2.1.1, Cycle 1, page 52; 10.2.1.2, Cycle 2, page 54(as a new sub-bullet for Day 7 
to 15 or 9 to 17 posttreatment activities)
○Vital signs (Day 7 or 9 only; within 30 minutes after completing the 
vadastuximab talirine infusion)
Section: 10.2.1.3, Cycle 3, page 55; 10.2.1.4, Cycle ≥4, page 56; 10.2.2.1, Cycle 1, page 57;
10.2.2.2, Cycle 2, page 58; 10.2.2.3, Cycle 3, page 59; 10.2.2.4, Cycles ≥4, page 60; (as a 
new sub-bullet for Day7 or 9 posttreatment activities)
○Vital signs (within 30 minutes after completing the vadastuximab talirine 
infusion)
Section: 10.2.1.3, Cycle 3, page 55; 10.2.1.4, Cycle ≥4, page 56 (as a new sub-bullet for 
Day7 or 9 posttreatment activities)
○Vital signs (within 30 minutes after completing the vadastuximab talirine 
infusion)
Section: Table 5 (renumbered), page 47; Table6 (renumbered), page 49
Change the spanner head over the last 3 columns of each table to read:
Bone Marrow Aspirate


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Change:
Day 22-2829
Section: 10.2.1.2, Cycle 2, Day 1, page 53
Delete:
• Serology laboratory tests (special autoimmune serologies; Section 11.7)
Section: 10.2.1.2, Cycle 2, page 54; 10.2.1.4, Cycles ≥4, page 56; 10.2.2.2, Cycle 2, page 58; 
10.2.2.4, Cycles ≥4, page 60; 
Change:
• Day 22 to2829:
Section: 10.4, Follow-Up, page 61
Add:
If subjects become candidates for stem cell transplant after enrollment, stem cell 
transplant should not be performed until at least 30 days after the last dose of 
vadastuximab talirine.
Section: 11.3, Bone Marrow Examination, page 62
UReplace:
In the Phase 1 Portion only, an additional bone marrow biopsy will be performed on Day 
28 of Cycle 1 (±7 days). This biopsy is to determine the presence of active MDS in order 
to determine if any observed cytopenias qualify as DLTs. The Cycle 1 biopsy is not 
required if there are no cytopenias that need to be assessed (ie, ANC >500/mcL AND 
platelet count >25,000/mcL, without transfusion support, by Day 28 of Cycle 1) or if 
there is other evidence of active MDS (eg, circulating blasts in the peripheral blood).
With:
In addition to response assessment time points, a bone marrow biopsy will be 
performed between Day 28 and Day 42 of any cycle in which the patient has not 
achieved hematologic recovery (as defined in Table 2). This biopsy is to determine 
the blast count and marrow cellularity, in order to determine ifdose modification / 
dose delay is required in the subsequent cycle (Table 2 and Table 3). This biopsy to 
assess cellularity is not required if counts have recovered (ie, ANC >1000/mm3AND 
platelet count >50,000/mm3, without transfusion support, by Day 28 of the cycle) or 
if there are circulating blasts in the peripheral blood (as evidence of active MDS).
Section: 11.4.3, Biomarker Analyses: Bone Marrow Aspirate, page 65-66
Add:
A portion of the bone marrow samples (aspirate)collected for disease assessment at 
baseline, for response assessment, and at the time of progression will be preserved for 
biomarker analyses. If baseline sample is collected prior to consent, a separate bone 


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marrow aspirate will be collected for biomarker analyses.Sample collection and 
preparation procedures are detailed in the laboratory manual.
Change:
o Day 22-2829(MDSC; CD33 expression)
…
o Day 22-2829(MDSC; CD33 expression; mutation profiling)
Section: 11.5, Physical Examination, ECOG Performance Status, andWeight, and Vital 
Signs(revised heading)
Add:
Vital signs (including temperature, heart rate, respiratory rate, and blood pressure) 
will be assessed at the time points indicated in Table 3 and recorded on the eCURF.
Section: 11.10, UResponse Assessment, page 68
Change:
…at the end of each even-numbered cycle (Day 22-2829) until CUR,…
Section: 12.1.4, Adverse Events of Special Interest, page 73
Add (new subsection):
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 according to safety reporting requirements. Events of 
SOS/VOD that occur within 180 days of the last dose of vadastuximab talirine will 
be reported to the Sponsor. Patients who undergo subsequent allo-HCT in the 
absence of relapse and additional therapy will be followed for SOS/VOD to 100 days 
post-transplant.
Section: Global
UReplace:
Version 02, Date 18 May 2016
With:
Version 03, Date 13 April 2017

SAP_001.pdf: 


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Table of Contents
Table of Contents......................................................................................................................................................................2
1.0 Introduction..........................................................................................................................................................................4
1.1 Changes from Protocol................................................................................................................................................4
2.0 Study Objectives.................................................................................................................................................................4
3.0 Study Design........................................................................................................................................................................5
3.1 Overall Study Design and Plan.................................................................................................................................5
3.1.1 Phase 1 Portion –Open-Label Dose Evaluation.........................................................................................5
3.1.2 Phase 2Portion –Randomized, Placebo-Controlled.................................................................................7
3.2 Sample Size Considerations.......................................................................................................................................8
3.3 Study Duration...............................................................................................................................................................8
3.4 Randomization...............................................................................................................................................................8
4.0 Study Variables and Covariates.....................................................................................................................................8
4.1 Primary Variable............................................................................................................................................................8
4.2 Secondary Variables.....................................................................................................................................................9
4.2.1 Efficacy....................................................................................................................................................................9
4.3 Other Variables..............................................................................................................................................................9
4.3.1 Pharmacokinetic and Antitherapeutic Antibody Assessments...............................................................9
4.3.2 Biomarker Assessments......................................................................................................................................9
4.3.3 Safety........................................................................................................................................................................9
4.3.4 Quality of Life......................................................................................................................................................10
4.4 Predetermined Covariates and Prognostic Factors...........................................................................................10
5.0 Definitions..........................................................................................................................................................................11
6.0 Analysis Sets......................................................................................................................................................................15
6.1 Intent-to-Treat Set.......................................................................................................................................................15
6.2 Safety Set.......................................................................................................................................................................15
6.3 DLT-Evaluable Set.....................................................................................................................................................15
6.4 Modified Intent-to-Treat Set....................................................................................................................................15
7.0 Interim Analyses...............................................................................................................................................................15
7.1 Safety Monitoring Committee.................................................................................................................................15
7.2 Independent Data Monitoring Committee......................................................................................................16
8.0 Data Review.......................................................................................................................................................................16
8.1 Data Handling and Transfer.....................................................................................................................................16
8.2 Data Screening.............................................................................................................................................................16
9.0 Statistical Methods...........................................................................................................................................................16
9.1 Subject Disposition.....................................................................................................................................................17
9.2 Protocol Deviations and Violations.......................................................................................................................18
9.3 Treatments.....................................................................................................................................................................18
9.3.1 Extent of Study Drug Exposure......................................................................................................................18
9.3.2 Concomitant Medications................................................................................................................................19
9.4 Demographic and Baseline Characteristics.........................................................................................................19
9.5 Efficacy Analyses........................................................................................................................................................20
9.5.1 Primary Efficacy Endpoint..............................................................................................................................20
9.5.2 Secondary Efficacy Endpoints........................................................................................................................20
9.5.3 Other Efficacy Endpoints.................................................................................................................................22
9.5.4 Methods for Handling Dropouts and Missing Data.................................................................................23
9.5.5 Multiplicity...........................................................................................................................................................23
9.5.6 Pooling of Sites....................................................................................................................................................24


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9.6 Safety Analyses............................................................................................................................................................24
9.6.1 Adverse Events....................................................................................................................................................24
9.6.2 Laboratory Data...................................................................................................................................................25
9.6.3 ECOG Performance Status..............................................................................................................................27
9.6.4 Physical Examinations, Electrocardiogram, and Other Observations Related to Safety.............27
10.0 Validation.........................................................................................................................................................................27
Appendix 1 Glossary of Abbreviations............................................................................................................................28
Appendix 2  Laboratory Standard Units..........................................................................................................................31
Appendix 3 CTCAE v4.03 Grading for Laboratory Values and QTc....................................................................32
Appendix 4 Imputation of Partially Unknown Adverse Event Dates...............................................................35
Appendix 5 Treatment Emergent Adverse Event Programming Guide.................................................................38


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1.0Introduction
This statistical analysis plan (SAP) describes the statistical methods to be used during the 
reporting and analyses of data collected under Seattle Genetics, Inc.Protocol SGN33A-004, 
entitled“A phase 1/2 study of vadastuximab talirine (SGN-CD33A) in combination with 
azacitidine in patients with previously untreated International Prognostic Scoring System (IPSS) 
Intermediate-2 or High risk myelodysplastic syndrome (MDS)”. Results of the proposed analyses 
will become the basis of the final clinical study report (CSR) for this protocol.
This SAP should be read in conjunction with the study protocol and case report form (CRF). 
This version of the plan has been developed using the protocol dated 13April, 2017and CRF 
dated 29August, 2017.Any further changes to the protocol or CRF may necessitate updates to 
the SAP.
The purpose of this plan is to provide specific guidelines from whichthe analysis will proceed.  
All planned analyses specified in this document will be performed. Any changes to this plan, in 
the form of “post hoc” or “data driven” analyses will be identified as such in the final clinical 
study report.  Any changes will be reflected in amendments to this plan before the database lock, 
detailed below, or specifically documented in the clinical study report. 
1.1Changes from Protocol
Disposition will be presented by dose level and total, and will not be presented by cycles. The 
summary of duration of treatment gives information on cycles received, so disposition by cycles 
is not needed. Hematologic improvement was not able to be calculated as the required data 
components were not captured in the data. 
2.0Study Objectives
Primary Objective:
• To determine the recommended vadastuximab talirine dose in combination with 
azacitidine in the open-label Phase 1 Portion of study
• To compare the overall response rate (ORR= complete response + partial response 
[CR+PR]) between treatment arms in the randomized, double-blind, placebo-controlled 
Phase 2 Portion of study
Secondary Objectives:
• To evaluate the safety of the combination of vadastuximab talirineand azacitidine(Phase 
1 and Phase 2 Portions)
• To compare the CR rate between treatment arms (Phase 2 Portion)
• To compare the hematologic improvement (HI) rate between treatment arms (Phase 2 
Portion)
• To compare the duration of response (DOR) between treatment arms (Phase 2 Portion)
• To compare progression-free survival (PFS) between treatmentarms (Phase 2 Portion)
• To compare the rate of transformation to acute myeloid leukemia (AML)between 
treatment arms (Phase 2 Portion)


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• To compare the overall survival (OS) between treatment arms (Phase 2 Portion)
Exploratory Objectives:
• To assess the pharmacokinetics (PK) and pharmacodynamics of vadastuximab talirine
(Phase 1 and Phase 2 Portions)
• To assess the incidence of antitherapeutic antibodies (ATAs) against vadastuximab 
talirine(Phase1 and Phase 2 Portions)
• To assess exploratory biomarkers of clinical activity of vadastuximab talirinein 
combination with azacitidine (Phase 1 and Phase2 Portions)
• To assess quality of life (QoL; Phase 2 Portion)
3.0Study Design
3.1Overall Study Design and Plan
This is a phase 1/2 study to evaluate the combination of vadastuximab talirineand azacitidine in 
subjects with previously untreated IPSS Intermediate-2 or High risk MDS. In the Phase 1 Portion 
of the trial, escalating doses of vadastuximab talirinewill be evaluated in combination with 
azacitidine, and 1 dose will be selected for the randomized, double-blind, placebo-controlled 
Phase 2 Portion of the study, which is designed to compare the ORR between the 2study arms.
3.1.1Phase 1 Portion –Open-Label Dose Evaluation
Cohorts of 6 dose-limiting toxicity (DLT)-evaluable subjects will be enrolled in an open-label 
fashion to receive vadastuximab talirinein combination with azacitidine in 28-day cycles, 
starting at 5mcg/kg vadastuximab talirine. DLT-evaluable population will include all Phase 1 
subjects who have completed atleast Cycle 1 of treatment (Cycle 1 of treatment is completed 
when the patient receives the first dose of azacitidine on Day 1 of Cycle 2) or discontinued study 
treatment because of adverse events (AEs) or for a safety-related reason before having had the
opportunity to receive the first dose of azacitidine on Day 1 of Cycle 2. In the phase 1 Portion of 
the study, DLTs will be defined as posttreatment grade 4 neutropenia or grade 4 
thrombocytopenia lasting >42 days from the start of therapy, in the absenceof evidence of active 
MDS, or any grade 3 or higher non-hematologic toxicity that is clearly NOT resulting from 
underlying MDS or azacitidine, with the exception of:
a. Grade 3 allergic reaction, fatigue, asthenia, anorexia, or constipation
b. Grade 3 nausea, vomiting, or diarrhea not requiring tube feeding or total parenteral 
nutrition  or hospitalization, 
c. Febrile neutropenia (which resolves with appropriate treatment or marrow recovery), 
infection, bleeding, or other expected direct complications of cytopenias due to active 
MDS. 
If 2 or more subjects in a 6-subject cohort have DLTs, that dose level will be considered to have 
exceeded the maximum tolerated dose (MTD). If 5mcg/kg vadastuximab talirinein combination 
with azacitidine is considered tolerable (≤1 of 6 subjects experiences a DLT), a cohort of 6 DLT-
evaluable subjects will receive 10 mcg/kg vadastuximab talirineand azacitidine. If 10mcg/kg 


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vadastuximab talirinein combination with azacitidine is considered tolerable,a cohort of 6DLT-
evaluable subjects will receive 15 mcg/kg, and if 15mcg/kg vadastuximab talirinein 
combination with azacitidine is considered tolerable, a cohort of 6DLT-evaluable subjects will 
receive 20 mcg/kg. If 5 mcg/kg vadastuximab talirinein combination with azacitidine is not 
considered tolerable (>1 of 6 subjects experiences a DLT), a cohort of 6DLT-evaluable subjects 
will receive 3 mcg/kg vadastuximab talirineand azacitidine. The dose escalation plan is 
presented in Figure1.
Figure1:
Study Schematic –Phase 1 Portion
Enroll 6
≤1DLT
Enroll 6
≤1DLT
Enroll 6
≤1DLT
Enroll 6
≤1DLT
5 mcg/kg
10 mcg/kg
15 mcg/kg
20 mcg/kg
>1DLT
>1DLT
>1DLT
>1DLT
Enroll 6
5 mcg/kg 
=MTD
10 mcg/kg 
=MTD
15 mcg/kg 
=MTD
3 mcg/kg
>1DLT
≤1DLT
20 mcg/kg
=MTD
End
3 mcg/kg
=MTD
DLT = dose-limiting toxicity; MTD = maximum tolerated dose.
Azacitidine will be given on 7 days per cycle, either on the first 7 days or 5 days on/2 days off/2 
days on; vadastuximab talirinewill be given after azacitidine on the last day of azacitidine 
administration in each cycle. Response assessments (bone marrow examination and complete 
blood count [CBC]) will be conducted on Day 22-28 of even-numbered cycles until CR, then 
every 4 cycles thereafter. Subjectsmay continue on study treatment until disease progression, 
relapse, or unacceptable toxicity. After discontinuation of study treatment, subjects who have not 
experienced progression or relapse will continue to be assessed for response every 4 months 
through 24 months after the end of treatment (EOT) or until initiation of another anticancer 
treatment, progression, or relapse, whichever comes first. All subjects will be contacted for 
survival status every 2 months after EOT in follow up until death or studyclosure, whichever 
comes first. Safety will be monitored through the surveillance of AEs, laboratory test measures, 
physical examination findings, and concomitant medication records. An additional bone marrow 
examination will be conducted for research purposes for subjects in the Phase 1 Portion of the 
study only.
After 6 DLT-evaluable subjects have had the opportunity to complete at least Cycle 1 (Cycle 1 of 
treatment is completed when the patient receives the first dose of azacitidine on Day 1 of 
Cycle2) of treatment in each planned dose cohort, the data will be aggregated and analyzed by a 
Safety Monitoring Committee(SMC)(Section7.1). The SMC will comprise medical experts 
from Seattle Genetics or their designee and a group of the investigators involved in the Phase 1 
Portion.Based on the evaluation of the data, including the incidence of DLT in each cohort, the 
SMC may recommend the dose of vadastuximab talirinefor the Phase 2 Portion of the study at
the time of the evaluation. If additional safety information is required to recommend a phase 2 
dose, the SMC could recommend enrollment of up to 12 additional treated subjects to continue to 
evaluate the safety of the combination at vadastuximab talirinedose(s) of 3, 5, 10, or 20 mcg/kg.


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3.1.2Phase 2 Portion –Randomized, Placebo-Controlled
The study arms in the phase 2 portion include the following: 
Experimental arm: azacitidine in combination with  vadastuximab talirine
Comparator arm: azacitidine in combination with  placebo
Subjects will be randomized in a 1:1 manner to one of the studyarms above. Randomization will 
be stratified by Eastern Cooperative Oncology Group (ECOG) performance status (0 vs 1 or 2) 
andInternational Prognostic Scoring System(IPSS)score (Intermediate-2 vs High risk).
Subjects will receive vadastuximab talirinein combination with azacitidine in 28-day cycles, 
starting at the dose level of vadastuximab talirinedetermined in phase 1. Response assessments 
(bone marrow examination and CBC) will be conducted once between Day 22 and Day 29of 
even-numbered cycles until CR, then every 4 cycles thereafter. Subjects may continue on study 
treatment until disease progression, relapse, or unacceptable toxicity. After discontinuation of 
studytreatment, subjects who have not had progression or relapse will continue to be assessed 
for response every 4 months through 24 months after EOT or until initiation of another 
anticancer treatment, progression, or relapse, whichever comes first. All subjects will be 
contacted for survival status every 2 months after EOT in follow up until death or study closure, 
whichever comes first. Safety will be monitored through the surveillance of AEs, laboratory test 
measures, physical examination findings, and concomitant medication records. AnIndependent 
Data Monitoring Committee (IDMC)(Section7.2) will also periodically assess the ongoing 
safety data and make recommendations to either continue evaluating the combination or to stop 
the study due to toxicity concerns. Figure2is a study schematic for the Phase 2 Portion.
Figure2:
Study Schematic –Phase 2 Portion
Screening
Randomization
AZA + SGN33A
Repeated 4-Week Cycles
(Disease assessment even-
numbered cycles until CR, then 
every 4 cycles)
Discontinuationa
Long-term
Follow-up
(Disease progression
b
and survival)
AZA + Placebo
Repeated 4-Week Cycles
(Disease assessment even-
numbered cycles until CR, then 
every 4 cycles
AZA = azacitidine; CR = complete response.
a
Subjects may continue to receive repeated cycles of treatment until disease progression, relapse, unacceptable 
toxicity, or other discontinuation criteria are met.
b
For subjects who discontinue without having experienced disease progression follow-up will include disease 
assessment (CBC and bone marrow) every 4 months for 24 months or until disease progression. Subjects will be 
followed every 2months for survival until death or the end of the study.
Unblinding a subject’s treatment assignment will be limited to emergency circumstances where 
knowledge of the treatment assignment would affect decisions regarding the management of the 


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subject. In the event of such an emergency circumstance, a formal unblinding procedure will be 
followed to allow the investigator to immediately access a subject’s treatment assignment. 
Information on study treatment assignment should not be distributed to any other personnel 
involved in the clinical trial.
Please refer to Table 4of the protocol for the full Schedule of Study Procedures and 
Assessments, Table 5for the Schedule of Pharmacokinetic, Immunogenicity, and Biomarker 
Assessments for thePhase 1 Portion and Table 6for Schedule of Pharmacokinetic, 
Immunogenicity, and Biomarker Assessments for thePhase 2 Portion.
3.2Sample Size Considerations
Phase 1 Portion (minimum of 6 subjects per cohort): Six subjects are adequate to appropriately 
assess the safety profiles and DLT rates of differing dose levels of vadastuximab talirinein 
combination with azacitidine. If the true incidence rate of DLT is 10%, the probability of 
considering a dose level tolerable (ie, ≤1 of 6 subjects experiences a DLT) will be 88.6%. If the 
true incidence rate of DLT is 50%, the probability of considering a dose level tolerable will be 
10.9%.
With this type of studydesign, the exact number of subjectsneeded to complete the Phase I 
Portionis unknown because it depends on the number of cohorts required to reach MTD. 
Approximately 24subjectsare expected to participate in the Phase 1 portion of this trial, 
assuming 4 dose-escalation cohorts of 6subjects.
Phase 2 Portion (106 subjects): A sample size of 106 subjects will provide 85% power to detect a 
treatment difference in ORR, assuming an ORR of 30% for azacitidine alone vs 55% for the 
combination vadastuximab talirinewith azacitidine, at a 2-sided 0.1 alpha level.
3.3Study Duration
There will be approximately 35 sites enrolling subjects in this study. The estimated duration of 
study treatment through final primary analysis is approximately 51 months from enrollment of 
the first subject to completion of the last subject. All subjects will be contacted for survival status 
every 2 months after EOT in follow up until death or study closure, whichever comes first.
3.4Randomization
During the Phase 2 Portion of the study, subjects will be randomized in a 1:1 manner to 
azacitidine with vadastuximab talirineand azacitidine with placebo. Randomization will be 
stratified by ECOG performance status (0 vs 1 or 2) and IPSS score (Intermediate-2 vs High 
risk).
4.0Study Variables and Covariates
4.1Primary Variable
The primary endpoint of the Phase 1 Portion of the study is to determine the recommended dose 
for the Phase 2 Portion, based upon the MTD.


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The primary efficacy endpoint of the Phase 2 Portion of the study is the ORR, defined as the
proportion of subjects who achieve any category of CR (CR and Marrow CR) or PR based on the 
2006 International Working Group (IWG) criteria for MDS.
4.2Secondary Variables
4.2.1Efficacy
Secondary efficacy endpoints of the Phase 2 Portion of the study are the following:
Complete response (CR) rate
Hematologic improvement (HI) rate
Duration of response (DOR)
Progression-free survival (PFS)
Rate of transformation to AML
Overall survival (OS)
4.3Other Variables
4.3.1Pharmacokinetic and Antitherapeutic Antibody Assessments
Estimates of selected PK parameters for plasma vadastuximab talirine and released SGD-
1882
Incidence of ATA
4.3.2Biomarker Assessments
Biomarker assessments may include 
CD33 expression level
Abundance of MDSC
Characterization of leukocyte subpopulations in peripheral blood (peripheral blood 
mononuclear cells; PBMCs)
Variation in sequence of CD33 and genes commonly mutated in MDS and hematologic 
malignancies
Soluble CD33
Abundance of a variety of cytokines
Testing for Paroxysmal Nocturnal Hemoglobinuria (PNH) and human leukocyte antigen 
(HLA)-DR15 
4.3.3Safety
Safety assessments for both the Phase 1 Portion and the Phase 2 Portion of the study will consist 
of thefollowing:


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Surveillance of AEs
Laboratory test measures
Physical examination findings
Concomitant medicationrecords.
4.3.4Quality of Life
Quality of life for both the Phase 1 Portion and the Phase 2 Portion of the study will be assessed 
with the Quality of Life Questionnaire (QLQ)-C30 patient reported outcomes (PRO) tool at 
protocol-defined time points.
4.4Predetermined Covariates and Prognostic Factors
Randomization will be stratified by ECOG performance status (0 vs 1 or 2) and IPSS score 
(Intermediate-2 vs High risk)to ensure some level of balance between treatment arms and these 
stratification factors will be used as covariates in statistical modelsfor the primary analysis.


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5.0Definitions
Absolute Dose Intensity (ADI):is defined as the actual dose (µg/kg) per unit of time that the 
subjectreceived over the entire treatment period.Actual time for the denominator will be 
calulcated separately for vadastuximab talirine and azacitidine as follows:
Vadastuxmab talirine: last day 1 dose date of azacitidine where vadastuximab talirine was 
received in that cycle +28 -first dose of any study drug
Azacitidine: last day 1 dose date of azacitidine +28 -first dose of any study drug
AEs Leading to Discontinuationof Study Drugs: are those indicated by “Reason for 
discontinuing treatment” of AE (linked by AE number) on the End of Treatment Summary page 
of the CRF.
Age (years): will be calculated with the SAS INTCK function using informed consent date and 
birth date.
ATA Incidence Rate:is defined as the proportion of patients that develop ATA at any time 
during the study.
Baseline:is defined as the most recent measurement prior to the first dose of any study treatment 
unless otherwise defined in a specific section of the SAP.
Complete Response:is defined as an answer of “Complete Remission” for the question 
“Response Assessment” in CRF form of “Response Assessment”.
Concomitant Medication: is defined as any medication ongoing at the start of vadastuximab 
talirineor Placebo dosing or with a start date on or after the first dose date of any study treatment
dose dateup to 30 days post last dose or EOT whichever is longer. Medications with start and 
end dates before the first dose date of any study treatmentmay be concomitant if the medication 
is marked as ongoing. For medications with missing or partial start dates, a missing start date 
will be imputed with the first dose date ofany study treatment, missing month and day for a 
partial start date will be imputed with January 1st, and missing day for a partial start date will be 
imputed with the first day of the month. 
Days: The following unit conversion will be implemented unlessotherwise specified:
Months = Days / 30.4375
Years =Days / 365.25.
Deaths:Subjectdeaths will be determined from End of Study CRF page(where reason for 
discontinuation is death) and from AE CRF page(where CTCAE grade is 5 or outcome is 
“fatal”) and from the follow-up CRF page (where the answer to the question “Is the patient 
alive?” is “No”). The number of days between vadastuximab talirineor placebo last dose and 
death will be calculated as (date of death –last vadastuximab talirineor placebo dose date + 1).
Dose-Limiting Toxicity:see Section 3.1.1. 
DLT Evaluable Subject:is defined as all Phase 1 subjects who have completed at least Cycle 1 
of treatment (Cycle 1 of treatment is completed when the patient receives the first dose of 
azacitidine on Day 1 of Cycle 2),or discontinued study treatment because of AEs or for a safety-
related reason(defined as AE, Investigator Decision, or Progressive Disease) before having had 


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the opportunity to receive the first dose of azacitidine on Day 1 of Cycle 2, or who experienced a 
DLT. 
Duration of Response:is defined as the time from first observation of response 
(PR+CR/Marrow CR) to disease progression/relapse or death from any cause, whichever occurs 
first.
Duration of Treatment:is defined as time from the first dose of any study drug until 28 days 
after the last day 1 dose date, or until :last contact date if the patient is still on treatment at the 
time of the analysis.
Minimum(Last day 1 dose date + 27, death date, last contact date)  –first dose date +1
Infusion Related Reactions AE:is defined for those AEsthat have responses of “Yes” for the 
question “Were there any infusion-related reactions?” in the CRF forms“Treatment –Blinded 
Study Drug”, “Treatment –Azacitidine”, or “Treatment –Vadastuximab Talirine”.
Hematologic Improvement:is defined in Table 1
Hematologic Improvement (HI) Rate:is defined in as the proportion of subjects with 
Erythroid response, Platelet response or Neutrophil response as defined in Table 1. 


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Table1:InternationalWorking Group Response Criteria for Hematologic Improvement
Hematologic 
improvement*
Response criteria (responses must last at least 8 weeks)
Erythroid response
(pretreatment
a, Hgb 
<11g/dL)
1. Hgb increase by ≥1.5 g/dL
  OR
2. Relevant reduction of units of red blood cell (RBC)transfusions 
by an absolute number of at least 4 RBC transfusions/8 weeks
compared with the pretreatment transfusion number in the previous 
8 weeks. Only RBC transfusions given for a Hgb of ≤9.0g/dL 
pretreatment will count in the RBC transfusion response evaluation
Platelet response
(pretreatment
a, Platelet 
<100×109/L)
1. Absolute increase of ≥30×109/L for patients starting with 
>20×109/L platelets;
OR
2. Increase from <20×109/L to >20×109/L and by at least 100%
Neutrophil response
(pretreatment
a, Neutrophil 
absolute <1.0×109/L)
At least 100% increase and an absolute increase >0.5×109/L
Progression or relapse 
after HI*
At least 1 of the following: 
At least 50% decrement from maximum response levels in 
granulocytes or 
   platelets
Reduction in Hgb by ≥1.5 g/dL
Transfusion dependence
a Pretreatment counts averages of at least 2 measurements (not influenced by transfusions) ≥1 week 
apart.
b In the absence of another explanation, such as acute infection, repeated courses of chemotherapy, 
gastrointestinal bleeding, hemolysis, and so forth. It is recommended that the 2 kinds of erythroid and 
platelet responses be reported overall as well as by the individual response pattern.
Adapted from:  Cheson BD, Greenberg PL, Bennett JM, et al.  Clinical application and proposal for 
modification of the International Working Group (IWG) response criteria in myelodysplasia.  Blood. 
2006;108:419-425.
Marrow Complete Response:is defined as an answer of “Marrow Complete Remission” for the 
question “Response Assessment”in CRF form of “Response Assessment”.
Objective Response Rate:is defined as the proportion of subjectswith PR+CR/Marrow CR . 
Subjectswho cannot be assessed for response will be counted as non-responders.
Pre-existing AEor Baseline AE:is defined as inAppendix 5.
Progression-Free Survival:PFS is defined as the time from first dose of study medication to 
first documentation of disease progression/relapse, or to death due to any cause, whichever 
occurs first. For subjectswithout disease progression/relapse or death on study, PFS will be 
censored at the time of the last on-study disease assessment demonstrating a lack of disease 
progression/relapse. If more than one date of progression is available, the earliest date will be 
used to determine PFS. Subjects who receive another antineoplastic therapy in the absence of 
documented progression will be censored at the time of receiving off-protocol therapy for 


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malignancy, EXCEPT that subjects who receive stem cell transplant in remission will continue to 
be followed for progression.
Relative Dose Intensity (RDI):is defined as the absolute dose intensity over the intended dose 
intensity,
RDI = ADI / IDI *100.
Where IDI(intended dose intensity)is defined as the intended dose of drug (mg/kg) per unit of 
time.
Study Drug: The study drug is vadastuximab talirine(SGN-CD33A)for the study.
Serious AE (SAE):is defined as an answer of “Yes” for the question “Was this Serious” in CRF 
form of “Adverse Events and Pre-Existing Conditions”.
Time Since Initial Diagnosis:is defined as 
Date of first dose –date of initial MDS diagnosis + 1.
Transformation to AML:is defined as an answer of “Yes” for the question “Has the patient 
progressed to AML” in CRF form of “Follow-Up”.
Treatment Arm, Actual
In the Phase 1 portion, the actual treatment arm will be the dose level of vadastuximab talirine
the subject receivedin Cycle 1, regardless of thecohort in which they were enrolled. 
In Phase 2 portion of the study, a subject’s actual treatment arm (azacitidine in combination with  
vadastuximab talirine or azacitidine in combination with  placebo) will be determined by 
whether the subject is administered vadastuximab talirine or placebo by merging the Treatment-
Blinded Study Drug CRF data and theMedication Packs List using the Medication ID Number
and the Kit Number. If asubject receives one or more dose of vadastuximab talirine, then the 
subject’s actual treatment arm will be azacitidine in combination with vadastuximab talirine. If a
subject receives only placebo, then the subject’s actual treatment arm will be azacitidine in 
combination with placebo.
Treatment Arm, Randomized
In Phase 2 portion of the study, asubject’s randomized treatment arm (azacitidine in 
combination with vadastuximab talirine or azacitidine in combination with placebo) will be the 
treatment arm associated with that subject’s randomization number in the IXRS randomization 
schedule.
Treatment-Emergent AE (TEAE):All AEs reported after initiation of treatment and pre-
existing conditions that worsen after initiation of treatment will be considered treatment-
emergent AEs (TEAEs). See Appendix 4and Appendix 5for imputation of partial AE dates and 
detailed pre-existing AE rules, respectively.Unless otherwise specified, summaries of AEs will 
only include treatment-emergent events.
Treatment-Related-AE:is defined as an answer of “Yes” for the question “Was this related to 
VadastuximabTalirine or Blinded Study Drug”in CRF form of “Adverse Events and Pre-
Existing Conditions”.




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enrollment suspension or study termination, as recommended by the SMC. The SMC may also 
recommend predetermined or intermediate dose levels for dose escalation and/or expansion for 
the Phase 2 portion of the study based on review of safety and efficacy data.In the event of a 
death or emergence of a life-threatening acute or chronic toxicity within the safety reporting 
period, enrollment to the study will be temporarily halted until the SMC convenes to review the 
aggregate safety data to determine if enrollment will resume, and the appropriate dose level 
moving forward.Additionally, the investigators and the PRA Medical Monitor will meet 
regularly (via teleconference, see section 7) to assess safety on an ongoing basis.
Meetings will be held approximately 1 week after the last patient completes the DLT period. The 
DLT period is defined as the time from start of study therapy in Cycle 1 through the start of day 
1 of Azacitidine during Cycle 2, or the time at which a patient discontinues treatment due to 
study treatment-related toxicity prior to receiving Day 1 Cycle 2 treatment. This will occur for 
each dose escalation cohort that has been initiated and on an ad hoc basis as needed based on 
emerging safety data.
7.2Independent Data Monitoring Committee
The IDMC will consist of 2 physicians and 1 statistician who are all external to Seattle Genetics, 
Inc. and free of any direct involvement with the conduct of this study beyond participation in the 
IDMC. The primary role of this IDMC will be to monitor safety dataduring the Phase 2 Portion 
of this study.
Details of the safety reviews will be provided in the IDMC charter.
8.0Data Review
8.1Data Handling and Transfer
Data handling and transfer specifications will be stated and conducted according to the Data 
Management Plan (DMP).
8.2Data Screening
Beyond the data review and cleaning built into the PRA DMP, the PRA programming of analysis 
datasets, and TFLsprovides additional data review. 
Review of a TFL dry run on the nearly finalized database will allow for further data review prior 
to finalization. The dry run TFLs will be discussed with the sponsor in a data review meeting to 
identify any final data issues and seek corrections prior to database lock. The PRA statistician 
and the sponsor must approve database lock.
9.0Statistical Methods
There are two phases to this study. The primary objective of the Phase 1 Portion of the studyis to 
determine the recommendedvadastuximab talirinedose in combination with azacitidine. All 
analyses in the Phase 1 Portion of the study will be descriptive. There will be no formal 
inferential analyses performed for the Phase 1 Portion of the study.


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The Phase 2 Portion of the study will use inferential statistics to explore the efficacy of 
vadastuximab talirinedose in combination with azacitidine. All inferential analyses will compare 
the effect of vadastuximab talirinedose in combination with azacitidineto placebo in 
combination with azacitidine. Hypotheses will be two sided in nature and will be performed at 
the alpha = 0.1 level. Inferential statistics for continuous variables will include the estimate, the 
standard error (SE)of the estimate, and a 90% confidence interval.Estimateswill be presented to 
1 decimal more than original data. SEwill be presented to 2 decimals more than original data.
Descriptive statistics (mean, median, standard deviations, minimum and maximum values) for 
continuous variables will be presented. Mean and median will be presented to 1 decimal more 
than original data. Standard deviation (SD) will be presented to 2 decimals more than original 
data. Minimum and maximum will match the decimal points in the original data. For categorical 
variables, summary measures will include the frequency and percentage (with 1 decimal place) 
of subjectsin each category. 
All data summaries and tabulations will be presented by dose level using the Safetysetfor the 
Phase 1 Portion of the analysis, and by treatment group for the ITTevaluableset for the Phase 2 
Portion of the analysis set unless otherwise noted. For efficacy and exploratory analyses, further 
subgroup analyses are not planned.
All data summaries and tabulations will beprepared with SAS Version 9.1.4or higher.
9.1Subject Disposition
An accounting of study subject disposition will be tabulated by dose level and total, and the 
number of subjectsin each analysis set will be summarized, i.e. all safety set andDLT-evaluable
set for the Phase 1 Portion of the study. A similar analysis by treatment armand total will be 
summarized for the ITT set, safety set, and efficacy evaluable set for the Phase 2 Portion of the 
study. 
A tabulation of the number and percentage of subjects enrolled in the study (as defined by 
answering Yesto the eCRF question of “Will the patient be enrolled into the study?”) at each site 
will be summarized by dose level and totalfor the Phase 1 and 2 Portion of the study. 
Subjectswho discontinue study treatment and subjects who withdraw from the study will be 
summarized by treatment arm and total along with reasons for discontinuation or withdrawal, 
alongwith number of subjects who are currently on study and on treatment. A summary table of 
follow up will be generated for the time from first dose to the time of last assessment, the time 
from end of treatment to the time of last assessmentand the time from end of treatment to end of 
study. The summary will be presented for all enrolled subjects for the Phase 1 Portion summary 
and for the ITT set for the Phase 2 Portion.
A listing of subjects of the safetyset forthe Phase 1 Portion of the study and the ITT set for the 
Phase 2 Portion of the study who discontinued from the study anddiscontinued from the 
treatment will be presented including subjects’ identifier, treatment center, the specific reason for 
discontinuation and/or for discontinuation of study treatment, the date of the last dose and the 
duration of treatment before discontinuation.A listing of subject eligibility and a listing of 
subject analysis sets will also be provided.


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9.2Protocol Deviations and Violations
Important protocol deviations (defined as protocol violations by Seattle Genetics) are those that 
represent a divergence from the protocol that could have a significant effect on the integrity of 
the study data, or on the subject’s rights, safety, or welfare. Important protocol deviations also 
include exemptions to the study inclusion/exclusion criteria and will be summarized by category,
treatment arm and/or dose level and total, and study portion.  A listingof subjectswith important 
protocol deviations will be presented.  
9.3Treatments
9.3.1Extent of Study Drug Exposure   
Phase 1 PortionExposure
During the Phase 1 Portion of the studyvadastuximab talirinewill be administered every 4 
weeks (after azacitidine on the last day of azacitidine administration) via IV at the assigned dose 
level (3 to20 mcg/kg), based on the dose evaluation cohort.
Subjectswill also receive azacitidine 75 mg/m2SC or IV (at the investigator’s discretion) for 7 
days (7consecutive days or 5 days on/2 days off/2 days on), beginning on Day 1 of repeated 
4-week cycles.
Phase 2PortionExposure
During the Phase 2 Portion of the study, subjects will be randomized to receive either 
vadastuximab talirineadministered every 4 weeks (after azacitidine on the last day of azacitidine 
administration) via IV push at the dose determined in the Phase 1 Portion or placebo every 
4weeks (after azacitidine on the last day of azacitidine administration) via IV push.
All subjects will also receive azacitidine 75 mg/m2SC or IV (at the investigator’s discretion) for 
7 days (7 consecutive days or 5 days on/2 days off/2 days on), beginning on Day 1 of repeated 
4-week cycles.
Treatment administration of both vadastuximab talirineand azacitidine will be summarized for 
both study phases by dose level using the safety set. The number and percentage of subjects 
whose dose was ever modified will be summarized by modification type, cycle and overall (i.e. 
over all drug administrations for a subject). Summary statistics related to duration of treatment 
and compliance will be presented as detailed below.  For the continuous parameters, the mean, 
SD, median, minimum and maximum will be presented. The following summary statistics 
related to drug exposure will be calculated by dose level:
The number and percentage of subjects with at least 1 dose delayed,the number of doses 
delayed,at least 1 dose reduced, the number of dosesreduced, the number of subjects with at 
least 1 dose unplanned adjustment and reasons for unplanned adjustment, and number of 
unplanned dose adjustments, the number of subjects with at least one infusion-related reaction, 
the number of infusion-related reactions, the number of subjects with a delayed hypersensitivity 
reaction, the number of delayed hypersensitivity reactions, the duration of treatment (weeks), the 


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number of doses received, the number of treatment cycles received (continuous summary), the 
number of subjects receiving 1, 2, 3, etc. cycles, the cumulative dose administered (µg/kg and 
total µg), the average dose per cycle (µg/kg and µg), absolute dose intensity (µg/kg), and relative 
dose intensity (%)will be presented.
A listing of intended dose regimen, intended dose, actual dose administered, and reasons for dose
delayed, dose reduced, dose adjustment, and/or infusion-related reactions will be displayed.
9.3.2Concomitant Medications
Other than the study drugs, any medication taken by subjectsduring the course of the study with 
a start date on or after the first dose of anystudy drug, start date prior to first dose date and end 
date after first dose date or marked as ongoing,will be considered concomitant. Medications 
stopped prior to the date of the first dose of any study drug will not be considered concomitant. 
Prior medications include all medications with a start date before the first day of treatment of any 
study drugand stopped prior to the date of first dose. Subjectsin the safety setwith multiple uses 
of a concomitant medication will be counted once for a given Anatomical-Therapeutic Chemical 
(ATC) and preferred name. 
The numberand percentage of subjectswith each concomitant medication will be summarized 
by ATC class and preferred name for all treated subjectsby planned dose levelfor each study 
portion. Preferred names will be presented in descending order of frequency in total.   
Additionally, all medicationswill be listed by subject, displaying verbatim name, synonym (if
applicable) and preferred name, indication, and start and stop dates. 
9.4Demographic and Baseline Characteristics
The number and percentage of subjectswill be provided for Sex(male, female),race (American 
Indian or Alaska Native, Asian, Black or African American, Native Hawaiian or Other Pacific 
Islander, White, Other), ethnicity (Hispanic or Latino, Not Hispanic or Latino), ECOG
performance status stratification category (0, 1 or 2), andIPSS stratification category
(intermediate-2, high risk). Descriptive statistics will be provided for age (years),weight (kg),
height (cm), and body surface area(BSA).
Baseline disease characteristics will be presented. The number and percentage of subjectswill be 
provided forMDS Subtype (WHO 2008 Classification), cytopenias (hemoglobin count < 10 
g/dL, absolute neutrophil count < 1500/µL, platelet count < 100,000/µL),blasts in the bone 
marrow (5-10%, 11-20%), cytogenetics (normal, all other abnormalities not valued as good or 
poor, 3 or more abnormalities or abnormal chromosome 7), IPSS classification (low, 
intermediate-1, intermediate-2, high), cytogenic category (very good, good, intermediate, poor, 
very poor), and IPSS-Rcategory (very low, low, intermediate, high, very high)at baseline. 
Descriptive statistics will be provided for IPSS-Rscore,time since initial diagnosis, hemoglobin 
(g/dL), absolute neutrophil count (x10
9/L), platelets (x10
9/L), and bone marrow blasts (percent).
Prior cancer-relatedtherapy data will be summarized as number and percentage for each therapy 
type(systemic therapy, radiotherapy)and current disease statusof prior cancer(complete 


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remission, stable disease, active disease).  In addition, the number and percentage of subjects
with any prior therapy will be displayed.
Medical history will be summarized by count and percentage of subjects experiencing medical 
history events by Medical Dictionary for Regulatory Activities (MedDRA)system organ class 
(SOC) and preferred term (PT).
Summaries will be presented by treatment group and study phase.Summaries for the Phase 1 
Portion will be presented using the Safety Set. Summaries for the Phase 2Portion will be 
presented using the ITTset.
By-subjectlistings include demographic and baseline characteristics, initial disease diagnosis, 
prior cancer-related therapy, and general medical history.
9.5Efficacy Analyses
The primary endpoint of the Phase 2 Portion is ORR, and the study will be unblinded for analysis 
of ORR after all subjectshave completed 6 cycles of therapy or have discontinued treatment for 
any reason before completing 6 cycles. Data collection for the secondary efficacy endpoints and 
the safety and other endpoints will continue in an unblinded or partially blinded fashionuntil all 
subjects have discontinued study treatment.
Primary and secondary endpoint analyses will be presented for the ITT set and the All Treated 
set for the Phase 2 Portion of the study. Summaries for the Phase 1 Portion of the study will be 
presented for the safety set.
9.5.1Primary Efficacy Endpoint
Subjects will be assigned a response status based on assessments at each visit. The primary 
efficacy endpoint of the Phase 2 Portion of the study is ORR, defined as the proportion of 
subjects who achieve any category of CR (CR and Marrow CR) or PR based on the 2006 IWG 
criteria for MDS that are summarized in Appendix18.6 of the protocol. ORR will be assessed 
during the on treatment period until EOT.Subjects who are not evaluable at any time during the 
treatment period will be considered non-responders.
The ORR will be summarized by treatment groupand the treatment difference in ORR will be 
tested using a Cochran-Mantel-Haenszel(CMH)teststratified by randomization strata (ECOG 
status at baseline,that is, 0 vs 1 or 2and IPSS category at baseline, that is, Intermediate-2 vs 
High risk).The 90% confidence intervalfor the treatment difference in ORR will be calculated.
ORR will be summarized descriptively, including 95% confidence intervals using the exact 
binomial method, by dose for the Safety setin the Phase 1 Portion of the study.
9.5.2Secondary Efficacy Endpoints
The following analyses for the secondary endpoints will be performed for the Safety set for the 
Phase 1 Portion and ITT and EE set for the Phase 2 Portion of the study, respectively.


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CR Rate, HI rate, and Rate of transformation to AML will be summarized descriptively by 
treatment armor dose level. The corresponding 90% confidence intervals for the difference in 
rate between the 2 treatment arms will be providedfor the 2 Portion of the study. 
The number and percent of subjects with disease response of CR, Marrow CR, PR, stable disease 
[SD], PD or Relapse from CR / PRas collected on the Response AssessmentCRF form willbe 
presentedat each visit bytreatment arm or dose level.
Time-to-event variables (DOR, PFS, and OS) will be summarized descriptively using the 
Kaplan-Meier methodologyusing the SAS LIFETEST procedure. Medians and quartiles and 
theirtwo sided 90% CI using the complementary log-log transformation method will be 
calculated, where possible. PFS probability at 3, 6, 9,…51months with corresponding CIs will 
be reported..Kaplan-Meier figures will be presented by treatment arm or dose level.
9.5.2.1Duration of Response
DOR(for PR/CR and CR)isdefined as the time from first observation of response 
(PR+CR/Marrow CR or CR/Marrow CR) to disease progression/relapse or death from any cause, 
whichever occurs first. Durations will be assessed in the ITT population with a PR or CR and 
calculated separately for subjects with CR/Marrow CR and those with PR+CR/Marrow CR 
combined. For subjects with a remission without subsequent disease progression/relapse or death 
on study, DOR will be censored at the time of the last disease assessment demonstrating a lack of 
disease progression/relapse. Subjects who receive another antineoplastic therapy in the absence 
of documented progression will be censored at the time of receiving off-protocol therapy for 
malignancy, EXCEPT that subjects who receive stem cell transplant in remission will continue to 
be followed for progression.Subjects who do not have a subsequent response assessment after 
their first observation of response will be censored at that date (day 1).
9.5.2.2Progression-Free Survival
PFS is defined as the time from first dose of study medication to first documentation of disease 
progression/relapse, or to death due to any cause, whichever occurs first. For subjects without 
disease progression/relapse or death on study, PFS will be censored at the time of the last on-
study disease assessment demonstrating a lack of disease progression/relapse. If more than one 
date of progression is available, the earliest date will be used to determine PFS. Subjects who 
receive another antineoplastic therapy in the absence of documented progression will be 
censored at the time of receiving off-protocol therapy for malignancy, EXCEPT that subjects 
who receive stem cell transplant in remission will continue to be followed for progression.
Subjects who do not have a post-baseline response assessment after will be censored at baseline 
(day 1).
9.5.2.3Overall Survival
OS is defined as the time from first dose of study medication to death due to any cause. For 
subjects not known to have died at the end of the study, OS will be censored at the time the 
subject was last known to be alive (including follow-up data).


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9.5.3Other EfficacyEndpoints  
9.5.3.1Quality of Life
The QLQ-C30 is composed of both multi-item scales and single-item measures. These include 
fivefunctional scales(Physical functioning, Role functioning, Emotional functioning, Cognitive 
functioning, Social functioning), three symptom scales(Fatigue, Nausea and vomiting, Pain), a 
global health status / QoL scale, and six single items(Dyspnoea, Insomnia, Appetite loss, 
Constipation, Diarrhoea, Financial difficulties).Each of the multi-item scales includes a different 
set of items –no item occurs in more than onescale.
The QLQ-C30 is collected at Cycle 1, Day 1 pretreatment. This will be the baseline measure. 
The questionnaire is collected on Day 1 of even-numberedcycles thereafter.
All of the scales and single-item measures range in score from 0 to 100. A high scale score
represents a higher response level.
Thus a high score for a functional scale represents a high / healthy level of functioning, a high 
score for the global health status / QoL represents a high QoL, but a high score for a symptom 
scale / item represents a high level of symptomatology / problems.
The principle for scoring these scales is the same in all cases:
1. Estimate the average of the items that contribute tothe scale; this is the raw score.
2. Use a linear transformation to standardize the raw score, so that scores range from 0 to 100; a
higher score represents a higher (“better”) level of functioning, or a higher (“worse”) level of
symptoms.
SAS coding of the scoring procedure is presented inthe scoring manual page 54 of the manual.
Data from the QLQ-C30 will be scored as recommended by the European Organization for 
Research and Treatment of Cancer and summarized descriptivelyfor the functional scales, 
symptom scales, individual items, and the global health status.Normalized scores and their 
changes from baseline will be summarized for functional scales, symptom scales, individual 
items, and the global health status.
9.5.3.2Pharmacokinetics and Immunogenicity 
Blood samples for PKand ATAassessmentswill be collected at the time points outlined in 
Table 4 and 5 in the protocol.Sensitive, qualified assays will be used to measure concentrations 
of antibody-drug conjugate (ADC)(vadastuximab talirine) and SGD-1882 in plasma and ATA in 
serum. Remaining PK samples will be archived for possible analysis of SGN-CD33-related 
species. The assays will include enzyme-linked immunosorbent assays (ELISA) and liquid 
chromatography/tandem mass spectrometry assays, as well as other assays if further 
characterization is required. A qualified electrochemiluminescence assay will be used to assess 
ATA.


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Estimates of selected PK parameters (vadastuximab talirine ADC and SGD-1882) and incidence 
of ATA to vadastuximab talirin will be summarized by phase and treatment arm or dose level.
9.5.3.3Biomarkers 
Biomarker assessments may include CD33 expression level, abundance of myeloid-derived 
suppressor cells (MDSC), characterization of leukocyte subpopulations in peripheral blood 
mononuclear cells(PBMC), variation in sequence of CD33 and genes commonly mutated in 
MDS and hematologic malignancies, soluble CD33, abundance of a variety of cytokines, and 
testing for paroxysmal nocturnal hemoglobinuria (PNH)and HLA-DR15 at protocol-specified 
time points. Methods of analysis may include flow cytometry, ELISA, deoxyribonucleic acid 
(DNA), and ribonucleic acid (RNA)sequencing.Biomarker results may be defined and 
presented in a separate report. 
9.5.4 Methods for Handling Dropouts and Missing Data
With the exception of time-related endpoints, missing observations will generally be treated as 
missing at random and will not be imputed, unless otherwise noted.
For time-related endpoints, DORand PFSwill follow Table 2below:
Table 2:
Kaplan-Meier Analysis Rules
Situation
Date of Progression or Censoring
Outcome
No baseline and/or post-baseline 
diseaseassessment
Dateof first dose
Censored
No documented progression
Date of last adequate responseassessment(or 
Study Day 1 in the absence of a post-baseline 
responseassessment)
Censored 
PD documented during or between
scheduled visits
Date of responseassessment demonstrating 
PD
Event
New subsequent cancer therapy 
initiated prior to documented 
progression 
Start date of new subsequent cancertherapy
Censored
Death before first PD assessment
Date of death
Event
Death between responseassessment 
visits
Date of death
Event
For concomitant medication dates, see Section 5for imputation rules. For missing or partial start 
and stop adverse event dates, see Appendix 4for imputation rules.
Note that the actual value for date (not imputed) will be presented in all data listings and imputed 
dates will be used for derivationsonly.
9.5.5Multiplicity
No adjustments for multiple testing will be utilized for anyanalyses.


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9.5.6Pooling of Sites
No pooling of sites will be used in any analyses.
9.6Safety Analyses
Safety data will be summarized for the safety setseparately for Phase 1and Phase 2 Portions by
treatment arm or dose level.For the Phase 2 Portion of the trial summaries will be by actual 
treatment received. Actual treatment for the Phase 2 Portion of the trial is defined as follows:
Any subject who receives at least one dose of vadastuximab talirinewill be assigned an 
“actual” treatment of vadastuximab talirine. 
Subjects who only receive azacitidinefor the duration of the trial will be assigned an 
“actual” treatment of azacitidine.
9.6.1Adverse Events
9.6.1.1Dose Limiting Toxicities
The incidence of DLTswill be summarized using the DLT evaluable set. The number and 
percentage of subjectsexperiencing a DLT and not experiencing a DLT will be presented for
each dose levelfor the DLT evaluable set..The DLTs observed will be summarized by dose 
level andby MedDRA PT. DLTs will also be summarized by category of NCI CTCAE(version 
4.03)gradeby SOCand PT.
9.6.1.2Adverse Events and Serious Adverse Events
AEs will be summarized by descending frequency of MedDRA PT unless otherwise specified. 
For incidence reporting, if a subjectreports more than one AE that was coded to the same SOC 
or PT, the subjectwill be counted only once for that specific SOC or PT. See Section 5for 
definition of pre-existing AEs, TEAEs,related AEs, SAEs, infusion-related reaction AEs and 
AEs leading to vadastuximab talirinetreatment discontinuation. All the AEs summarized in 
tables are TEAEs, except related AEs or unless otherwise indicated.All AEs will be coded by 
SOC, MedDRA PT, andseverity grade using NCI CTCAE. All recorded AEs will be included in 
the data listings.
A summary table of number and percent of thefollowingAE categories will be provided by 
treatment or dose level and total as follows:
• Pre-existing AEs
• All TEAEs
• TEAEsrelated to vadastuximab talirineor placebo 
• TEAEs related to azacitidinetreatment
• TEAEs with outcome of death
• Treatment-emergent SAEs
• Treatment-emergent SAEs related to vadastuximab talirineor placebo 
• Treatment-emergent SAEs related to azacitidinetreatment


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• TEAEs leading to dose delay of vadastuximab talirineor placebo treatment
• TEAEs leading to dose delay of azacitidinetreatment
• TEAEs leading to dose interruption (full dose received) of vadastuximab talirineor 
placebo treatment
• TEAEs leading to dose interruption (full dose received) of azacitidinetreatment
• TEAEs leading to dose being stopped early (full dose not received) of vadastuximab 
talirineor placebo treatment
• TEAEs leading to dose being stopped early (full dose not received) of azacitidine
treatment
• TEAEs leading to dose reduction of vadastuximab talirineor placebo treatment
• TEAEs leading to dose reduction of azacitidinetreatment
• TEAEs leading to treatment discontinuation
• Treatment-emergent SAEs leading to treatment discontinuation
• Vadastuximab Talirine-related TEAEs leading to treatment discontinuation
• Azacitidine-related TEAEs leading to treatment discontinuation
• Grade 3-5 TEAEs
• Grade 3-5 vadastuximab talirineor placebo treatment-related TEAEs
• Grade 3-5 azacitidinetreatment-related TEAEs
• Infusion-related reaction TEAEs
All the above categories of AEs as well as TEAEs that started during infusion andTEAEs that 
started within 24 hours post infusionwill be displayed by descending frequency of PT by total. 
TEAEs will be summarizedby SOC, PT by treatment or dose level,and total. TEAEs will also 
be summarized by SOC, PT, maximum severity, treatment or dose level, and total. The listings 
include subjects with TEAE leading to treatment discontinuation. All AEs (including non-
treatment-emergentevents) recorded on the CRF will be listed.
9.6.1.3Deaths and Serious Adverse Events
The number of total deaths (see definition in Section 5), deaths that occur within 30 days of last 
vadastuximab talirinetreatment, and deaths that occur more than 30 days after last vadastuximab 
talirinetreatment as well as the relationship to disease will be summarized bytreatment ordose 
level and total.. The number and percentage of subjectswho died will be summarized by 
category of disease related or not. They will be also summarized in the same way and stratified 
by death date within or after 30 days of last vadastuximab talirinedose.
The 30-day and 60-day mortality rates(see definition in Section 5) and the associated 90% CIs 
will be summarized by treatment group.
Death information will be listed by subject.Additionally, listingsof AEs leading to deathand 
SAEswill be generated.
9.6.2Laboratory Data
Hematology laboratory parameters include white bloodcell count, red blood cell count, 
hemoglobin, hematocrit and platelets, and the differential includes: neutrophils, lymphocytes, 
monocytes, eosinophils, and basophils. 


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The chemistry tests  includes: Albumin, alkaline phosphatase (ALP), alanine aminotransferase 
(ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), calcium, creatinine, 
chloride, ferritin, lactate dehydrogenase (LDH), phosphorus, potassium, sodium, total bilirubin, 
uric acidand lipase, amylase, and hemoglobin A1c (at screening only)andCreatinine Clearance 
as estimated by the central lab asGlomerular Filtration Rate.
Inflammatory serologiesinclude: C-reactive protein (CRP), C3, and C4.
Specialty autoimmune serologiesinclude:Anti-neutrophil cytoplasmic antibodies (ANCA), 
anti-double-stranded DNA (anti-dsDNA), quantitative immunoglobulins (IgM, IgG, IgA), 
rheumatoid factor (RF), antinuclear antibodies (ANA), and Direct Coomb’s.
Laboratory data values will be converted to standard units by conversion programming. A list of 
Standard units used to present laboratory data is provided in Appendix 2.
Where laboratory values are categorized into NCI CTCAE version 4.03 grades, the categories 
are defined according to the criteria available on the following website:
http://evs.nci.nih.gov/ftp1/CTCAE/About.html
NCI CTCAE grades will be applied for the following lab parameters (given in Appendix 3).
Laboratory measurements that are within their institutional limits of normal and are not graded as 
1-4, per the CTCAE, will be summarized as “Grade 0,” which is defined as normal.
Hematology: White blood cell (WBC)count with 5-part differential (neutrophils, lymphocytes, 
monocytes, eosinophils, and basophils), red blood cell count, platelet count, hemoglobin, and 
hematocrit.
Chemistry: Albumin, alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), blood urea nitrogen (BUN), calcium, creatinine, chloride, ferritin, 
lactate dehydrogenase (LDH), phosphorus, potassium, sodium, total bilirubin, uric acid, lipase, 
and amylase).
Clinical laboratory data (hematology, complete blood count [CBC] with differential,serum 
chemistry, inflammatory serologies, and specialty autoimmune serologies) will be presented 
graphically (mean and standard deviation) for selected laboratory tests, by treatment or dose 
level and scheduled visit. Summary statistics may be tabulated where appropriate. The worst 
post-baseline NCI CTCAE v4.03 will be presented by treatment or dose level and total for each 
laboratory test. Subjectswith at least one on-study measurement for each laboratory parameter 
will be included, regardless of whether or not a baseline assessment is present.
Laboratory results and NCI CTCAE grades for hematology, and serum chemistry will be 
presented in data listings. Normal ranges will be documented and out-of-range values will be
flagged by subjectlistings of grade 3 or higher abnormal lab results.Continuous summaries will
be presented by clinical laboratory results, clinical visit, treatment group or dose level and study 
portion for actual results and changes from baseline. A shift table from baseline to worst 
observed post-baseline measure will also be presented.


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9.6.3ECOG Performance Status
Shifts from baseline to the best and worst post-baseline score will be tabulated bytreatment or
dose level.
A by-subject listing of ECOG performance status will be generated.
9.6.4Physical Examinations, Electrocardiogram, and Other Observations Related to Safety
Clinically significant findings observed during physical examinations will be recorded on the AE 
and pre-existing condition CRFs. No analyses for physical examinations will be performed.
By-subject listings of weight, height ,electrocardiogram (ECG) results, and subsequent cancer-
related therapies will be generated.
10.0Validation
PRA seeks to ensure the quality of the results provided for the study in the form of TFLs, and the 
derived datasets used in their creation, through the following processes:
The entire set of TFLs will be checked for completeness and consistency prior to its delivery to 
the client by the lead analysis programmer, the lead statistician, and a senior level statistician, or
above, who is not a member of the project team.
The PRA validation process will be repeated any time TFLs are redelivered using different data. 
Execution of this validation process will be documented through the study Table of Programs 
that will be provided to Seattle Genetics at study conclusion.




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IPSS
International Prognostic Scoring System
ITT
Intent to Treat
IWG
International Working Group
LDH
Lactate Dehydrogenase
MDS
Myelodysplastic Syndrome
MDSC
Myeloid-Derived Suppressor Cells 
MedDRA
Medical Dictionary for Regulatory Activities
MTD
Maximum Tolerated Dose
NCI
National Cancer Institute 
ORR
Overall Response Rate
OS
Overall Survival
PBMC
Peripheral Blood Mononuclear Cells
PD
Progressive Disease
PFS
Progression Free Survival
PK
Pharmacokinetic
PNH
Paroxysmal Nocturnal Hemoglobinuria
PR
Partial Response
PRO
Patient ReportedOutcome
PT
Preferred Term
QoL
Quality of Life
QLQ
Quality of Life Questionnaire
RDI
Relative Dose Intensity
RF
Rheumatoid Factor
RNA
Ribonucleic Acid
SAP
Statistical Analysis Plan
SAE
Serious Adverse Event
SD
Standard Deviation
SE
Standard Error
SMC
Safety Monitoring Committee
SOC
System Organ Class
TEAE
Treatment-emergent Adverse Event


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TFL
Tables, Listings, and Figures
WBC
White Blood Cell 












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AE start date will be imputed as the minimum of (AEcondition end date*, first dose date 
of investigational agent)
If the month/year is before the month/year of first dose of investigational agent:
AE start date will be imputed as the minimum of (AE condition end date*, last day of the 
month)
If the month/year is after the month/year of first dose of investigational agent:
AE start date will be imputed as the minimum of (AE condition end date*, last day of the 
month)
* only use condition end date if known and full end date is available.
The following algorithm should be used to impute AE condition end dates. The AE records for a 
condition/event should be sorted by the imputed start dates then record position (order of entry 
into the eCRF). After sorting, if any condition end date month/year is greater than any 
subsequent record end date month/year, then change the imputed start day only to end of month. 
Repeat as necessary. 
After sorting the AE records, apply the following rules to partial or missing AE condition end 
dates:
For all records excluding the last chronological record for a condition/event
AE condition end date will be imputed as the start date of the subsequent record
For the last chronological record for a condition/event
If outcome is “recovered/resolved”,”recovered/resolved with sequelae”, or “fatal” apply the 
following: 
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 31stof 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 31stof 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 5Treatment Emergent Adverse Event Programming Guide
Term
Standard Definition
Treatment 
emergent
Any newly occurring or worsening AE, where newly occurring means an AE 
that was not present at baseline. Eg, if the patient had a grade 1 headache at 
baseline that resolved and later had another grade 1 headache, that second 
headache would NOT be considered a TEAE. See below for more algorithm 
details.
Where:
1. Get first dose date/time of any study treatment(the earliest of Azacitidine 
orvadastuximab talirine/placebo)
2. Define baseline AEs as AEs with:
an onset period of (“started before the signing of informed consent”, 
or “started after consent but before the first dose of any study 
treatment”.  If the onset period of the AE is missing, then look for AE 
start date < first dose date (from 1). If AE start date is missing, use AE 
start date imputation rule. 
<AND>
a stop date that is:
≥first dose date <OR>
missing with outcome equal to
recovering/resolving (this outcome may or may not 
have a date with it), or
not recovered/not resolved, or
unknown
Note: AEs with no outcome and missing stop dates 
should be queried. 
Note:  If the event ended on Day 1 (the day of first dose) it will be 
considered a baseline event.
  
3. Define post-baseline AEs as AEs with an onset period of (“started after the 
first dose of any study treatment”.  If the onset period of the AE is missing, 
then look for AE start date >= first dose date (from 1). If AE start date is 
missing, use AE start date imputation rule.
4. Compare post-baseline AEs to baseline AEs using lower level term (LLT). 
If terms match from baseline to post-baseline:
CompareCTC grades. If post-baseline CTC grade is > 
baseline CTC grade, then TEAE=YES. If post-baseline CTC 
grade is <= Baseline CTC grade, then TEAE=NO. 
If there are no matching terms from baseline to post-baseline, then 
TEAE=Yes. 


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If post-baseline AEs are uncoded, then TEAE = Yes. 
NOTE: if TEAE = 1 or . then include in output,i.e. only exclude TEAE= 0 
for “Treatment-emergent” outputs.