Conditions: Leukemia, Myeloid, Acute
Keywords: Leukemia, myeloid, acute DACOGEN Decitabine JNJ-56022473 CLS362
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 326
Healthy volunteers: no

Brief summary:
The primary objective of study Part A is to assess the safety of talacotuzumab (formerly CSL362) monotherapy and confirm the recommended Phase 2 dose (RP2D) in participants with acute myeloid leukemia (AML) for whom experimental therapy is appropriate. The primary objective of study Part B are to assess complete response (CR) rate and overall survival (OS) in participants with AML who are not eligible for intense induction chemotherapy and who are randomly assigned to receive decitabine plus talacotuzumab at the RP2D or decitabine alone.

Detailed description:
This is a 2-part, open-label, multicenter, Phase 2/3 study conducted in participants with AML who are suitable for experimental therapy (Part A) and in participants with untreated AML who are not eligible for intense induction chemotherapy or hematopoeitic stem cell transplantation (HSCT) (Part B). In Study Part A, the safety, pharmacokinetic (PK) and pharmacodynamic (PD) profile will be assessed to confirm the RP2D of 9 milligram per kilogram (mg/kg) talacotuzumab. In Study Part B, participants will be randomized in a 1:1 ratio into either decitabine + talacotuzumab (arm 1) or decitabine alone (arm 2). Blood and bone marrow sampling will be done in Part A and B for disease assessment, PK, PD, and biomarkers will be collected in all participants. Safety will be monitored throughout the study.

Arms:
arm 1: Part A: For Cycle 1 of Part A, participants will receive talacotuzumab on Day 1. Starting from Cycle 2 of Part A, participants may receive decitabine on Day 1, 2, 3, 4, and 5, and talacotuzumab on Day 8 and 22 of a 28-day cycle.

Part B Arm 1: Participants will receive decitabine on Day 1, 2, 3, 4, and 5, and talacotuzumab on Day 8 and 22 of a 28-day cycle. arm 2: Participants in Part B Arm 2 will receive decitabine on Day 1,2, 3, 4 and 5 of a 28-day cycle.

Interventions: intervention 1: Decitabine 20 mg/m^2 intervention 2: Talacotuzumab 9 mg/kg
Intervention descriptions: intervention 1: Decitabine 20 milligram per square meter (mg/\[m\^2\]) from Day 1, 2, 3, 4 and 5 of a 28-day cycle. intervention 2: Talacotuzumab 9 milligram per kilogram mg/kg on Day 8 and 22 of a 28-day cycle.

Protocol document:
Prot_000.pdf: 
1
Status: Approved, Date: 31 October 2017 
Janssen Research & Development*
Clinical Protocol
A Randomized Phase 2/3 Study of DACOGEN® (Decitabine) Plus Talacotuzumab 
(JNJ-56022473; Anti-CD123) Versus DACOGEN (Decitabine) Alone in Patients with AML 
who are not Candidates for Intensive Chemotherapy
Protocol 56022473AML2002; Phase 2/3
Amendment 7
Talacotuzumab (JNJ-56022473)
*Janssen Research & Development is a global organization that operates through different legal entities in 
various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development 
studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen 
Biologics, BV; Janssen-Cilag International NV; Janssen, Inc; Janssen Sciences Ireland UC, or Janssen 
Research & Development, LLC. The term “sponsor” is used throughout the protocol to represent these 
various legal entities; the sponsor is identified on the Contact Information page that accompanies the 
protocol.
This study will be conducted under US Food & Drug Administration IND regulations (21 CFR 
Part 312).
EudraCT NUMBER: 2015-001611-12
Status:
Approved
Date:
31 October 2017
Prepared by:
Janssen Research & Development, a division of Janssen Pharmaceutica NV
EDMS number:
EDMS-ERI-91414970, 10.0
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements. 
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or 
confidential and may not be disclosed unless such disclosure is required by applicable law or regulations. In any 
event, persons to whom the information is disclosed must be informed that the information is privileged or 
confidential and may not be further disclosed by them. These restrictions on disclosure will apply equally to all 
future information supplied to you that is indicated as privileged or confidential.
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Status: Approved, Date: 31 October 2017   
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF ATTACHMENTS............................................................................................................................ 6
LIST OF IN-TEXT TABLES.......................................................................................................................... 6
PROTOCOL AMENDMENTS....................................................................................................................... 7
SYNOPSIS.................................................................................................................................................. 20
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS .................................................................................... 20
OBJECTIVES ............................................................................................................................................. 20
TIME AND EVENTS SCHEDULE – TABLE 1A [PART A]........................................................................ 27
TIME AND EVENTS SCHEDULE – TABLE 1B [PART B] UP TO AND INCLUDING 
AMENDMENT 5................................................................................................................................. 32
TIME AND EVENTS SCHEDULE – TABLE 1C [PART B] DURING AMENDMENT 6............................. 37
TIME AND EVENTS SCHEDULE – TABLE 1D [PART B] FOLLOWING AMENDMENT 7 ..................... 37
TIME AND EVENTS SCHEDULE (PK AND BIOMARKERS) – TABLE 2A [PART A]............................. 38
TIME AND EVENTS SCHEDULE (PK AND BIOMARKERS) – TABLE 2B [PART B] UP TO AND 
INCLUDING AMENDMENT 5 ............................................................................................................ 39
ABBREVIATIONS ...................................................................................................................................... 41
1.
INTRODUCTION................................................................................................................................ 43
1.1.
Talacotuzumab (JNJ-56022473; CSL362): Second Generation Anti-CD123 Antibody ................ 44
1.2.
CSL362 Phase 1 Experience......................................................................................................... 44
1.2.1.
Recommended Phase 2 Dose (RP2D):...................................................................................... 47
1.3.
DACOGEN (decitabine) ................................................................................................................. 48
1.4.
Overall Rationale for the Study...................................................................................................... 49
2.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS........................................................................... 51
2.1.
Objectives and Endpoints .............................................................................................................. 51
2.1.1.
Objectives ................................................................................................................................... 51
2.1.2.
Endpoints.................................................................................................................................... 52
2.2.
Hypothesis ..................................................................................................................................... 53
3.
STUDY DESIGN AND RATIONALE ................................................................................................. 53
3.1.
Overview of Study Design.............................................................................................................. 53
3.2.
Study Design Rationale.................................................................................................................. 57
4.
SUBJECT POPULATION.................................................................................................................. 59
4.1.
Inclusion Criteria ............................................................................................................................ 60
4.2.
Exclusion Criteria ........................................................................................................................... 61
4.3.
Prohibitions and Restrictions ......................................................................................................... 63
5.
TREATMENT ALLOCATION AND BLINDING................................................................................. 63
6.
DOSAGE AND ADMINISTRATION .................................................................................................. 63
6.1.
Dosing Schedule............................................................................................................................ 63
6.1.1.
Part A.......................................................................................................................................... 63
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Status: Approved, Date: 31 October 2017   
6.1.2.
Part B.......................................................................................................................................... 64
6.2.
Decitabine ...................................................................................................................................... 65
6.2.1.
Preparation and Administration of Decitabine ............................................................................ 65
6.2.2.
Decitabine: Premedication.......................................................................................................... 65
6.2.3.
Decitabine Dose Modifications ................................................................................................... 65
6.3.
Talacotuzumab............................................................................................................................... 66
6.3.1.
Preparation and Administration of Talacotuzumab .................................................................... 66
6.3.2.
Talacotuzumab: Premedication .................................................................................................. 66
6.3.3.
Talacotuzumab Dosing Modifications......................................................................................... 67
6.3.4.
Management of Potential Hypersensitivity/ Infusion-related Reactions ..................................... 68
6.3.4.1.
Guidelines for the Interruption of Talacotuzumab Infusion due to Infusion-related 
Reaction................................................................................................................................... 69
7.
TREATMENT COMPLIANCE............................................................................................................ 69
8.
PRESTUDY AND CONCOMITANT THERAPY ................................................................................ 69
8.1.
Permitted Medications and Supportive Therapies ......................................................................... 70
8.2.
Prohibited Therapies...................................................................................................................... 70
8.3.
Subsequent Antineoplastic Therapies ........................................................................................... 70
9.
STUDY EVALUATIONS .................................................................................................................... 71
9.1.
Study Procedures........................................................................................................................... 71
9.1.1.
Overview..................................................................................................................................... 71
9.1.2.
Screening Phase ........................................................................................................................ 72
9.1.3.
Open-Label Treatment Phase .................................................................................................... 72
9.1.4.
Follow-up Phase......................................................................................................................... 72
9.1.5.
Disease Evaluation and Clinical Cutoff....................................................................................... 73
9.2.
Efficacy........................................................................................................................................... 73
9.2.1.
Evaluations ................................................................................................................................. 73
9.2.1.1.
Disease Status ........................................................................................................................ 73
9.3.
Pharmacokinetics and Immunogenicity ......................................................................................... 75
9.3.1.
Evaluations ................................................................................................................................. 75
9.3.2.
Analytical Procedures................................................................................................................. 75
9.3.3.
Pharmacokinetic Parameters ..................................................................................................... 76
9.3.4.
Immunogenicity Assessments .................................................................................................... 76
9.4.
Pharmacokinetic/Pharmacodynamic Evaluations.......................................................................... 77
9.5.
Biomarkers ..................................................................................................................................... 77
9.5.1.
Assessment of Pharmacodynamic Markers (Part A and Part B)................................................ 77
9.5.2.
Assessment of CD123 Expression (Part B)................................................................................ 77
9.5.3.
Minimal Residual Disease Assessment (Part B) ........................................................................ 78
9.5.4.
Immunophenotyping (Part B)...................................................................................................... 78
9.5.5.
Cytokine Analysis ....................................................................................................................... 78
9.6.
Pharmacogenomic (DNA and RNA) Evaluations (Part B) ............................................................. 78
9.7.
Patient-reported Outcomes............................................................................................................ 79
9.7.1.
FACT-Leu ................................................................................................................................... 79
9.7.2.
EQ-5D-5L.................................................................................................................................... 79
9.8.
Medical Resource Utilization.......................................................................................................... 79
9.9.
Safety Evaluations ......................................................................................................................... 80
9.10.
Sample Collection and Handling.................................................................................................... 82
10.
DISCONTINUATION OF STUDY TREATMENT/ WITHDRAWAL FROM STUDY........................... 82
10.1.
Completion ..................................................................................................................................... 82
10.2.
Discontinuation of the Treatment Phase........................................................................................ 83
10.3.
Withdrawal From the Study............................................................................................................ 83
10.4.
Withdrawal From the Use of Samples in Future Research............................................................ 84
11.
STATISTICAL METHODS................................................................................................................. 84
11.1.
Subject Information ........................................................................................................................ 84
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11.2.
Interim and Final Analyses............................................................................................................. 84
11.3.
Sample Size Determination ........................................................................................................... 86
11.4.
Efficacy Analyses ........................................................................................................................... 87
11.5.
Pharmacokinetic Analyses............................................................................................................. 87
11.6.
Immunogenicity Analyses .............................................................................................................. 88
11.7.
Pharmacokinetic/Pharmacodynamic Analyses.............................................................................. 88
11.8.
Biomarker Analyses ....................................................................................................................... 89
11.9.
Pharmacogenomic Analyses ......................................................................................................... 89
11.10.
Patient-reported Outcomes and Medical Resource Utilization ...................................................... 89
11.11.
Safety Analyses ............................................................................................................................. 89
11.12.
Independent Data Monitoring Committee ...................................................................................... 90
12.
ADVERSE EVENT REPORTING ...................................................................................................... 90
12.1.
Definitions ...................................................................................................................................... 91
12.1.1.
Adverse Event Definitions and Classifications ........................................................................... 91
12.1.2.
Attribution Definitions.................................................................................................................. 92
12.1.3.
Severity Criteria .......................................................................................................................... 93
12.2.
Special Reporting Situations.......................................................................................................... 93
12.3.
Procedures..................................................................................................................................... 94
12.3.1.
All Adverse Events...................................................................................................................... 94
12.3.2.
Serious Adverse Events ............................................................................................................. 95
12.3.3.
Pregnancy................................................................................................................................... 96
12.4.
Contacting Sponsor Regarding Safety........................................................................................... 96
13.
PRODUCT QUALITY COMPLAINT HANDLING.............................................................................. 97
13.1.
Procedures..................................................................................................................................... 97
13.2.
Contacting Sponsor Regarding Product Quality ............................................................................ 97
14.
STUDY DRUG INFORMATION......................................................................................................... 97
14.1.
Physical Description of Study Drug(s) ........................................................................................... 97
14.2.
Packaging ...................................................................................................................................... 97
14.3.
Labeling.......................................................................................................................................... 97
14.4.
Preparation, Handling, and Storage............................................................................................... 98
14.5.
Drug Accountability ........................................................................................................................ 98
15.
STUDY-SPECIFIC MATERIALS....................................................................................................... 98
16.
ETHICAL ASPECTS ......................................................................................................................... 99
16.1.
Study-Specific Design Considerations........................................................................................... 99
16.2.
Regulatory Ethics Compliance..................................................................................................... 100
16.2.1.
Investigator Responsibilities ..................................................................................................... 100
16.2.2.
Independent Ethics Committee or Institutional Review Board ................................................. 100
16.2.3.
Informed Consent ..................................................................................................................... 102
16.2.4.
Privacy of Personal Data .......................................................................................................... 103
16.2.5.
Long-Term Retention of Samples for Additional Future Research .......................................... 103
16.2.6.
Country Selection ..................................................................................................................... 104
17.
ADMINISTRATIVE REQUIREMENTS ............................................................................................ 104
17.1.
Protocol Amendments.................................................................................................................. 104
17.2.
Regulatory Documentation .......................................................................................................... 104
17.2.1.
Regulatory Approval/Notification .............................................................................................. 104
17.2.2.
Required Prestudy Documentation........................................................................................... 105
17.3.
Subject Identification, Enrollment, and Screening Logs .............................................................. 106
17.4.
Source Documentation................................................................................................................. 106
17.5.
Case Report Form Completion .................................................................................................... 107
17.6.
Data Quality Assurance/Quality Control ...................................................................................... 108
17.7.
Record Retention ......................................................................................................................... 108
17.8.
Monitoring .................................................................................................................................... 109
17.9.
Study Completion/Termination..................................................................................................... 109
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17.9.1.
Study Completion/ End of Study............................................................................................... 109
17.9.2.
Study Termination..................................................................................................................... 109
17.10.
On-Site Audits .............................................................................................................................. 110
17.11.
Use of Information and Publication.............................................................................................. 110
REFERENCES.......................................................................................................................................... 112
INVESTIGATOR AGREEMENT ............................................................................................................... 122
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Status: Approved, Date: 31 October 2017   
LIST OF ATTACHMENTS
Attachment 1: 
Sample FACT-Leu (Version 4) ................................................................................. 114
Attachment 2: 
Sample EQ-5D-5L .................................................................................................... 117
Attachment 3: 
ECOG Performance Status Score............................................................................ 120
Attachment 4:
Anticipated Events.................................................................................................... 121
LIST OF IN-TEXT TABLES
TABLES
Table 1:
Treatment-Emergent Adverse Events Occurring in 2 or More Subjects in Study 
CSLCT-AML-11-73 ................................................................................................................... 46
Table 2: 
Dosing Schedule for Part A ...................................................................................................... 64
Table 3: 
Dosing Schedule for Part B - Arm 1.......................................................................................... 64
Table 4: 
Dosing Schedule for Part B - Arm 2.......................................................................................... 64
Table 5:
Premedication for Subjects Receiving Talacotuzumab ............................................................ 67
Table 6: 
Response Assessments ........................................................................................................... 74
Table 7:
Overall Statistical Inference ...................................................................................................... 85
Table 8:
Study Continuation Decision Rule, Operating Characteristics ................................................. 86
Table 9:
Sample Size Determination ...................................................................................................... 87
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Status: Approved, Date: 31 October 2017   
PROTOCOL AMENDMENTS
Protocol Version
Issue Date
Original Protocol
06 April 2015
Amendment 1
Amendment 2
Amendment 3
Amendment 4
Amendment 5
14 January 2016
28 June 2016
14 October 2016
29 March 2017
26 April 2017
Amendment 6
02 August 2017
Amendment 7
31 October 2017
Amendments below are listed beginning with the most recent amendment.
Amendment 7 (31 October 2017)
This amendment is considered to be nonsubstantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union, in that it does not significantly 
impact the safety or physical/mental integrity of subjects, nor the scientific value of the study.
The overall reason for the amendment: To further clarify the end of the study, as the end of study data collection
to permit subjects who are deriving benefit from decitabine treatment to continue to receive decitabine after the end 
of study data collection. 
Applicable Section(s)
Description of Change(s)
Rationale: To further clarify the end of the study, as the end of study data collection and to limit the monitoring of 
subjects who continue to receive decitabine to serious adverse events only. 
Synopsis: Overview of 
Study Design; Section 3.1 
Overview of Study Design; 
Section 9.1.4 Follow-up 
Phase; Section 10.1
Completion; Section 14.5 
Drug Accountability;
Section 17.9.1 Study 
Completion/ End of Study
Changed “end of study” to “end of study data collection”. Clarified that for subjects 
who are continuing to derive benefit from decitabine treatment and are continuing to 
receive decitabine, only serious adverse events will be monitored and entered into the 
Company safety repository.   
Rationale: To limit monitoring of subjects who continue to receive decitabine to serious adverse events only.
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Clinical Protocol 56022473AML2002 Amendment 7
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Status: Approved, Date: 31 October 2017   
Applicable Section(s)
Description of Change(s)
Synopsis: Efficacy 
Evaluations, Safety 
Evaluations; Time and 
Events Schedules 1C and 
1D; Section 6.1 Dosing 
Schedule; Section 8 
Prestudy and Concomitant 
Therapy; Section 9 Study 
Evaluations; Section 9.9 
Safety Evaluations; Section 
12.3 Procedures; Section 
16.1 Study-Specific Design 
Considerations
Section 6.2.3 Decitabine 
Dose Modifications
Section 7 Treatment 
Compliance
Modified Time and Events Schedules; Clarified that for subjects who are continuing 
to derive benefit from decitabine treatment and are continuing to receive decitabine, 
only serious adverse events will be monitored and entered into the Company safety 
repository
Deleted sentence requiring consultation with Sponsor to resume decitabine treatment 
following a 28-day dose delay
Added statement that eCRFs will be closed
Amendment 6 (02 August 2017)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment: This amendment is based on Independent Data Monitoring Committee 
(IDMC) recommendation after results from the second interim analysis (final analysis for response endpoints and 
first analysis for overall survival [OS]) were reviewed. The IDMC recommended to close study enrollment and 
stop talacotuzumab treatment due to lack of efficacy in the talacotuzumab arm. Subjects in the combination arm 
should stop treatment of with talacotuzumab and can continue to receive DACOGEN only, in accordance with 
Principal Investigator decision and subject agreement.
Applicable Section(s)
Description of Change(s)
Rationale: Study conduct was changed due to IDMC recommendation after review of results from the second 
interim analysis.
Synopsis: Overview of 
Study Design Part B; 
Section 3.1: Overview of 
Study Design; Section 3.2: 
Study Design Rationale; 
Section 5: Treatment 
Allocation and Blinding; 
Section 6.1.2 Part B; 
Section 16.1: Study-
Specific Design 
Considerations
Enrollment in the study was closed; Subjects receiving talacotuzumab should 
discontinue talacotuzumab treatment and may continue decitabine treatment 
according to Principal Investigator decision and subject agreement.
Rationale: Data collection for ongoing subjects was changed due to changes in study conduct. 
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Talacotuzumab (JNJ-56022473)
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Status: Approved, Date: 31 October 2017   
Applicable Section(s)
Description of Change(s)
Synopsis: Overview of 
Study Design Part B, 
Efficacy Evaluations, Safety 
Evaluations; Time and 
Events Schedules 1B, 1C, 
and 2B; Section 3.1: 
Overview of Study Design; 
Section 3.2: Study Design 
Rationale; Section 9.1.1 
Overview; Section 9.1.3 
Open-label Treatment 
Phase; Section 9.1.4:
Follow-up Phase; Section 
9.2.1 Evaluations; Section 
9.5.2 Assessment of CD123 
Expression; Section 9.9 
Safety Evaluations; Section 
12.3: Procedures; Section 
16.1: Study-Specific Design 
Considerations; 
Added Time and Events Schedule 1C: all subjects will continue to be followed for 
survival and subsequent anti-cancer therapy. Subjects during the treatment phase 
with decitabine will be monitored for serious adverse events.
Rationale: End of study definition and time of final OS analysis was changed due to changes in study conduct.
Synopsis: Overview of 
Study Design, Statistical 
Methods; Section 3.1: 
Overview of Study Design; 
Section 9.1.4: Follow-up 
Phase; Section 9.1.5:
Disease Evaluation and 
Clinical Cut-off; Section 
10.1: Completion; Section 
17.9.1 Study Completion/ 
End of Study
Changed definition of end of study to 270 deaths or 6 months after the last subject 
was enrolled, whichever comes first; Changed time of final OS analysis to 270 
deaths or 6 months after the last subject was enrolled, whichever comes first. 
Amendment 5 (26 April 2017)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union. 
The overall reason for the amendment: This amendment specifies enhanced precautionary measures to 
mitigate infusion-related reactions for subjects receiving talacotuzumab infusion.
Applicable Section(s)
Description of Change(s)
Rationale: To clarify procedures during talacotuzumab infusion to reduce the incidence of infusion-related reactions
Section 6.3.1 Preparation 
and Administration of 
Talacotuzumab
Changed infusion-rate guidance to slow initial infusion rate to 10 mL/hr with a 
maximum rate of 60 mL/hr for the first 4 cycles
Rationale: To add premedications for talacotuzumab infusion to reduce the incidence of infusion-related reactions
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Status: Approved, Date: 31 October 2017   
Applicable Section(s)
Description of Change(s)
Synopsis: Dosage and 
Administration; Section 
6.3.2 Talacotuzumab: 
Premedications
Amended dexamethasone 8 mg from 12 hours prior to infusion to BID approximately 
2 days prior to infusion and approximately 3 hours prior to infusion. Added 
cimetidine
Rationale: To change maximum infusion rates after occurrence of an infusion-related reaction 
Section 6.3.4.1 Guidelines 
for the Interruption of 
Talacotuzumab Infusion 
due to Infusion-Related 
Reaction
Changed the maximum infusion rates following infusion-related reaction to 60 mL/hr 
for Cycles 1 to 4 and 150 ml/hr for subsequent cycles 
Rationale: To increase the maximum volume of blood collected for subjects in the Talacotuzumab + DACOGEN 
arm to account for cytokine sampling
Section 9.1.1 Overview
Increased maximum blood volumes for samples from subjects in the DACOGEN 
plus Talacotuzumab arm
Rationale: To add samples for cytokine analysis to investigate the mechanism of IRRs
Time and Events Schedule 
2B; Section 9.5.5 Cytokine 
Analysis (new section)
Added blood sampling for cytokine analysis
Amendment 4 (29 March 2017)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union. 
The overall reason for the amendment: This amendment specifies new guidance for patient monitoring and 
availability of resuscitation equipment during talacotuzumab infusion.
Applicable Section(s)
Description of Change(s)
Rationale: To clarify procedures during talacotuzumab infusion 
Section 6.3.1 Preparation 
and Administration of 
Talacotuzumab
Added clarification for patient monitoring during talacotuzumab infusion and 
availability of resuscitation equipment due to the occurrence of a fatal event of 
infusion-related reaction during talacotuzumab infusion; changed infusion-rate 
guidance and increased monitoring from 30 minutes to 1 hour after completion of 
infusion
Rationale: To continue ECG monitoring though no safety signal is seen
Time and Events Schedule 
1B; Section 9.9 Safety 
Evaluations
Removed language to stop ECG monitoring if no safety signal is seen
Rationale: To clarify biomarker and cytogenetic testing of bone marrow samples
Time and Events Schedule 
1B
Added language to clarify biomarker and cytogenetic testing to be performed per 
local standard of care at screening, suspected CR/CRi, and every disease assessment 
until, relapse or EOT 
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Status: Approved, Date: 31 October 2017   
Amendment 3 (14 October 2016)
This amendment is considered to be nonsubstantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union, in that it does not significantly 
impact the safety or physical/mental integrity of subjects, nor the scientific value of the study.
The overall reason for the amendment: This amendment specifies additional required premedication prior 
to talacotuzumab infusion in order to reduce the risk and severity of infusion-related reactions.
Applicable Section(s)
Description of Change(s)
Rationale: To reduce the risk and severity of infusion-related reactions.
Synopsis; Section 6.3.2 
Talacotuzumab: 
Premedication; Section 
16.1 Study Specific 
Design Considerations
Added dexamethasone, montelukast, and specified diphenhydramine as 
premedications prior to infusion of talacotuzumab; clarified premedication procedures
Rationale: To change the name of JNJ-56022473 to talacotuzumab
Throughout the protocol
Changed name of JNJ-56022473 to talacotuzumab
Rationale: To clarify when disease evaluations are performed
Time and Events Schedule 
1B
Changed disease evaluation from “at the end of each cycle” to every 2 cycles between 
Day 14 and Day 28 and at time of suspected CR /CRi and at time of suspected
treatment failure or relapse from CR/CRi.
Rationale: To provide clarity for biomarker sampling 
Time and Events 
Schedules 1B and 2B
Clarified table for biomarker sampling 
Rationale: To correct reasoning for leukopheresis and hydroxyurea treatment
Section 4.1 Inclusion 
Criteria #3
Changed wording from “leukopheresis or hydroxyurea is permitted to decrease blast 
count” to “permitted to decrease WBC count”
Rationale: To clarify that prior systemic therapies for MDS or MPN are collected at screening
Section 8: Prestudy and 
Concomitant Therapies
Added language that prior therapies for MDS and MPN should be collected during 
screening
Rationale: To align with previous amendment changing inclusion criterion 1
Section 4.2: Exclusion 
Criteria; Attachments
Deleted “New York Heart Association class 3 or 4 congestive heart failure scale” 
from exclusion criteria to align with inclusion criterion 1; Deleted Attachment 3
Rationale: To correct definition of end of study
Section 10.1 Completion; 
Section 17.9.1 Study 
Completion/ End of Study
Corrected definition of end of study to when 270 deaths have occurred or 6 months 
after the last subject is randomized, whichever occurs later.
Rationale: Minor errors were noted and corrected
Throughout the protocol
Minor grammatical, formatting, or spelling changes were made.
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Status: Approved, Date: 31 October 2017   
Amendment 2 (28 June 2016)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment: This amendment was prepared in response to health authority review 
and clarifies inclusion criteria and the recommended dose of preinfusion medications prior to JNJ-56022473 
administration.
Applicable Section(s)
Description of Change(s)
Rationale: To allow flexibility in scheduling due to patient / provider availabilities
Time and Events Schedule 
1B; Section 6.1.2 Part B
Added a ± 48 hour window (unless otherwise indicated) for Day 1 procedures
For JNJ-56022473 administration window is ± 24 hours
Rationale: To provide clarity regarding sponsor oversight of subjects prior to inclusion
Time and Events Schedule 
1B
Added sponsor review of key eligibility data required prior to randomization
Rationale: To align with modifications that will be made to eligibility
Time and Events Schedule 
1B
Laboratory assessments for HBV surface antigen and hepatitis C antibodies removed 
and replaced by active hepatitis or history of HIV
Rationale: Bone marrow block no longer required at screening
Time and Events Schedule 
1B; Section 9.5.2 
Assessment of CD123 
Expression (part B)
Removed requirement for a bone marrow block at screening, and bone marrow 
aspirate/biopsy to be collected within 6 weeks of randomization; however, bone 
marrow samples are collected as indicated in the Time and Events schedule for central 
analysis
Rationale: To clarify the role of the IDMC and Sponsor in overall study decisions
Synopsis Overview of 
Study Design Part B; 
Section 3.1 Overview of 
Study Design Part B
Clarified IDMC role and deleted wording that implied the IDMC was to decide upon 
study conduct; deleted repeated sentence in third paragraph
Rationale: To add objective per health authority feedback
Synopsis, Secondary 
Objectives; Section 2.1.1 
Objectives
Added rate of CR plus MRD negative CRi as an objective
Rationale: To add endpoint per health authority feedback
Synopsis, Secondary 
Endpoints; Section 2.1.2 
Endpoints; Section 11.4 
Efficacy Analyses
Added rate of CR plus MRD negative CRi as an endpoint
Rationale: Added inclusion criteria to define subjects ineligible for intensive chemotherapy 
Synopsis Subject 
Population Part B; Section 
4.1 Inclusion Criteria, 
Criterion 3.1
Added inclusion criteria to define subjects ineligible for intensive chemotherapy; 
aligned other criteria to agree with additions
Rationale: Aligned criteria to agree with added inclusion criteria
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Talacotuzumab (JNJ-56022473)
Clinical Protocol 56022473AML2002 Amendment 7
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Status: Approved, Date: 31 October 2017   
Applicable Section(s)
Description of Change(s)
Section 4.2 Exclusion 
Criteria
Clarified criteria regarding other malignancies, removed chronic respiratory disease 
and LVEF <45% to align with modifications to inclusion criteria
Rationale: To define exclusion of subjects who have an active infection requiring treatment
Section 4.2 Exclusion 
Criteria
Clarified criteria regarding infection 
Rationale: There is no known hepatotoxicity or hepatitis reactivation with JNJ-56022473, so medical history 
of these conditions is acceptable for study entry
Section 4.2 Exclusion 
Criteria
Exclusion criteria changed to active liver disease or hepatitis infection
Rationale: To agree with language and format of protocol template
Section 4.3 Prohibitions 
and Restrictions
Added this section
Rationale: To increase monitoring and minimize the severity of infusion reactions
Synopsis, Dosage and 
Administration; Section 
6.3.1 Preparation and 
Administration of JNJ-
56022473; Section 6.3.2 
JNJ-56022473: 
Premedication
Section 6.3.4.1 Guidelines 
for the Interruption of JNJ-
56022473 Infusion due to 
Infusion-related Reactions
Clarified maximum rate of infusion and monitoring of subjects; Increased mandatory 
premedication to 100 mg methylprednisolone and clarified number of cycles for 
premedication; 
Rationale: To clarify JNJ-56022473 dosing modifications
Section 6.3.3 JNJ-
56022473 Dosing 
Modifications
Clarified text regarding JNJ-56022473 dose delays
Rationale: To provide clarity for recommended supportive therapies
Section 8.1 Permitted 
Medications and 
Supportive Therapies 
Clarified wording regarding growth factor and anti-infective use
Rationale: To clarify that plasmapheresis must be discontinued prior to start of study therapy
Section 8.2 Prohibited 
Therapies
Clarified that plasmapheresis must be discontinued prior to start of study therapy
Rationale: Corrected blood volumes collected during the study
Section 9.1.1. Overview
Changed blood volumes to agree with section 16.1
Rationale: To provide the definition of end of study
Section 9.1.4 Follow-up 
Phase
End of study was redefined as when 270 deaths have occurred or 6 months after the 
last subject is randomized
Rationale: To ensure discontinuation criteria defined in the protocol are met
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Talacotuzumab (JNJ-56022473)
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Status: Approved, Date: 31 October 2017   
Applicable Section(s)
Description of Change(s)
Section 9.2.1.1 Disease 
Status; Section 10.2 
Discontinuation of the
Treatment Phase
Added text to ensure that criteria for discontinuation of subjects is reviewed by the 
Sponsor prior to discontinuation 
Rationale: Proteomics evaluations s will not be performed
Section 9.5.5 Proteomics 
Evaluation (Part B)
Deleted this section
Rationale: To align with modified eligibility criteria
Section 9.9 Safety 
Evaluations
Removed HBsAg and hepatitis C virus antibody testing at screening
Rationale: To provide clarity and to document the level of sponsor oversight
Section 10.2 
Discontinuation of the 
Treatment Phase
Added text that all treatment discontinuations will be reviewed and approved by the 
Sponsor
Rationale: To conform to health authority feedback
Synopsis, Statistical 
Methods, Section 11.2 
Interim and Final 
Analyses
Clarified role of the IDMC. Modified text and statistical parameters for efficacy 
analyses 
Rationale: To clarify the composition and role of the IDMC
Section 11.12 Independent 
Data Monitoring 
Committee
Added text defining the IDMC and function of the IDMC
Rationale: To provide anticipated events
Section 12.3.1 All 
Adverse Events; 
Attachment 4
Added language regarding anticipated adverse events
Rationale: To provide reference for suitable bloods volumes withdrawn during the study
Section 16.1 Study-
specific Design 
Considerations
Removed blood volumes withdrawn for the study; added reference for suitability of 
blood volume withdrawn
Rationale: Minor errors were noted and corrected
Throughout the protocol
Minor grammatical, formatting, or spelling changes were made.
Amendment 1 (14 January 2016)
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Talacotuzumab (JNJ-56022473)
Clinical Protocol 56022473AML2002 Amendment 7
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Status: Approved, Date: 31 October 2017   
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment: The study was originally designed as a Phase 2 study with a total
of 120 subjects and a primary endpoint of event-free survival (EFS). An interim analysis with 45 EFS events was 
planned in the original study to determine if the study would be continued toward the end with 120 subjects. This 
amendment changes the primary endpoint of the study to 2 primary endpoints of complete response (CR) rate and 
overall survival (OS) and up to 400 subjects enrolled. An interim analysis is included in the amended protocol
after 80 subjects have been randomized (approximately 40 subjects per arm) and followed for 4 months. The 
results of this interim analysis will provide guidance for a decision to continue enrollment to 400 subjects or stop 
enrollment.
Applicable Section(s)
Description of Change(s)
Rationale: To emphasize study endpoints
Synopsis Objectives, 
Endpoints and 
Hypothesis; Section 2.1 
Objectives and Endpoints
Moved subsection that defined study endpoints
Rationale: To advance development of JNJ-56022473 
Synopsis Objectives and 
Endpoints; Section 2.1 
Objectives and 
Endpoints; Section 9.5.3 
Minimal; Residual 
Disease Assessment (Part 
B)
Changed primary and secondary objectives and endpoints for Part B of the study; 
Added minimal residual disease evaluation as a secondary endpoint
Rationale: To change the hypothesis based on changes in primary objectives
Synopsis Hypothesis; 
Section 2.2 Hypothesis
Changed the hypothesis to reflect complete response rate and overall survival as 
primary objectives
Rationale: To change the timing of and agent used for premedication for subjects who receive JNJ-56022473
Synopsis Dosage and 
Administration; Section 
6.3.2 JNJ-56022473 
Premedication; Section 
16.1 Study Specific 
Design Considerations
The use of hydrocortisone as a premedication agent was switched to 
methylprednisolone for the first 2 cycles of JNJ-56022473 treatment
Rationale: To change the study design to permit accelerated development of JNJ-56022473 if predefined
statistical criteria are met
Synopsis Overview of 
Study Design; Section 3.1 
Overview of Study 
Design; Section 11.2 
Interim and Final 
Analyses
Added details of a revised design to continue Part B; limited Study Evaluation Team 
evaluations to Part A; Added Independent Data Monitoring Committee participation 
in Part B; Added independent central review of efficacy
Rationale: It can take 2 to 4 weeks for cytogenetic results. Newly diagnosed patients cannot wait this long to 
begin treatment for acute myeloid leukemia (AML). The remaining stratification factors (Eastern Cooperative 
Oncology group [ECOG] performance status score and primary vs secondary AML) adequately account for 
factors that influence outcomes in patients with AML.
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Talacotuzumab (JNJ-56022473)
Clinical Protocol 56022473AML2002 Amendment 7
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Status: Approved, Date: 31 October 2017   
Applicable Section(s)
Description of Change(s)
Synopsis Overview of 
Study Design; Section 3.1 
Overview of Study 
Design; Section 3.2 Study 
Design Rationale; Section 
5 Treatment Allocation 
and Blinding; Section 
11.4 Efficacy Analyses
Removed cytogenetic (adverse vs other) as a stratification factor
Rationale: To describe interim and final analyses for Part B of the study 
Synopsis Statistical 
Methods; Section 11.2 
Interim and Final 
Analyses
Described statistical decision making rules for Part B of the study
Rationale: To update Time and Events Schedule 1B based on investigator feedback and consistency with rest of 
protocol
Time and Events 
Schedule 1B; Section 9.9 
Safety Evaluations 
Expanded the window for pre-dosing assessments for each cycle from 48 hours to 3 
days; added Medical Resource Utilization determination as a procedure under Safety 
Assessments; added peripheral blast counts to Hematology Laboratory Assessments; 
clarified that the diagnostic bone marrow block required at screening may be from a 
historic sample; added a procedure that defines disease evaluation under Disease 
Evaluations; changed frequency of Day 1 bone marrow assessments from Cycle 4 to 
every second cycle starting at Cycle 2.
Rationale: To expand cardiac testing of subjects
Time and Events
Schedule 1B; Section
9.9 Safety Evaluations
Added LVEF determination at end-of-treatment; Added ECG monitoring during the 
study for both treatment arms and at end-of-treatment.
Rationale: To clarify criteria and measurement of LVEF
Time and Events
Schedule 1A and 1B; 
Section 4.2 Exclusion 
Criteria
Added LVEF determination as clinically indicated during the study to the Time and 
Events Schedule for consistency with Section 9.9; revised exclusion criterion #12 so 
that only LVEF<45% is excluded 
Rationale: To clarify Adverse event information collected during the follow-up phase
Time and Events 
Schedule 1A and 1B, 
Section 9.9 Safety 
Evaluations, Section 
12.3.1 All Adverse 
Events
Drug-related ≥Grade 3 adverse events and drug-related serious adverse events will 
be followed until resolution during the follow-up phase
Rationale: To clarify source documentation for eligibility criteria
Time and Events 
Schedules 1A and 1B 
Added note regarding source documentation and to assess the clinical status of the 
subject again prior to the first dose of study drug
Rationale: To Clarify Disease Evaluations to include clinical presentation
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Talacotuzumab (JNJ-56022473)
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Status: Approved, Date: 31 October 2017   
Applicable Section(s)
Description of Change(s)
Synopsis Efficacy 
Evaluations; Time and 
Events Schedule 1B;
Section 3.1 Overview of 
Study Design; Section 
9.2.1 Efficacy 
Evaluations
Added clinical presentation to disease assessments evaluated for efficacy; clarified 
details for bone marrow biopsy/aspirate
Rationale: To update Time and Events Schedule 2B to remove unneeded pharmacokinetic (PK) and biomarker
samples
Time and Events 
Schedule 2B; Section 
9.5.4 
Immunophenotyping 
(Part B)
Removed the JNJ-56022473 PK sample on Day 1 Cycle 4; limited PK sampling 
after 120 subjects have enrolled; removed samples for testing NK cell directed 
ADCC and T-cell mediated cytotoxicity assay
Rationale: To update safety information for CSL362
Section 1.2 CSL362 
Phase 1 Experience
Updated safety information with a clinical cut-off date of 28 January 2015
Rationale: To change the rationale to accommodate the change in primary objectives and endpoints
Section 3.2 Study Design 
Rationale
Changed rationale for primary endpoints
Rationale: To Provide a statement that waivers to eligibility criteria are not allowed
Section 4 Subject 
Population
Added statement: Waivers are not allowed.
Rationale: To clarify inclusion criteria for blood cell counts
Section 4.1 Inclusion 
Criteria
Clarified that the platelet count of ≥ 10 X 109/L was with or without transfusion; 
defined the white blood cell count criteria as ≤ 40 x 109/L
Rationale: To Expand the exception to exclusion criterion to include patients with myelofibrosis 
Section 4.2 Exclusion 
Criteria
Deleted repetitive criterion of Hepatitis B or C virus positivity 
Rationale: To clarify treatment discontinuation for Part B
Section 6.12 Part B; 
Section 6.23 Decitabine 
Dose Modifications; 
Section 6.33 JNJ-
56022473 Dose 
Modifications; Section 
9.1.3 Open-Label 
Treatment Phase; Section 
10.2 Discontinuation of 
the Treatment Phase
Clarified that subjects in Arm 1 (Part B) could discontinue 1 drug treatment and 
continue treatment with the other agent 
Rationale: To Extend the maximum delay of decitabine dosing to 28 days
Section 6.2.3 Decitabine 
Dose Modifications
Changed the maximum delay for decitabine treatment to 28 days from 14 days 
Rationale: To further define the administration of JNJ-56022473 to minimize infusion-related reactions
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Talacotuzumab (JNJ-56022473)
Clinical Protocol 56022473AML2002 Amendment 7
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Status: Approved, Date: 31 October 2017   
Applicable Section(s)
Description of Change(s)
Section 6.3.1 Preparation 
and Administration of 
JNJ-56022473
Clarified that JNJ-56022473 dosing is based on the weight of the subject at the Day 
1 Assessment of each cycle; Clarified that the volume of infusion is 250 mL; 
Defined the infusion rates for JNJ-56022473 
Rationale: To Change requirements for dose modifications due to Grade 4 hematological toxicity based upon 
investigator feedback
Section 6.3.3 JNJ-
56022473 Dosing 
Modifications
Changed the requirement for dose delays of JNJ-56022473 due to hematological 
toxicity from not responsive to supportive care to per investigator judgment 
Rationale: To Clarify the clinical management of infusion-related reactions and JNJ-56022473 dose 
modifications due to infusion-related reactions
Section 6.3.4 
Management of Potential 
Hypersensitivity/ 
Infusion-related 
Reactions
Defined the recommended management of infusion-related reactions and 
modifications for JNJ-56022473 treatment
Rationale: To expand permitted medications for febrile neutropenia
Section 8.1 Permitted 
Medications and 
Supportive Therapies
Added recommendations for growth factor use
Rationale: To allow vaccination with killed virus vaccines 
Section 8.2 Prohibited 
Therapies
Restricted prohibited therapies to live attenuated vaccination
Rationale: To describe clinical cutoffs in Part B of the study
Section 9.1.5 Disease 
Evaluation and Clinical 
Cutoff
Added clinical cutoff in Part B of the study
Rationale: To define an Independent Data Monitoring Committee
Section 11.12 
Independent Data 
Monitoring Committee; 
Section 16.1 Study-
Specific Design 
Considerations
Added details for a Data Monitoring Committee
Rationale: To modify sample size for revised study design
Section 11.3 Sample Size 
Determination
Described operational characteristics for Part B of the study
Rationale: To describe statistical analyses for CR, OS primary endpoints
Section 11.4 Efficacy 
Analyses
Described analyses for primary endpoints for Part B of the study
Rationale: To define immunogenicity results formats
Section 11.5 
Immunogenicity Analyses
Added description of immunogenicity analysis result formats
Rationale: Provide description of methods for adverse event detection
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Talacotuzumab (JNJ-56022473)
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Status: Approved, Date: 31 October 2017   
Applicable Section(s)
Description of Change(s)
Section 12 Adverse Event 
Reporting
Added subsection of methods of detecting adverse events and serious adverse events
Rationale: To Provide an eSource system as an alternate data source for clinical data
Section 17.4 Source 
Documentation
Defined the eSource system
Rationale: To clarify language regarding Case Report Form completion
Section 17.5 Case Report 
Form Completion
Clarified language regarding Case Report Form completion 
Rationale: Minor errors were noted and corrected
Throughout the protocol
Minor grammatical, formatting, or spelling changes were made.
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Talacotuzumab (JNJ-56022473)
Clinical Protocol 56022473AML2002 Amendment 7
20
Status: Approved, Date: 31 October 2017   
SYNOPSIS
A Randomized Phase 2/3 Study of DACOGEN® (Decitabine) Plus Talacotuzumab (JNJ-56022473; Anti-
CD123) Versus DACOGEN (Decitabine) Alone in Patients with Acute Myeloid Leukemia (AML) who 
are not Candidates for Intensive Chemotherapy
EudraCT NUMBER: 2015-011611-12
DACOGEN (decitabine) is a hypomethylating agent approved in the European Union and 21 other
countries for the treatment of patients with AML who are over the age of 65 and who are not candidates 
for intensive chemotherapy.
DACOGEN (decitabine) is also recommended in the National 
Comprehensive Cancer Network (NCCN) Guidelines in the USA for the treatment of patients with AML.
For the purposes of this protocol the generic name decitabine will be used hereafter to refer to the agent to 
be used in this study.
Talacotuzumab, previously known as JNJ-56022473 or CSL-362, is a fully humanized monoclonal IgG1 
antibody directed against the α-subunit of the interleukin-3 (IL-3) receptor also known as the CD123 
antigen. 
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS
OBJECTIVES
Primary Objectives
Part A
The primary objectives of Part A of the study are to assess safety and to confirm the recommended 
Phase 2 dose (RP2D) of talacotuzumab monotherapy.
Part B
The primary objectives of Part B of the study are to assess complete response (CR) rate and overall 
survival (OS) in patients with previously untreated AML who are not eligible for intense induction 
chemotherapy and who are randomly assigned to receive decitabine plus talacotuzumab at the RP2D or 
decitabine alone. 
Secondary Objectives
Part B
The secondary objectives are to assess the event-free survival (EFS), the overall response rate (ORR, 
defined as the rate of CR + complete response with incomplete blood count recovery [CRi]), the rate of 
CR plus MRD negative CRi, relapse-free survival (RFS), time to and duration of response, and the safety 
profile of study treatments; to assess the pharmacokinetics (PK) of decitabine and talacotuzumab when 
used alone or in combination; to assess the immunogenicity of talacotuzumab in combination with 
decitabine, to evaluate minimal residual disease (MRD) and to evaluate patient-reported outcomes 
measures (PRO) using the FACT LEU and EQ-5D-5L instruments.
ENDPOINTS
Part A

To assess safety and determine dose-limiting toxicities (DLTs)
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Talacotuzumab (JNJ-56022473)
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Status: Approved, Date: 31 October 2017   
Part B
2 Primary Endpoints (Part B)

CR rate

Overall survival (OS)
Secondary Endpoints (Part B)

EFS, defined as the time from randomization to treatment failure, relapse from CR/CRi, or death 
from any cause, whichever occurs first. Treatment failure is defined as >25% absolute increase in the 
bone marrow blast count from baseline to the present assessment.

ORR (CR + CRi);

Rate of CR plus MRD negative CRi;

Time to response, defined for subjects who achieved best response of CR or CRi as time from 
randomization to achieving the best response;

Duration of response, defined for subjects who achieved best response of CR or CRi as time from 
achieving CR or CRi to relapse;

Relapse-free survival (RFS) defined for subjects who achieved CR or CRi as the time from achieving 
CR or CRi to disease relapse or death from any cause;

Safety profile;

Pharmacokinetics; 

Immunogenicity;

MRD;

Patient-reported outcomes (PROs) using the FACT-Leu and EQ 5D 5L. 
Exploratory Endpoints (Part B)

Pharmacokinetic/pharmacodynamic relationships associated with biomarkers, pharmacodynamic 
(PD) markers and clinical end points;

To explore biomarkers associated with clinical response;

Medical resource utilization.
Hypothesis
In patients with untreated AML who are not eligible for intense induction chemotherapy it is 
hypothesized that treatment with a combination regimen of decitabine and talacotuzumab as compared 
with decitabine alone will improve the CR rate or extend survival or both.
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Talacotuzumab (JNJ-56022473)
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Status: Approved, Date: 31 October 2017   
OVERVIEW OF STUDY DESIGN
Part A
This is an open label, multicenter study; in Part A, the RP2D of talacotuzumab monotherapy will be 
confirmed in subjects with AML for whom experimental therapy is appropriate (as assessed by their 
treating physician). Part A will include approximately 6 subjects to assess the clinical safety and 
pharmacokinetics/pharmacodynamics (PK/PD) of talacotuzumab as part of the comparability testing 
package for talacotuzumab, a monoclonal antibody with the same amino acid sequence as CSL362, but 
produced in a different cell line with a different process. A prior Phase 1 study of CSL362 assessed the 
safety and PK profile and established the RP2D as 9 mg/kg. Comparability testing of talacotuzumab and 
CSL362 has shown the antibodies to behave similarly in biophysical, biochemical, and preclinical 
assessments. Pharmacodynamic studies in cynomolgus monkeys showed similar levels of biological 
activity between CSL362 and talacotuzumab (ie, basophil and plasmacytoid dendritic cell [pDC]
depletion; natural killer [NK] cell number and activity). Additionally, the PK profiles of talacotuzumab
following 30 and 100 mg/kg IV dosing of cynomolgus monkeys are highly similar to those of CSL362. 
Following the first weekly IV dose, mean Cmax and AUC0-167h of talacotuzumab are 91% and 94% of those 
observed for CSL362, respectively. Further detail regarding preclinical studies of CSL362 and 
talacotuzumab is provided in the JNJ-56022473 Investigator’s Brochure.  
Subject participation will include a Screening Phase, a Treatment Phase, and a Follow-up Phase. During 
Part A, the safety, PK, and PD of talacotuzumab will be assessed. After 1 dose of single-agent 
talacotuzumab and a 14-day post-dose assessment period, subjects will be assessed for safety to confirm
the RP2D and will then start subsequent cycles of combination therapy of decitabine + talacotuzumab
using the same dosing schedule described for Part B. 
Part B
In Part B, subjects with AML who are not candidates for intensive chemotherapy will be assigned 
randomly in a 1:1 ratio to receive decitabine + talacotuzumab (Arm 1) or decitabine alone (Arm 2). 
Approximately 400 subjects will be enrolled in Part B.
Part B of the study will begin after the RP2D of talacotuzumab is confirmed in Part A. Randomization 
will be stratified by Eastern Cooperative Oncology Group (ECOG) performance status (0-1 versus 2) and
type of AML (de novo versus secondary). Subjects in both treatment arms will receive decitabine
(20 mg/m2 per day) on Days 1 to 5 of each 28-day cycle. For subjects randomized to the decitabine + 
talacotuzumab arm, talacotuzumab will be administered intravenously (IV) at the RP2D determined in 
Part A on Day 8 and Day 22 every 28 days. Treatment is continued until treatment failure, relapse from 
CR or CRi, unacceptable toxicity, or death.
Part B is designed to be a seamless Phase 2/3 study with 2 primary endpoints, CR rate and OS. The study 
will have 3 interim analyses. The first interim analysis will occur after approximately 80 subjects 
(40 subjects per arm) have been randomized and followed for at least 4 months. Guided by predefined 
statistical criteria based on CR and CR+CRi the study will continue enrollment to the prespecified Phase 
3 sample size of 400 subjects or discontinues enrollment. Approximately 120 subjects are expected to 
have been randomized by the time the outcome of the interim analysis is available; this is the estimated 
Phase 2 sample size. No changes in design elements are planned based on this interim analysis.
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Talacotuzumab (JNJ-56022473)
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Status: Approved, Date: 31 October 2017   
If the enrollment continues to 400 subjects (approximately 200 subjects per arm), the pre-specified design 
elements are:

A second interim analysis occurs after approximately 160 subjects (approximately 80 subjects per 
arm) have been randomized and followed for at least 4 months; this is the final analysis for CR and 
the first interim analysis for OS. The study will not be stopped on the basis of the CR results;

A third interim analysis (ie, the second interim analysis of OS) will be conducted when 180 deaths 
have occurred;

The final analysis of OS will take place when 270 deaths have occurred or 6 months after the last 
subject was enrolled whichever occurs first.
If the study stops enrollment at the first interim analysis, it is expected that approximately 120 subjects 
will have been randomized. These subjects will continue to be followed. The clinical cut-off in this case 
will be when the pre-specified 90 EFS events have occurred.
Safety reviews will be performed in Part A and Part B. The safety assessments in Part A will occur prior 
to the initiation of Part B. This will include safety and available PK and PD data from single-agent 
talacotuzumab and the preliminary safety of the combination of decitabine + talacotuzumab. A Study 
Evaluation Team (SET) will monitor safety and study conduct on an ongoing basis during Part A of the 
study.
An Independent Data Monitoring Committee (IDMC) will be established to evaluate safety and efficacy 
data collected during Part B of the study as described in Section 3.1.
In addition to evaluations by investigators, disease status will be reviewed and determined by independent 
central review in a blinded fashion. Disease status based on independent central review will be the 
primary source for efficacy analyses.
After review of the data from Interim Analysis #2, the IDMC informed the Sponsor that the futility 
criterion for OS was met and that the CR rate did not meet per-protocol defined statistical significance. 
Given the lack of efficacy advantage of talacotuzumab + decitabine versus decitabine alone, the incidence 
of infusion-related reactions, and the complexities with premedications for drug administration, the 
benefit/ risk ratio is not favorable to continue treatment with talacotuzumab. The IDMC recommended 
closure of enrollment to the study and that subjects receiving talacotuzumab + decitabine should 
discontinue talacotuzumab treatment and may continue decitabine alone, according to Principal 
Investigator decision and subject agreement. All subjects will continue to be followed for survival and 
subsequent anti-cancer therapy. During the treatment phase with decitabine, subjects will be monitored 
for serious adverse events.
The end of study data collection is defined as when 270 deaths have occurred or 6 months after the last 
subject is enrolled, whichever occurs first. At that time, follow up of subjects will end. Subjects who are 
continuing to derive benefit from decitabine treatment as assessed by their investigator may continue to 
receive decitabine; during this period, only serious adverse events will be monitored and entered into the 
Company safety repository as described under Amendment 7.
SUBJECT POPULATION
Part A
Key eligibility criteria include the following: subjects diagnosed with AML according to the World 
Health Organization (WHO) 2008 classification system fulfilling all of the following criteria:

Patients with AML (treatment naive or relapsed) for whom experimental therapy is appropriate as 
assessed by their treating physician; subjects should not have had prior treatment with a 
hypomethylating agent;
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Talacotuzumab (JNJ-56022473)
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Status: Approved, Date: 31 October 2017   

White blood cell (WBC) count ≤ 40 X 109/L.
Part B
Key eligibility criteria include the following: subjects who are:

Age ≥75 years old

Age ≥65 up to 75 and have at least 1 of the following:
1.
Congestive heart failure or ejection fraction ≤50%
2.
Creatinine >2 mg/dL, dialysis or prior renal transplant
3.
Documented pulmonary disease with lung diffusing capacity for carbon monoxide (DLCO) 
≤65% of expected, or forced expiratory volume in 1 second (FEV1) ≤65% of expected or 
dyspnea at rest requiring oxygen
4.
ECOG performance status of 2
5.
Prior or current malignancy that does not require concurrent treatment
6.
Unresolved infection
7.
Comorbidity that, in the Investigator’s opinion, makes the patient unsuitable for intensive 
chemotherapy which must be documented and approved by the Sponsor before randomization

De novo or secondary AML according to the World Health Organization (WHO) 2008 classification;
(post myelodysplastic syndrome [MDS] or myeloproliferative neoplasm [MPN] or after 
leukemogenic chemotherapy),

Previously untreated AML (except emergency leukopheresis and/or hydroxyurea during the 
screening phase to control hyperleukocytosis but must be discontinued at least one day prior to start 
of study therapy;

Not eligible for an allogeneic hematopoietic stem cell transplantation,

Eastern Cooperative Oncology Group (ECOG) Performance Status score of ≤ 2
DOSAGE AND ADMINISTRATION
Part A
In Part A, 6 subjects will receive 1 dose of talacotuzumab at 9 mg/kg on Day 1 as a 180-minute IV 
infusion. Dose-limiting toxicities (DLTs) will be assessed during the DLT evaluation period which is 
Cycle 1 (14 days). If no DLTs are observed or are observed in 1 of the 6 subjects, the dose of 9 mg/kg 
talacotuzumab may be established as the RP2D by the SET. If DLTs are observed in ≥2 of the 6 subjects, 
Part A may continue with additional enrollment of 3 to 6 subjects at a lower dose level of talacotuzumab
to be determined by the SET. All subjects will receive premedication with hydrocortisone or equivalent 
IV steroid to prevent infusion reactions. After completion of Cycle 1, all subjects in Part A will then start 
subsequent cycles of combination therapy of decitabine + talacotuzumab.
Part B
In Part B of the study, subjects in the decitabine plus talacotuzumab arm will receive talacotuzumab IV at 
the RP2D over approximately 180 minutes. Talacotuzumab will be administered on Days 8 and 22. 
Decitabine will be administered at 20 mg/m2 as a 1-hour IV infusion for 5 consecutive days (Days 1 to 5)
every 28 days (1 treatment cycle) to subjects in both treatment arms. During the first 4 treatment cycles, 
all subjects in the decitabine + talacotuzumab arm must receive premedication with dexamethasone, 
methylprednisolone, acetaminophen (paracetomol), cimetidine, diphenhydramine, and montelukast prior 
to talacotuzumab dosing to prevent infusion-related reactions. If no infusion-related reactions are seen for 
NCT02472145


Talacotuzumab (JNJ-56022473)
Clinical Protocol 56022473AML2002 Amendment 7
25
Status: Approved, Date: 31 October 2017   
2 consecutive cycles during the first 4 cycles, then premedication may be modified by the investigator 
after discussion with the Sponsor for Cycle 5 and subsequent talacotuzumab treatments. In the event an 
infusion-related reaction (independent of severity) occurs in Cycle 5 and subsequent talacotuzumab
treatments, premedications need to be reintroduced.
Subjects in the decitabine only arm will receive the 5-Day decitabine dosing regimen (20 mg/m2 as a 
1-hour IV infusion for 5 consecutive days every 28 days) alone.
EFFICACY EVALUATIONS
Disease evaluations will include peripheral blood assessments, bone marrow assessments, and clinical 
presentation. Disease status will be evaluated according to Response Criteria in AML with modifications 
for treatment failure. Survival status and subsequent anticancer therapy will also be collected. Blood 
samples will also be collected to assess pharmacokinetics, immunogenicity, pharmacodynamics, MRD, 
and biomarkers.
Following Amendment 6, which incorporated the IDMC’s recommendations to close enrollment to the 
study and discontinue talacotuzumab treatment for subjects receiving talacotuzumab + decitabine and 
offer to continue decitabine alone, all subjects will continue to be followed for survival and subsequent 
anti-cancer therapy. During the treatment phase with decitabine, subjects will be monitored for serious 
adverse events.
Following Amendment 7 and when 270 deaths have occurred or 6 months after the last subject is enrolled
(whichever occurs first), follow up of subjects and data collection will end. Subjects who are continuing 
to derive benefit from decitabine treatment as assessed by their investigator may continue to receive 
decitabine; during this period, only serious adverse events will be monitored and entered into the 
Company safety repository.
SAFETY EVALUATIONS
Safety evaluations will include adverse event monitoring, vital signs measurements, physical 
examinations, electrocardiograms, clinical laboratory parameters (hematology and chemistry), and ECOG 
performance status. Other malignancies will also be recorded. 
In addition, a safety review by the IDMC of the accumulative data will be performed when approximately 
20 subjects (10 subjects from each arm) have been enrolled in Part B and followed for at least 1 month to 
assess the safety and tolerability of the combination treatment. This review will also include all safety, 
PK, and PD data available from Part A.
Following Amendment 6, which incorporated the IDMC’s recommendations to close enrollment to the 
study and discontinue talacotuzumab treatment for subjects receiving talacotuzumab + decitabine and 
offer to continue decitabine alone, all subjects will continue to be followed for survival and subsequent 
anti-cancer therapy. During the treatment phase with decitabine, subjects will be monitored for serious 
adverse events.
Following Amendment 7 and when 270 deaths have occurred or 6 months after the last subject is enrolled
(whichever occurs first), follow up of subjects and data collection will end. Subjects who are continuing 
to derive benefit from decitabine treatment as assessed by their investigator may continue to receive 
decitabine; during this period, only serious adverse events will be monitored and entered into the 
Company safety repository.
STATISTICAL METHODS
Approximately 6 subjects will be enrolled in Part A of the study in order to confirm the recommended 
dose of talacotuzumab for Part B. The SET consisting of selected investigators, sponsor medical 
monitors, the sponsor’s statistician, and the sponsor’s clinical pharmacologist, will review all available 
NCT02472145


Talacotuzumab (JNJ-56022473)
Clinical Protocol 56022473AML2002 Amendment 7
26
Status: Approved, Date: 31 October 2017   
data upon completion of the 14-day period following 9 mg/kg talacotuzumab treatment (Cycle 1) to 
determine DLTs, if the dose is acceptable, and subsequently, will confirm the RP2D. If no DLTs are 
observed or are observed for 1 of the 6 subjects, the dose of 9 mg/kg talacotuzumab may be established as 
the RP2D by the SET. If DLTs are observed in ≥2 of the 6 subjects, Part A may continue with additional 
enrollment of 3 to 6 subjects at a lower dose level of talacotuzumab to be determined by the SET.
Additionally, the SET will review accumulated safety data from Part A prior to the initiation of Part B.
Part B of the study includes an interim analysis based on response rates of CR and CR+CRi that will 
occur after approximately 80 subjects (40 subjects per arm) have been randomized and followed for at 
least 4 months. The results of this interim analysis will be used to guide if the study continues enrollment 
to the prespecified 400 subjects or stops enrollment. Enrollment will continue during the interim analysis; 
it is estimated that approximately 120 subjects will have been randomized by the time the results of the 
first interim analysis are available. 
The statistical criteria to guide the decision making will be based on the difference (Δ) in response rate 
between the 2 treatment arms (decitabine + talacotuzumab minus decitabine alone) as the following:

If ΔCR ≥15% or Δ(CR+CRi) ≥25%, then the study may continue enrollment to 400 subjects

If ΔCR <15% and Δ(CR+CRi) <25%, then the study may stop enrollment at approximately 
120 subjects
Event-free survival and all available safety, PK, PD, MRD, and biomarker data will also be reviewed at 
the time of this interim analysis. The final decision to continue enrollment will be based on the totality of 
the data and other development considerations.
If the study continues enrollment to 400 subjects, then the overall Type 1 error of 0.05 (2-sided) will be 
allocated between the primary endpoints of CR rate and OS using a gate-keeping procedure as described 
below:

There will be a formal statistical testing for superiority for CR at the interim analysis of 80 subjects 
with 2-sided α=0.001. The final analysis of CR (in terms of formal statistical hypothesis testing) will 
take place 4 months after 160 subjects have been randomized (to occur at the same time as the first 
interim analysis of OS) with 2-sided α=0.009. The study and collection of response data continue 
after the final CR analysis regardless of the outcome of the analysis.

Overall 2-sided α=0.04 for OS; and if the final analysis of CR achieves statistical significance, then 
α=0.009 allocated to CR can be reclaimed by the OS analysis, ie, OS can be tested at the overall 
level of 0.049.

The 2 interim analyses and final analysis for OS will utilize the O’Brien-Fleming α-spending 
procedure.
If the study continues enrollment to 400 subjects, a clinical cut-off will be when 270 deaths have 
occurred. If the study stops enrollment after the first interim analysis, the clinical cut-off will be when 
90 EFS events have occurred. Enrollment was terminated after Interim Analysis #2 and the study will end 
6 months after the last subject was enrolled.
Statistical details of the interim analysis, decision guidance, and study conduct are provided in 
Section 11.2.
NCT02472145


Talacotuzumab (JNJ-56022473)
Clinical Protocol 56022473AML2002 Amendment 7
27
Status: Approved, Date: 31 October 2017   
TIME AND EVENTS SCHEDULE – TABLE 1A [PART A]
Procedure (Part A)
Notes
Screening 
Phase
Open-Label Treatment Phase
Follow-up Phase
Within 28 days 
before Day 1
Cycle 1
(14 days)
Day 1 of each 
subsequent cycle
(28 days) unless 
otherwise noted
EOT
Every 3 months (7 days)
NOTE: The EOT Visit should occur within 30 days (7 days) of last dose for subjects. The Follow-up Phase will continue until death, loss to follow-up, consent 
withdrawal for study participation, or study end, whichever occurs first.
Screening/Administrative
Informed consent
ICF must be signed before any 
study-related procedures
X
Demography/medical history
X
Eligibility criteria
Minimum criteria for the 
availability of documentation 
supporting the eligibility criteria are 
described in Section 17.4, Source 
Documentation. Check clinical 
status again before first dose of 
study medication.
X
Study Drug Administration (for details see also Section 6)
Decitabine
Days 1, 2, 3, 4 
and 5
Talacotuzumab
Day 1 
Days 8 and 22
Safety Assessments
Physical examination
Must be assessed within 48 hrs of 
Day 1 of each specified cycle, 
reviewed prior to starting the cycle 
and changes that are clinically 
significant must be reported on the 
AE page
X
X
X 
X
ECOG performance status 
evaluation
Must be assessed within 48 hrs of 
Day 1 of each specified cycle
X
X
X
X
NCT02472145


Talacotuzumab (JNJ-56022473)
Clinical Protocol 56022473AML2002 Amendment 7
28
Status: Approved, Date: 31 October 2017   
Procedure (Part A)
Notes
Screening 
Phase
Open-Label Treatment Phase
Follow-up Phase
Within 28 days 
before Day 1
Cycle 1
(14 days)
Day 1 of each 
subsequent cycle
(28 days) unless 
otherwise noted
EOT
Every 3 months (7 days)
Vital signs
Temperature, blood pressure (BP) 
and heart rate (HR) will be assessed 
prior to each study treatment dosing;
On 
talacotuzumab
dosing 
days 
BP/HR are measured pre-dose and 
every 15 min during the first 
90 min, and then at 30-min intervals 
for the remainder of the infusion. 
For the first infusion, also every 
30 min. post-infusion up to 1.5 hr 
after the infusion;
as clinically 
indicated.
X
X
X
X
Weight
Must be assessed prior to dosing on 
Day 1 of each specified cycle, in 
case of weight loss of >10% within 
a cycle, the dose of study drug must 
be recalculated
X
X
X
X
Height
X
LVEF
MUGA scan is preferred. 
Echocardiogram can be used if MUGA 
is not available.
X
as clinically indicated
ECG
QTcF will be assessed at the time of 
screening. If QTcF is >470 msec, 
repeat ECG 2 additional times 
approximately 3 – 5 minutes apart. 
Average the QTcF of all 3 ECGs to 
determine if the subject meets the 
QTc eligibility criteria
X
Only if clinically indicated
Concomitant medications
See Section 8 for detailed 
instructions; includes transfusion 
requirements
Continuous from the time of signing of ICF until 30 days after last 
study drug dose
Concomitant medications 
for related AEs of Grade ≥3 
and SAEs regardless of 
relationship only;
subsequent anticancer
therapy
NCT02472145


Talacotuzumab (JNJ-56022473)
Clinical Protocol 56022473AML2002 Amendment 7
29
Status: Approved, Date: 31 October 2017   
Procedure (Part A)
Notes
Screening 
Phase
Open-Label Treatment Phase
Follow-up Phase
Within 28 days 
before Day 1
Cycle 1
(14 days)
Day 1 of each 
subsequent cycle
(28 days) unless 
otherwise noted
EOT
Every 3 months (7 days)
Adverse events
See Section 12 for detailed 
instructions.
Continuous from the time of signing of ICF until 30 days after last 
dose of last study drug
Related AEs of Grade 3 
and related SAEs; follow 
until resolution
Patient-reported outcomes
FACT-Leu
PROs should be performed on Day 
1 of each cycle before dosing and 
before any study tests or procedures 
or consultations are conducted.
X
X 
X
Only at first FU
EQ-5D-5L
X
X
X
Only at first FU
Laboratory Assessments
Hematology
At least the following parameters 
(hemoglobin, platelet count, WBC,
monocytes, basophils, eosinophils,
absolute neutrophil count, absolute 
lymphocyte count, and peripheral 
blasts) must be assessed within 48 
hrs of the indicated days of each 
cycle and results reviewed prior to 
dosing.
X
Day 1
Days 1, 8 and 22
X
Coagulation panel
aPTT, INR or prothrombin time 
(PT) must be assessed at screening 
and as clinically indicated
X
Clinical chemistry
At least the following parameters 
(AST, ALT, sodium, potassium, 
magnesium, BUN, phosphate, uric 
acid, calcium, alkaline phosphatase, 
creatinine, LDH, total bilirubin) 
must be assessed within 48 hrs of 
Day 1 of each cycle and results 
reviewed prior to starting the cycle.
X
X
X
X
HBV surface antigen and 
hepatitis C (antibodies)
X
NCT02472145


Talacotuzumab (JNJ-56022473)
Clinical Protocol 56022473AML2002 Amendment 7
30
Status: Approved, Date: 31 October 2017   
Procedure (Part A)
Notes
Screening 
Phase
Open-Label Treatment Phase
Follow-up Phase
Within 28 days 
before Day 1
Cycle 1
(14 days)
Day 1 of each 
subsequent cycle
(28 days) unless 
otherwise noted
EOT
Every 3 months (7 days)
Serum β-hCG or urine 
pregnancy test
For women of childbearing potential 
only
X
Only if clinically indicated
Disease Evaluations: Every effort should be made to conduct disease evaluations as per schedule (window ±7 days). Refer to Section 9.2 for details on efficacy 
evaluations
Bone marrow aspirate/biopsy
Bone marrow diagnostic block 
required at screening from historic 
sample
X
Disease status evaluation 
X
At time of 
suspected 
treatment 
failure
At Cycle 5
(between Day 14 
to 28)
At time of 
suspected 
CR /CRi
At time of
suspected
treatment failure
or relapse from 
CR/CRi
X (unless 
done within 
2 weeks)
Imaging
Per local standard of care and as 
clinically indicated. Report the 
disease assessment for AML related 
abnormalities including all sites of 
extramedullary disease
X
Repeat as clinically indicated per local standards. If 
extramedullary disease at baseline, repeat imaging (using the 
same modality) at time of best response 
Survival, subsequent 
therapy, other malignancies
X
NCT02472145


Talacotuzumab (JNJ-56022473)
Clinical Protocol 56022473AML2002 Amendment 7
31
Status: Approved, Date: 31 October 2017   
Procedure (Part A)
Notes
Screening 
Phase
Open-Label Treatment Phase
Follow-up Phase
Within 28 days 
before Day 1
Cycle 1
(14 days)
Day 1 of each 
subsequent cycle
(28 days) unless 
otherwise noted
EOT
Every 3 months (7 days)
Pharmacokinetic, Pharmacodynamic, and Biomarker Assessments see TIME AND EVENTS SCHEDULE (PK AND BIOMARKERS) – TABLE 2A
Abbreviations: AE=adverse event; ALT= alanine aminotransferase; AML=acute myeloid leukemia; AST= aspartate aminotransferase; β-hCG=beta human chorionic 
gonadotropin; BP=blood pressure; BUN= blood urea nitrogen; CR= complete response; CRi= complete response with incomplete blood cell count recovery;
ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; EOT=end of treatment; EQ=EuroQol; F/U= follow-up; HBV: hepatitis B virus; HR=heart rate; 
ICF=informed consent form; INR= international normalized ratio; LDH= lactate dehydrogenase; LVEF= left ventricular ejection fraction; MUGA= Multi Gated 
Acquisition Scan; NK= natural killer (cells); PD=pharmacodynamics(s); PK=pharmacokinetic(s); PRO= patient-reported outcomes; PT= prothrombin time; aPTT= 
partial thromboplastin time; SAE=serious adverse event; T&E=Time & Events; WBC= white blood cell.
NCT02472145


Talacotuzumab (JNJ-56022473)
Clinical Protocol 56022473AML2002 Amendment 7
32
Status: Approved, Date: 31 October 2017   
TIME AND EVENTS SCHEDULE – TABLE 1B [PART B] UP TO AND INCLUDING AMENDMENT 5
Procedure (Part B)
Notes
Screening 
Phase
Open-Label Treatment Phase
Follow-up Phase
Within 28 days 
before 
randomization 
Day 1 of each cycle (± 48 hours) 
unless otherwise indicated
(each cycle = 28 days)
EOT
Every 3 months 
(7 days)
NOTE: The EOT Visit should occur within 30 days (7 days) of last dose for subjects. The Follow-up Phase will continue until death, loss to follow-up, consent 
withdrawal for study participation, or study end, whichever occurs first.
Screening/Administrative
Informed consent
ICF must be signed before any study-related procedures
X
Demography/
medical history
X
Eligibility criteria
Minimum criteria for the availability of documentation 
supporting the eligibility criteria are described in 
Section 17.4, Source Documentation. Sponsor review 
of key eligibility and approval is required prior to 
randomization. Check clinical status again before first 
dose of study medication.
X
Study Drug Administration (for details see also Section 6)
Randomization
Within 3 days prior to the first dose
X
Decitabine
Days 1, 2, 3, 4, and 5
Talacotuzumab
Subjects randomized to Arm 1
Days 8 and 22 (± 24 hours)
Safety Assessments
Physical examination
Must be assessed within 3 days of Day 1 of each 
specified cycle, reviewed prior to starting the cycle and 
changes that are clinically significant must be reported 
on the AE page
X
X 
X
ECOG performance 
status evaluation
Must be assessed within 3 days of Day 1 of each 
specified cycle
X
X
X
Vital signs
Temperature, blood pressure (BP) and heart rate (HR) 
will be assessed prior to each study treatment dosing 

On talacotuzumab
dosing days
BP/HR are 
measured pre-dose and every 15 min during the 
first 90 min, and then at 30-min intervals for the 
remainder of the infusion. For the first infusion, 
obtain every 30 min post-infusion up to 1.5 hr 
after the infusion 
X
X
X
NCT02472145


Talacotuzumab (JNJ-56022473)
Clinical Protocol 56022473AML2002 Amendment 7
33
Status: Approved, Date: 31 October 2017   
Procedure (Part B)
Notes
Screening 
Phase
Open-Label Treatment Phase
Follow-up Phase
Within 28 days 
before 
randomization 
Day 1 of each cycle (± 48 hours) 
unless otherwise indicated
(each cycle = 28 days)
EOT
Every 3 months 
(7 days)
Weight
Must be assessed within 3 days prior to dosing on Day 
1 of each specified cycle, in case of weight loss of 
>10% within a cycle, the dose of study drug must be 
recalculated
X
X
X
Height
X
LVEF
MUGA scan is preferred. Echocardiogram can be used 
if MUGA is not available.
X
as clinically indicated
X
ECG
QTcF will be assessed at the time of screening. If 
QTcF is >470 msec, repeat ECG 2 additional times 
approximately 3 – 5 minutes apart. Average the QTcF 
of all 3 ECGs to determine if the subject meets the 
QTc eligibility criteria
X
For subjects in Arm 1, ECG 
monitoring will occur on 
Cycle 1 Day 8 and Day 22 
after the talacotuzumab IV 
infusion, then every other
cycle thereafter on Day 22 
after the talacotuzumab IV 
infusion. 
For subjects in Arm 2, ECG 
monitoring will occur on 
Cycle 1 Day 5 after the 
decitabine IV infusion and 
then every 2 cycles thereafter 
on Day 5 after the decitabine 
IV infusion.
X
Concomitant medications
See Section 8 for detailed instructions; Includes
transfusion requirements
Continuous from the time of signing of ICF until 30 days 
after last study drug dose
Concomitant 
medications for 
related AEs of 
Grade 3 and 
SAEs regardless 
of relationship;
subsequent 
anticancer therapy
NCT02472145


Talacotuzumab (JNJ-56022473)
Clinical Protocol 56022473AML2002 Amendment 7
34
Status: Approved, Date: 31 October 2017   
Procedure (Part B)
Notes
Screening 
Phase
Open-Label Treatment Phase
Follow-up Phase
Within 28 days 
before 
randomization 
Day 1 of each cycle (± 48 hours) 
unless otherwise indicated
(each cycle = 28 days)
EOT
Every 3 months 
(7 days)
Adverse events
See Section 12 for detailed instructions.
Continuous from the time of signing of ICF until 30 days 
after last dose of last study drug
Related AEs of 
Grade 3 and
related SAEs; 
follow until 
resolution
Medical resource 
utilization
Information on all health care needs during treatment 
(eg, physiotherapist) to be collected
Continuous from the time of signing of the ICF until 30 days 
after the last dose of study drug
Patient-reported outcomes
FACT-Leu
PROs should be performed on Day 1 of each cycle 
before dosing and before any study tests or procedures 
are conducted.
X
X
Only at first FU
EQ-5D-5L
X
X
Only at first FU
Laboratory Assessments
Hematology 
At least the following parameters (hemoglobin, platelet 
count, absolute WBC count, absolute monocyte count, 
absolute basophil count, absolute eosinophil count
absolute neutrophil count, absolute lymphocyte count, 
and peripheral blast count) must be assessed within 
3 days of the indicated days of each cycle and results 
reviewed prior to starting dosing if applicable.
X
Days 1, 8, and 22
X
Coagulation panel
aPTT, INR or prothrombin time (PT) must be assessed 
at screening and as clinically indicated afterward
X
Clinical chemistry
At least the following parameters (AST, ALT, sodium, 
potassium, magnesium, BUN, phosphate, uric acid, 
calcium, 
alkaline 
phosphatase, 
creatinine, 
total 
bilirubin) must be assessed within 3 days of Day 1 of 
each cycle and results reviewed prior to starting the 
cycle.
X
X
X
Assessment for active 
hepatitis or history of 
HIV
X
Serum β-hCG or urine 
pregnancy test
For women of childbearing potential only
X
Only if clinically indicated
NCT02472145


Talacotuzumab (JNJ-56022473)
Clinical Protocol 56022473AML2002 Amendment 7
35
Status: Approved, Date: 31 October 2017   
Procedure (Part B)
Notes
Screening 
Phase
Open-Label Treatment Phase
Follow-up Phase
Within 28 days 
before 
randomization 
Day 1 of each cycle (± 48 hours) 
unless otherwise indicated
(each cycle = 28 days)
EOT
Every 3 months 
(7 days)
Disease Evaluations: A +/- 7-day window exists for completion of disease evaluation visits. Refer to Section 9.2 for details on efficacy evaluations
Bone marrow 
aspirate/biopsy
A portion of each sample should be sent to the central 
lab for confirmation of disease status. A portion of the 
aspirate should be sent to the central lab for MRD and 
biomarker analysis at Screening, at suspected CR/CRi, 
then every disease assessment until relapse or EOT.
Blood samples at matching time points will be taken 
for biomarker evaluations (CD123 expression, 
genomic characterization, and immunophenotyping).
Molecular genetics and cytogenetics samples analyzed 
per the local standard of care at screening, at suspected 
CR/CRi and  then every disease assessment until 
relapse or EOT
X (A biopsy 
can be used for 
confirmation of 
disease if taken 
within 6 weeks 
of 
randomization, 
but a fresh 
aspirate is 
required for 
MRD and 
biomarker 
analysis.)

Every 2 Cycles starting at 
Cycle 2 (between Day 14
and 28) until treatment 
failure or relapse from 
CR/CRi or CCO

At time of suspected CR 
/CRi

At time of suspected 
treatment failure or 
relapse from CR/CRi
X 
(unless done 
within 2 
weeks)
Imaging
Per local standard of care and as clinically indicated.
Report the disease assessment for AML related 
abnormalities including all sites of extramedullary 
disease
X
To repeat as clinically indicated per local standards. If 
extramedullary disease at baseline, repeat imaging (using the same 
modality) at time of best response 
Disease evaluation
Disease evaluation should be done based on 
information available; hematology, clinical 
presentation and bone marrow assessments. 

Every 2 Cycles starting 
at Cycle 2 (between Day 
14 and 28) until treatment 
failure or relapse from 
CR/CRi or CCO

At time of suspected CR 
/CRi

At time of suspected 
treatment failure or 
relapse from CR/CRi
X
Survival, subsequent 
therapy, other 
malignancies
X
NCT02472145


Talacotuzumab (JNJ-56022473)
Clinical Protocol 56022473AML2002 Amendment 7
36
Status: Approved, Date: 31 October 2017   
Procedure (Part B)
Notes
Screening 
Phase
Open-Label Treatment Phase
Follow-up Phase
Within 28 days 
before 
randomization 
Day 1 of each cycle (± 48 hours) 
unless otherwise indicated
(each cycle = 28 days)
EOT
Every 3 months 
(7 days)
Pharmacokinetic, Pharmacodynamic, and Biomarker Assessments see TIME AND EVENTS SCHEDULE (PK AND BIOMARKERS) – TABLE 2B
Abbreviations: AE=adverse event; ALT= alanine aminotransferase; AML=acute myeloid leukemia; ANC= absolute neutrophil count; AST= aspartate aminotransferase; 
β-hCG=beta human chorionic gonadotropin; CCO=clinical cut-off; CR= complete response; CRi= complete response with incomplete blood count recovery; BP=blood 
pressure; BUN= blood urea nitrogen; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; EOT=end of treatment; EQ=EuroQol; HBV: hepatitis B 
virus; HR=heart rate; ICF=informed consent form; INR= international normalized ratio; LDH= lactate dehydrogenase; LVEF= left ventricular ejection fraction; MRD= 
minimal residual disease; MUGA= multi gated acquisition scan; NK= natural killer (cells); PD=pharmacodynamics(s); PK=pharmacokinetic(s); PT= prothrombin time; 
aPTT= partial thromboplastin time; SAE=serious adverse event; T&E=Time & Events; WBC= white blood cell.
NCT02472145


Talacotuzumab (JNJ-56022473)
Clinical Protocol 56022473AML2002 Amendment 7
37
Status: Approved, Date: 31 October 2017   
TIME AND EVENTS SCHEDULE – TABLE 1C [PART B] DURING AMENDMENT 6
Procedure (Part B)
Notes
Screening 
Phase
Open-Label Treatment Phase
Follow-up Phase
Within 28 days 
before 
randomization 
Day 1 of each cycle (± 48 hours) 
unless otherwise indicated
(each cycle = 28 days)
EOT
Every 2 months 
(7 days)
NOTE Following Amendment 6, which incorporated the IDMC’s recommendations to close enrollment to the study and discontinue talacotuzumab 
treatment for subjects receiving talacotuzumab + decitabine and offer to continue decitabine alone, all subjects will continue to be followed for survival 
and subsequent anti-cancer therapy. During the treatment phase with decitabine, subjects will be monitored for serious adverse events.
Serious adverse events
Follow until resolution
X
Survival, 
subsequent 
therapy
X
X
X
EOT= end-of-Treatment; IDMC= Independent Data Monitoring Committee
TIME AND EVENTS SCHEDULE – TABLE 1D [PART B] FOLLOWING AMENDMENT 7
Procedure (Part B)
NOTE Following Amendment 7 and when 270 deaths have occurred or 6 months after the last subject is enrolled (whichever occurs first), follow up of 
subjects and data collection will end. Subjects who are continuing to derive benefit from decitabine treatment as assessed by their investigator may
continue to receive decitabine; during this period, only serious adverse events will be monitored and entered into the Company safety repository.
NCT02472145


Talacotuzumab (JNJ-56022473)
Clinical Protocol 56022473AML2002 Amendment 7
38
Status: Approved, Date: 31 October 2017   
TIME AND EVENTS SCHEDULE (PK AND BIOMARKERS) – TABLE 2A [PART A]
PART A
Cycle 1
Cycle 2
Cycles 3 and 5
EOT1
Talacotuzumab alone 
Decitabine + Talacotuzumab
Day 1
Day 2
Day 3
Day 4
Day 8
Day 1
Day 8
predose 
30 min 
after end 
of infusion
24 hour
postdose 
48 hour
postdose 
72 hour
postdose 
168 hours 
postdose
predose
Talacotuzumab
predose
Talacotuzumab PK sample2
X
X3
X
X
X
X
X
X
X
Immunogenicity Evaluation2, 4
X
X
X
PD/RO/biomarker sample (blood)5
X
X
X
X
X
X
X
Notes: EOT= End-of-Treatment (up to 30 days (+/- 7 days) after last dose of any study drug) Visit; PD= pharmacodynamics; 
PK= pharmacokinetics; RO= receptor (CD123) occupancy
1 The End-of-Treatment visit is after combination treatment. 
2 For subjects who experience a talacotuzumab infusion reaction, if possible, an unscheduled PK/immunogenicity sample should be drawn as soon as possible after the reaction.
3 In the case that the talacotuzumab infusion is terminated before all the drug is administered, an additional PK sample will be taken immediately after the infusion is stopped.
4 An aliquot from the talacotuzumab PK sample will be used to assess immunogenicity. 
5 Including assessment of NK cell activity by flow cytometry
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TIME AND EVENTS SCHEDULE (PK AND BIOMARKERS) – TABLE 2B [PART B] UP TO AND INCLUDING AMENDMENT 5
PART B
Screening
Cycles 1 and 4
Cycle 2
EOT
First 
Follow 
Up
Day 1
Day 5
Day 8
Day 9
Day 22
Day 23
Day 1
Day 8
Day 9
decitabine
talacotuzumab
Predose Predose
5 minutes 
prior to
end of 
infusion
1 hour after 
end of 
infusion
Predose 
30 min 
after end 
of 
infusion
24 hour 
postdose 
Predose 
(14d post 1st 
dose)
24hr post 
2nd dose 
Predose 
decitabine
Predose 
talacotuzuma
b
Decitabine PK
X1
X1
X1
Talacotuzumab PK 
sample,2,3
X4
X
X5
X1
X
X1
X1
X
X
X
Immunogenicity 
Evaluation2,3,6
X
X
X
X
PD/RO sample 
(blood)
X
X
X1,2
X2
X1,2
X1,2
X2
X
Biomarker sample 
for Methylation/ 
GEP (blood)
X
X
X
X
X
Cytokine sample 
(blood): Cycles 1 
and 2 only7
X
Cycle 1 
only: at 
end of 
infusion 
and 2 hrs 
after (30 
min 
collection 
is not 
taken)
X
Cycle 1 
only (if 
feasible)
X and at end 
of infusion 
and 2 hrs 
after
X (if 
feasible)
Notes: EOT= End of Treatment; GEP= gene expression profiling; PD= pharmacodynamics; PK= pharmacokinetics; RO= receptor occupancy
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1 Sampling to be done for the first 120 subjects only
2 Decitabine + talacotuzumab arm only.
3 For subjects who experience a talacotuzumab infusion-related reaction, if possible, an unscheduled PK/immunogenicity sample should be drawn as soon as possible after the reaction.
4 Cycle 4 only
5 In the case that the talacotuzumab infusion is terminated before all the drug is administered, an additional PK sample will be taken immediately after the infusion is stopped.
6 An aliquot from the talacotuzumab PK sample will be used to assess immunogenicity.
7 For subjects who experience a talacotuzumab infusion-related reaction in any cycle, a blood sample should be drawn as soon as possible after the reaction and another approximately 
1 day later, if feasible.
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ABBREVIATIONS
ADCC
antibody-dependent cell cytotoxicity
AE
adverse event
ALT
alanine transaminase
AML
acute myeloid leukemia
ANC
absolute neutrophil count
aPTT
activated partial thromboplastin time
AST
aspartate transaminase
AUC
area under the concentration-time curve 
β-HCG
beta human chorionic gonadotropin
BP
blood pressure
BUN
blood urea nitrogen
CI
confidence intervals
CL
total systemic clearance of drug after IV administration
Cmax
maximum observed concentration
Cmin
minimum observed concentration
CR
complete response/remission
CRi
complete response with incomplete recovery
CRp
Complete response with incomplete platelet recovery
CTCAE
Common Terminology Criteria for Adverse Events
DLT
dose-limiting toxicity
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
eDC
electronic data capture
EFS
event-free survival
EOT
end-of-treatment
EQ
EuroQol
EU
European Union
FFPE
formalin-fixed paraffin-embedded
FLT3-ITD
FLT3-Internal Tandem Duplication
F/U
follow-up
GCP
Good Clinical Practice
HBsAg
hepatitis B surface antigen
HIV
human immunodeficiency virus
HBV
hepatitis B virus
HR
heart rate
HSC
hematopoietic stem cells
HSCT
hematopoietic stem cell transplantation
ICF
informed consent form
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IHC
Immunohistochemistry
IL-3
interleukin-3
INR
International normalized ratio 
IRB
Institutional Review Board
IWRS
interactive web response system
LDH
lactate dehydrogenase
LSC
leukemic stem cells
LVEF
left ventricular ejection fraction
MDS
myelodysplastic syndrome
MedDRA
Medical Dictionary for Regulatory Activities
MFI
mean fluorescent intensity
MRD
minimal residual disease 
MRU
medical resource utilization
MUGA
multi-gated acquisition scan
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NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NK
natural killer (cells)
NPM
Nucleophosmin
ORR
overall response rate
OS
overall survival
PD
Pharmacodynamics
pDC
plasmacytoid dendritic cell
PK
Pharmacokinetics
PQC
Product Quality Complaint
PRO
patient-reported outcomes
PT
prothrombin time
Q2W
every 2 weeks
RFS
relapse-free survival
RO
receptor occupancy
RP2D
recommended Phase2 dose
RT-PCR
reverse transcriptase – polymerase chain reaction
SAE
serious adverse event
SET
Study Evaluation Team
SNP
single nucleotide polymorphism
T&E
Time and Events (Tables)
WBC
white blood cells
WHO
World Health Organization
βc
beta common
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1.
INTRODUCTION
Acute myeloid leukemia (AML) is a heterogeneous disease characterized by uncontrolled clonal 
expansion of hematopoietic progenitor cells.26 As the second most common form of leukemia, 
AML accounts for the largest number of annual deaths from leukemia. This poor prognosis is in 
part due to the fact that AML affects patients at a more advanced median age of 67 years with a 
third of patients diagnosed at an age of over 75 years.26,28 Advanced age associated with 
comorbidities, concomitant end-organ dysfunction, and poor performance status severely limits 
tolerance to cytotoxic chemotherapy. In addition, the biology of AML in the elderly also 
contributes to the poor therapeutic outcome. In older patients, AML arises more frequently from 
an overt or unrecognized myelodysplastic syndrome (MDS), and appears to be associated with 
complex, monosomal, or combination karyotypes, adverse cytogenetics, as well as a multidrug 
resistant phenotype.25 Although these patients may respond to chemotherapy, increased 
drug-related deaths offset clinical benefit.20 As a consequence, major therapeutic advances 
associated with intensification of chemotherapies and the broader availability of curative 
allogeneic stem cell transplantation have primarily benefited the smaller subpopulation of 
younger AML patients. In contrast, the choice of more effective treatment options for the 
majority of elderly patients has remained very limited. In recent years, the hypomethylating 
agent decitabine (formulated product, DACOGEN®) has emerged as one of the preferred 
therapies for AML patients who cannot tolerate intense induction and consolidation 
chemotherapy.5,25
Decitabine promotes cellular differentiation by reversing
epigenetic 
suppression of gene expression, thus inducing durable responses in a subset of patients with 
AML. In a Phase 3 study, DACOGEN demonstrated a higher rate of complete responses (CRs) 
compared to the standard of care therapy of low-dose cytarabine (17.8% versus 7.8%).21 Given 
the well described and predictable safety profile, multiple clinical studies are currently underway 
to improve the efficacy of decitabine in AML patients in novel combination regimens. 
In this Phase 2/3 study, the safety and clinical efficacy of a combination of decitabine with the 
novel, therapeutic antibody talacotuzumab, directed against the α-subunit of the interleukine-3 
receptor (CD123) overexpressed on leukemic blasts and leukemic stem cells (LSCs), will be 
explored in patients with previously untreated AML who are not eligible for intense induction 
chemotherapy.
For the most comprehensive nonclinical and clinical information regarding talacotuzumab and 
decitabine, refer to the latest version of the Investigator's Brochure and Addenda.15,16 The term 
"sponsor" used throughout this document refers to the entities listed in the Contact Information 
page(s), which will be provided as a separate document.
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1.1.
Talacotuzumab (JNJ-56022473; CSL362): Second Generation Anti-CD123 
Antibody
Acute myeloid leukemia is a disorder of early hematopoietic progenitor cells, characterized by 
the proliferation and accumulation of immature, clonal, myeloid cells. Constitutive 
overexpression of the α-subunit of the interleukin-3 receptor ie, IL-3Ris a hallmark of the 
early AML progenitor cell population (ie, leukemic stem cells) as well as leukemic blasts. 
CD123 is unique to the IL-3 receptor and is responsible for the high specificity and low affinity 
binding of IL-3. Upon ligand binding, the α-subunit CD123 associates with the βc-subunit 
(CD131) to form a high-affinity receptor complex initiating an intracellular signaling cascade 
through phosphorylation and activation of at least 3 distinct signal transduction pathways: the 
JAK/STAT-kinase, MAP-kinase-, and PI3-kinase-pathways. Under physiological conditions, 
activation of the IL-3 receptor induces proliferative, anti-apoptotic, and differentiating signals.12
Talacotuzumab (JNJ-56022473; CSL362) is a second generation antibody developed from the 
murine 7G3 anti-CD123 monoclonal antibody (mAb) in a stepwise process of humanization, 
affinity maturation, and Fc engineering. To enhance the cytotoxicity of the first-generation 
antibody CSL360, the proprietary Xencor (Xmab®) technology was applied and two amino acid 
mutations (S239D and I332E) were introduced into the Fc region.16 These amino acid 
substitutions led to improved binding to CD16 (FcγRIIIa) on natural killer (NK) cells and 
significantly enhanced the ability to induce antibody-dependent cell-mediated cytotoxicity 
(ADCC).3
The talacotuzumab drug product that will be used in this study is produced in a different cell line 
with a different process compared with CSL362, the drug product used in the Phase 1 study 
CSLCT-AML-11-73 described below. Comparability testing of talacotuzumab and CSL362 has 
shown the antibodies to behave similarly in biophysical, biochemical, and preclinical 
assessments. The primary structure, charge heterogeneity, size heterogeneity, purity, higher order 
structure, and process impurities were found to be highly similar between CSL-362 and 
talacotuzumab. Pharmacodynamic (PD) studies in cynomolgus monkeys showed similar levels 
of biological activity between CSL362 and talacotuzumab (ie, basophil and pDC depletion; NK 
cell number and activity). Additionally, the PK profiles of talacotuzumab following 30 and 
100 mg/kg IV dosing of cynomolgus monkeys are highly similar to those of CSL362. Following 
the first weekly IV dose, mean Cmax and AUC0-167h of talacotuzumab are 91% and 94% of those 
observed for CSL362, respectively. 
1.2.
CSL362 Phase 1 Experience
CSL362 entered clinical development in 2012 in the ongoing study (CSLCT-AML-11-73;
NCT01632852) entitled “A Phase 1 Study of CSL362 (Anti-IL3Rα/Anti-CD123 Monoclonal 
Antibody) in Patients with CD123+ Acute Myeloid Leukemia in Complete Remission or 
Complete Remission with Incomplete Platelet Recovery at High Risk for Early Relapse.” 
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Design, Objectives: The study follows a 3+3 dose escalation design. The primary and secondary 
objectives are to evaluate the safety, pharmacokinetics, and immunogenicity of repeated doses of 
CSL362 in AML patients in CR. Exploratory endpoints include CSL362 effects on 1) 
CD123-expressing normal blood cells (basophils and plasmacytoid dendritic cells [pDCs], NK 
cells), 2) levels of serum cytokines, 3) binding to CD123 on monocytes, as well as 4) changes in 
the status of minimal residual disease (MRD) measured by flow cytometry and RT-PCR.
Study Therapy: The study therapy consists of IV CSL362 antibody infusion given every 
14 days for 6 doses over a total treatment period of 12 weeks. The final evaluation for safety is 
conducted at Study Week 16. As of a data cutoff of 28 January 2015, 27 subjects had been 
enrolled and dosed.
Safety: The most frequent adverse event was severe infusion-related reaction characterized by
fever and chills, nausea, vomiting, pain, headache, dizziness, breathlessness, chest pain, low or 
high blood pressure, rash, itchiness or weakness. The majority of these infusion-related reactions 
were observed in the first 2 dose cohorts (0.3 mg/kg and 1 mg/kg) in which premedication with 
hydrocortisone was not used. After mandatory pre-medication (including corticosteroids, see
Section 6.3.2) was instituted and the infusion time was extended, no additional adverse events of 
severe infusion-related reaction were observed from the third cohort (0.75 mg/kg) onward up to 
the highest dose (9 mg/kg) given to date. A cohort exploring the safety of 12 mg/kg of CSL362
is underway. 
For the 27 subjects treated with CSL362 as of the data cutoff of 28 January 2015, the most 
frequently reported (≥2 subjects) adverse events are summarized in Table 1.
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Table 1:
Treatment-Emergent Adverse Events Occurring in 2 or More Subjects in
Study CSLCT-AML-11-73
Number of Subjects (%)
CSL-362
0.3 mg/kg
(N=6)
n (%)
CSL-362
0.75 mg/kg
(N=3)
n (%)
CSL-362
1.0 mg/kg
(N=6)
n (%)
CSL-362
3.0 mg/kg
(N=3)
n (%)
CSL-362
9.0 mg/kg
(N=9)
n (%)
CSL-362
Overall
(N=27)
n (%)
Infusion-related 
reaction
6 (100)
2 (66.7)
3 (50.0)
0
5 (55.6)
16 (59.3)
Headache
4 (66.7)
1 (33.3)
3 (50.0)
1 (33.3)
2 (22.2)
11 (40.7)
AML Recurrent
1 (16.7)
2 (66.7)
1 (16.7)
0
4 (44.4)
8 (29.6)
Fatigue
1 (16.7)
2 (66.7)
2 (33.3)
0
2 (22.2)
7 (25.9)
Nausea
2 (33.3)
1 (33.3)
3 (50.0)
0 
0
6 (22.2)
Chills
0
0
2 (33.3)
1 (33.3)
2 (22.2)
5 (18.5)
Dizziness
1 (16.7)
1 (33.3)
0
0
3 (33.3)
5 (18.5)
Pyrexia
0
0
1 (16.7)
0
3 (33.3)
4 (14.8)
Arthralgia
1 (16.7)
0
2 (33.3)
0
1 (11.1)
4 (14.8)
Hypotension
1 (16.7)
0
1 (16.7)
2 (66.7)
0
4 (14.8)
Vomiting
2 (33.3)
1 (33.3)
1 (16.7)
0
0
4 (14.8)
Diarrhea
0
0
2 (33.3)
0
2 (22.2)
4 (14.8)
Hypertension
2 (33.3)
0
1 (16.7)
0
0
3 (11.1)
Tachycardia
2 (33.3)
0
1 (16.7)
0
0
3 (11.1)
Constipation
0
1 (33.3)
1 (16.7)
0
1 (11.1)
3 (11.1)
Contusion
1 (16.7)
0
0
0
2 (22.2)
3 (11.1)
CRP Increased
0
0
1 (16.7)
1 (33.3)
1 (11.1)
3 (11.1)
Neuropathy 
peripheral
0
0
0
0
2 (22.2)
2 (7.4)
Chest discomfort
0
1 (33.3)
1 (16.7)
0
0
2 (7.4)
Chest pain
0
0
2 (33.3)
0
0
2 (7.4)
Oedema peripheral
0
1 (33.3)
0
0
1 (11.1)
2 (7.4)
Blood urea increased
0
0
1 (16.7)
1 (33.3)
0
2 (7.4)
Neutrophil count 
decreased
0
1 (33.3)
0
0
1(11.1)
2 (7.4)
Hyperglycaemia
1 (16.7)
0
0
1 (33.3)
0
2 (7.4)
Hypokalaemia
0
0
1(16.7)
1 (3.3)
0
2 (7.4)
Hypomagnesaemia
0
0
2 (33.3)
0
0
2 (7.4)
Nasopharyngitis
0
0
0
1 (33.3)
1 (11.1)
2 (7.4)
Upper respiratory 
tract infection
0
1 (33.3)
0
0
1 (11.1)
2 (7.4)
Urinary tract 
infection
0
0
1 (16.7)
0
1 (11.1)
2 (7.4)
Pain in extremity
0
1 (33.3)
0
0
1 (11.1)
2 (7.4)
Cough
0
0
0
1 (33.3)
1 (11.1)
2 (7.4)
Hypoxia
0
0
2 (33.3)
0
0
2 (7.4)
Thrombocytopenia
0
0
0
0
2 (22.2)
2 (7.4)
Data cutoff date: 28 January 2015
Source: CSLCT-AML-11-73 Interim report
The majority of adverse events were Common Terminology Criteria for Adverse Events 
(CTCAE) Grade 1 or 2. Four subjects were reported with Grade 3 adverse events related to 
treatment with CSL362. One subject from the 0.3 mg/kg cohort was reported with Grade 3 
hypertension. The remaining subjects with drug-related adverse events were from the 1.0 mg/kg
cohort. One subject was reported with Grade 3 pyrexia, another subject was reported with Grade 
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3 infusion-related reaction, and another subject was reported with Grade 3 chills, chest pain, 
hypoxia, and infusion-related reaction. All subjects recovered from the adverse events. No 
Grade 4 drug-related events have been observed. Serious adverse events considered related to 
CSL362 treatment were reported for 3 subjects including 2 cases of infusion-related reaction and 
a single case of transient Grade 2 delirium associated with multiple concomitant medications. 
The safety data are preliminary and are subject to change.
Pharmacokinetics and Immunogenicity: The serum CSL362 concentrations appear to be dose 
proportional for doses ranging from 3 to 9 mg/kg. The terminal half-life determined after the 6th 
dose at 3 mg/kg was 4.7 days and the accumulation index after every 2 weeks dosing was 1.7 for 
maximum observed concentration (Cmax) and 1.9 for the area under the curve (AUC). Low level 
anti-CSL362 antibody titers were detected coincident with trough concentrations of CSL362 in 
6 of 18 subjects tested thus far, with no apparent effects on pharmacokinetics or association with 
adverse events. 
Pharmacodynamics and Biomarkers: Indicative of the specific mode-of-action, ADCC, a 
rapid and complete in vivo depletion of CD123-expressing basophils and pDCs in the peripheral 
blood was observed for up to 15 days at CSL362 doses ≥3 mg/kg. Binding of CSL362 to CD123 
on monocytes demonstrates rapid and sustained saturation over the 14-day inter-dosing interval 
at CSL362 dose levels ≥3 mg/kg. 
1.2.1.
Recommended Phase 2 Dose (RP2D):
Based on PK, PD, and safety data generated in the ongoing Phase 1 study, 9 mg/kg of CSL362 
every 14 days has been selected as the dose and regimen for Phase 2 based on the following 
considerations:
Adequate PK and consistent saturation of CD123 target receptors on surrogate monocytes, 
and desired concentration of CSL362 at all sites of action, including bone marrow.
Based on preliminary data from the Phase 1 study, PK/PD modeling revealed that the 
concentration of 3 µg/mL of serum CSL362 is the upper boundary of the 90% CI of systemic 
concentration corresponding to at least 90% target engagement on monocytes.
While CD123 receptor occupancy on monocytes provides a convenient measure to monitor and 
characterize the PK/PD relationship in the peripheral compartment, it is important to note that a
key pharmacological target of CSL362 is in the leukemic stem cell niche in the bone marrow. 
Only a fraction of an antibody dose (approximately 30%) is distributed to the bone marrow,1 and
it is anticipated that the PD effect may be reduced in the bone marrow at doses that completely 
saturate peripheral targets. In addition, patients with active AML may also have higher leukemic 
blasts and higher levels of CD123 targets than the patient population in the Phase 1 study 
CSLCT-AML-11-73. Thus, higher systemic exposure may be required in order to ensure 
sustained target saturation throughout the dosing interval at the site of action.
Taking into consideration the serum CSL362 concentration of 3 µg/mL (which ensures 
peripheral target engagement and the limited biodistribution into the site of action), the desired 
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target serum concentration of CSL362 is projected to be 9 µg/ml, approximately 3 fold higher to 
ensure adequate and sustained exposure at the site of action. 
Based on simulations from a preliminary population PK model, 9 mg/kg every 14 days is the 
selected dose/dosing regimen to achieve sustained exposure above 9 µg/mL throughout the 
dosing interval. 
Acceptable safety profile 
No DLT or AEs ≥Grade 3 related to CSL362 occurred in subjects dosed at 9 mg/kg every 
14 days. Premedication with hydrocortisone and a prolongation of the infusion time to 3 hours 
effectively protected against Grade ≥ 3 infusion reactions. Since implementation of the protocol 
amendment to premedicate with hydrocortisone, no subjects treated at the 3 mg/kg or 9 mg/kg 
dose levels experienced a severe (Grade ≥ 3) infusion-related reaction. A cohort testing a higher 
dose of 12 mg/kg every 14 days is currently open for enrollment in the Phase I trial 
(CSLCT-AML-11-73). In summary, 9 mg/kg every 14 days is a well-tolerated dose and is the 
lowest dose that provides adequate exposure and sustained target saturation at the site of action 
throughout the entire dosing interval.
1.3.
DACOGEN (decitabine)
Decitabine (5 aza-2’-deoxycytidine) has a unique molecular mode-of-action. As a deoxycytidine 
nucleoside analog decitabine is primarily an inhibitor of DNA methyltransferase interfering with 
cytosine methylation in DNA.15 At low doses decitabine induces a hypomethylating effect when 
incorporated into DNA thus, reversing the aberrant epigenetic silencing of critical tumor 
suppressor genes through DNA hypermethylation. However, at higher doses decitabine may 
produce direct cytotoxic effects via DNA strand breaks.8 These activities of decitabine have been 
shown to correlate with the re-expression of silenced genes, cellular differentiation as well as 
with the inhibition of cell growth and the induction of apoptosis.24
In a randomized Phase 2 study comparing three dosing regimens, DACOGEN at a dose of 
20 mg/m2 per day infused IV over one hour on 5 consecutive days every 28 days optimally 
induced hypomethylation and provided the best clinical efficacy.19 With this regimen the 
half-life of decitabine was determined to be approximately 30 minutes and systemic
accumulation was not observed. In a randomized Phase 3 study conducted in patients with newly 
diagnosed AML and poor- or intermediate-risk cytogenetics, DACOGEN given as the 5-Day 
regimen demonstrated superior clinical efficacy compared to a treatment choice of supportive 
care or low-dose cytosine arabinoside.21 Decitabine treatment resulted in significantly improved 
rates of CR and CR without platelet recovery (CRp) compared with treatment choice.26 While 
the primary analysis for OS demonstrated an advantage favoring decitabine (7.7 months versus
5 months), which was however not statistically significant (p=0.108), an unplanned analysis of 
more mature survival data reached statistical significance (p=0.037).26 Based on the results of 
this Phase 3 study, DACOGEN was approved in the European Union (EU) and 21 other 
countries (as of November 2014) for the treatment of adult patients age ≥ 65 years with newly 
diagnosed de novo or secondary acute myeloid leukemia (AML), who are not candidates for 
standard induction chemotherapy. In addition, in the USA decitabine is a recommended 
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treatment option for AML patients 60 years or older who are not candidates for intensive 
chemotherapy according to the guidelines of the National Comprehensive Cancer Network.28
The adverse event profile of decitabine primarily includes myelosuppression (neutropenia, 
anemia, and thrombocytopenia) and consequences of myelosuppression (infections, fatigue, and 
febrile neutropenia). Nonhematologic adverse events associated with decitabine include nausea, 
vomiting, diarrhea, stomatitis, and alopecia. Generally these toxicities can be managed with 
supportive care measures, pharmacologic intervention, and dose adjustments. Specific 
information on the safety of decitabine is outlined in the prescribing information and can be 
found in the Investigator Brochure.15
1.4.
Overall Rationale for the Study
Similar to normal hematopoiesis, AML arises from a distinct population of leukemic stem cells 
(ie, LSCs) residing in the bone marrow that are able to self-renew and to propagate into leukemic 
blasts.37 In contrast to the highly proliferative blast cells, the pool of LSCs is often not affected 
by cytotoxic chemotherapies because these stem cells (i) persist in a quiescent G0 cell cycle 
phase and are not actively dividing (ii) reside in the bone marrow microenvironment that 
provides protection against apoptosis, and (iii) overexpress the multidrug resistance protein that 
enhances drug efflux.30
Effective AML therapies have to target both the highly proliferative and chemotherapy-sensitive 
leukemic blast cells as well as the quiescent and resistant LSC pool in order to achieve higher 
rates of durable CRs and more importantly longer disease-free- and overall survival (OS). As an 
antimetabolite and hypomethylating agent, decitabine targets proliferating leukemic blast cells 
and is a recognized treatment option for the therapy of patients with AML who are not eligible 
for intense chemotherapy or HSCT. Among different agents that may be used to deplete the LSC 
pool and kill leukemia blasts, antibodies that are able to penetrate the bone marrow and are 
capable of eliciting a potent, cytotoxic immune response have the potential to improve clinical 
outcomes.11,29 Effective targeting of the LSC pool is dependent on the ability of the antibody to 
specifically ablate leukemic blasts and the population of LSCs without affecting the regeneration 
of normal hematopoietic stem cells.
Although the exact phenotypes of CD34+/CD38- AML stem cells remain controversial, the 
constitutive over-expression of the CD123 antigen is common.11 CD123 over-expression on 
LSCs is conserved on the emerging leukemic blast cells and constitutes a marker of poor clinical 
prognosis because of the association with (i) known adverse immune-phenotypes such as FLT3 
internal tandem duplication (FLT3-ITD), (ii) a lower rate of complete responses following 
conventional chemotherapy and (iii) shorter disease-free survival and overall survival 
(OS).10,34,36 Levels of CD123 in normal hematopoietic stem cells and early hematopoietic 
progenitor cells are considerably lower than the overexpression found on LSCs and blasts in 
AML.10,17 Results from the ongoing Phase 1 study of CSL362 suggest that targeting 
CD123-overexpressing LSC and leukemic blast cells with an anti-CD123 antibody may not 
affect normal hematopoiesis.
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The safety assessments and confirmation of the RP2D in Part A of this study have been designed 
to supplement the biophysical and preclinical toxicology comparability testing of the anti-CD123 
monoclonal antibody produced in different Chinese hamster ovary cell lines; CSL362 was 
produced in the CHO-S cell line and used for the Phase 1 study while talacotuzumab was 
produced in GS-CHOK1SV cells and will be used for all subsequent clinical studies. Results 
from preclinical testing are provided in Section 1.1 and the talacotuzumab (JNJ-56022473)
Investigator’s Brochure.16
The scientific rationale for the seamless Phase 2/3 portion of this study (Part B) is that the
combination of decitabine and talacotuzumab may have a complimentary/synergistic effect on 
the leukemic cells. 
The complimentary and as such more pronounced therapeutic efficacy of the combination 
regimen is expected to evolve from the different underlying mechanisms of action and the 
different leukemic cell populations targeted by the two agents. Therapy with decitabine reverses 
the hypermethylation-induced gene silencing and restores the proliferation control and the 
apoptosis sensitivity in proliferating leukemic blast cells. Talacotuzumab has the potential to
elicit a direct immunotherapeutic effect against CD123 overexpressing quiescent LSCs and 
leukemic blasts through re-direction of NK-cells and induction of ADCC. These 2 agents are 
also expected to have non-overlapping toxicity profiles; decitabine is primarily myelosuppressive 
while the most frequent toxicity from administration of talacotuzumab is infusion reactions.
Additionally, the administration of the 2 agents is sequential and staggered, minimizing the 
likelihood of toxicities due to the combination treatment.
In addition, the combination of decitabine and talacotuzumab may also lead to a potent, 
synergistic therapeutic effect. It has been shown that decitabine at continuous, low doses 
improves innate immunity by stimulating proliferation, survival, and activity of NK-cells.23,31 In 
an initial series of experiments, decitabine treatment stimulated and augmented NK reactivity 
measured by IFNγ mRNA expression and protein release in response to activating stimuli in 
vitro.31 In a follow-up study, it was demonstrated that exposure to decitabine at low doses
(7 mg/m2) over 5 days decreased the expression of inhibitory receptors (eg, KIR) and increased 
the expression of activating receptors (eg, NKG2D and NKp44) on activated NK cells in vitro.23
The authors propose that novel therapeutic strategies involving decitabine should aim at 
combining the “direct effect of decitabine on malignant cells with its ability to enhance reactivity 
of NK cells in immunotherapeutic approaches”.31 Thus, decitabine exposure at the approved low 
dose of 20 mg/m2 over the extended treatment period of 5 days may stimulate innate NK 
cell-mediated immunity and thus enhance the ADCC-dependent anti-leukemic activity of
talacotuzumab. 
In the dosing schedule proposed for the combination regimen, talacotuzumab will be given after
decitabine in order to take advantage of the potential stimulation of the innate immunity. This 
will allow the combination of full therapeutic doses of decitabine (eg, 20 mg/m2) and 
talacotuzumab (9 mg/kg, confirmed in Part A). Additionally, the safety profiles of the agents
indicate that toxicities are not overlapping and adverse events will be managed with monitoring 
and supportive care.
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2.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS
2.1.
Objectives and Endpoints
2.1.1.
Objectives
Primary Objectives
Part A: to assess the safety of talacotuzumab monotherapy and confirm the RP2D in subjects
with AML for whom experimental therapy is appropriate (as assessed by their treating 
physician).
Part B: The primary objectives of the study are to assess CR rate and OS in subjects with 
previously untreated AML who are not eligible for intense induction chemotherapy and who are 
randomly assigned to receive decitabine plus talacotuzumab at the RP2D or decitabine alone. 
Secondary Objectives (Part B)
The secondary objectives are: 

To assess EFS;

To determine the overall response rate (ORR) defined as rate of complete response (CR) and 
complete response with incomplete blood count recovery (CRi);

To determine the rate of CR plus MRD negative CRi

To assess the relapse-free survival (RFS);

To assess time to response and duration of response for subjects who achieve CR/CRi;

To assess minimal residual disease (MRD); 

To assess the safety profile of talacotuzumab in combination with decitabine;

To assess the pharmacokinetics of talacotuzumab and decitabine alone and in combination;

To assess the immunogenicity talacotuzumab alone (Part A) and in combination with 
decitabine (Part B);

To assess patient-reported outcomes (PROs) using the FACT-Leu and EQ-5D-5L.
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Exploratory Objectives
The exploratory objectives are:

To explore PK/PD relationships of talacotuzumab through analysis of talacotuzumab PK,
biomarkers, PD markers, and clinical end points;

To explore biomarkers predictive of clinical response;

To collect medical resource utilization (MRU) data that may be used in future economic 
modeling (the construction and reporting of the economic model will be conducted 
separately from this study).
2.1.2.
Endpoints
Primary Endpoint (Part A)
Safety and DLT determination
2 Primary Endpoints (Part B)

CR rate

OS 
Secondary Endpoints (Part B)

EFS, defined as the time from randomization to treatment failure, relapse from CR/CRi, or 
death from any cause, whichever occurs first. Treatment failure is defined as >25% absolute 
increase in the bone marrow blast count from baseline to the present assessment.

ORR rate (CR + CRi);

Rate of CR plus MRD negative CRi;

Time to response, defined for subjects who achieved best response of CR or CRi as time 
from randomization to achieving the best response;

Duration of response, defined for subjects who achieved best response of CR or CRi as time 
from achieving CR or CRi to relapse;

Relapse-free survival (RFS) defined for subjects who achieved CR or CRi as the time from 
achieving CR or CRi to disease relapse or death from any cause;

Safety profile;

Pharmacokinetics; 

Immunogenicity;

MRD;

Patient-reported outcomes (PROs) using the FACT-Leu and EQ 5D 5L. 
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Exploratory Endpoints (Part B))

Pharmacokinetic/pharmacodynamic relationships associated with biomarkers, PD markers 
and clinical end points; 

To explore biomarkers associated with clinical response;

Medical resource utilization.
2.2.
Hypothesis
In patients with previously untreated AML who are not eligible for intense induction 
chemotherapy it is hypothesized that treatment with a combination regimen of decitabine and 
talacotuzumab as compared with decitabine alone, will improve CR rate or extend survival or 
both.
3.
STUDY DESIGN AND RATIONALE
3.1.
Overview of Study Design
This is a 2-part, open-label, multicenter, seamless Phase 2/3 study conducted in subjects with 
AML who are suitable for experimental therapy (Part A) and in subjects with untreated AML 
who are not eligible for intense induction chemotherapy or hematopoietic stem cell 
transplantation (HSCT; hereafter referred to as not eligible for intense chemotherapy) (Part B).
In Study Part A, the safety, PK and PD profile, and RP2D of 9 mg/kg talacotuzumab will be 
confirmed. In Part B, subjects will be randomized 1:1 into either Arm 1 (decitabine + 
talacotuzumab) or Arm 2 (decitabine alone). Blood and bone marrow sampling for disease 
assessment, PK, PD, and biomarkers will be mandatory for all subjects in the study.
Part A: Recommended Phase 2 Dose Confirmation 
The safety assessments and confirmation of the RP2D in Part A of this study have been designed 
to supplement the biophysical and preclinical toxicology comparability testing of the anti-CD123 
monoclonal antibody produced in different Chinese hamster ovary cell lines. Comparability 
testing of talacotuzumab and CSL362 has shown the antibodies to behave similarly in 
biophysical, biochemical, and preclinical assessments. See Section 1.1 and the talacotuzumab
(JNJ-56022473) Investigator’s Brochure16 for information regarding the biophysical and 
preclinical toxicology studies.
Six subjects will be enrolled in Part A and receive 1 dose of talacotuzumab at 9 mg/kg on Day 1 
as a 180-minute IV infusion. Dose-limiting toxicities (DLTs) will be assessed during the DLT 
evaluation period (Cycle 1; 14 days). All subjects will receive premedication with 
hydrocortisone or equivalent IV steroid to prevent infusion reactions. Refer to the Dosage and 
Administration schedule (Section 6 Dosage and Administration) for further detail.
Pharmacokinetic and pharmacodynamic assessments will be conducted during the 14-day 
talacotuzumab evaluation period (see Time and Events Schedule Table 2A). Upon completion of 
dosing, there will be a review of all available study data by a Study Evaluation Team (SET) to 
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confirm the RP2D of 9 mg/kg talacotuzumab. If no DLTs are observed or are observed in 1 of 
the 6 subjects, the dose of 9 mg/kg talacotuzumab may be established as the RP2D by the SET. If 
DLTs are observed in ≥2 of the 6 subjects, Part A may continue with additional enrollment of 
3 to 6 subjects at a lower dose level of talacotuzumab to be determined by the SET.
Dose-limiting toxicities (DLT) are adverse events that occur up to the end of Cycle 1, meet the 
following criteria, and are confirmed by the SET:

CTCAE Grade 4 non hematological toxicities

CTCAE Grade 3 non hematological toxicities that persists for ≥7 days despite best 
supportive care according to institutional standards. 
After the RP2D for talacotuzumab is confirmed, Part B can be initiated.
Subjects in Part A will continue on study (remaining in Part A) and start subsequent cycles of the 
combined study therapy with decitabine at the dose of 20 mg/m2 IV on Day 1 to Day 5 followed 
by 9 mg/kg (or a lower dose if determined by the SET) talacotuzumab on Day 8 and Day 22 of a 
28-day cycle. Subjects will continue study therapy as outlined in Section 6 until treatment failure 
(as defined in Section 9.2.1.1), relapse from CR/CRi, unacceptable toxicity, or death as described 
in Section 10.2.
Part B:
Part B is designed to be a seamless Phase 2/3 study with 2 primary endpoints, CR rate and OS. 
Subjects will be randomized in a 1:1 ratio to receive either decitabine + talacotuzumab (Arm 1) 
or decitabine alone (Arm 2). Randomization will be stratified by baseline ECOG performance 
status (0-1 versus 2) and type of AML (de novo versus secondary). The study will have 3 interim 
analyses. The first interim analysis will occur after approximately 80 subjects (40 subjects per 
arm) have been randomized and followed for at least 4 months. Guided by predefined statistical 
criteria based on CR and CR+CRi rates and central review of data (see Section 11.2), the study 
will either continue enrollment to the full pre-specified Phase 3 sample size of 400 subjects or 
discontinues enrollment. A total of approximately 120 subjects are expected to have been 
randomized by the time the outcome of the interim analysis is available. No changes in design 
elements are planned based on this interim analysis.
If the enrollment continues to 400 subjects (approximately 200 subjects per arm), the 
pre-specified design elements are:

A second interim analysis occurs after 160 subjects (approximately 80 subjects per arm) 
have been randomized and followed for at least 4 months; this is the final analysis for CR 
and the first interim analysis for OS. The study will not be stopped on the basis of the CR 
results;

A third interim analysis (ie, the second interim analysis of OS) will be conducted when 
180 deaths have occurred;

The final analysis of OS will take place when 270 deaths have occurred or 6 months after 
the last subject was enrolled whichever occurs first.
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If the study stops enrollment based on the pre-specified criteria, it is expected that approximately 
120 subjects will have been randomized. These subjects will continue to be followed. The 
clinical cut-off in this case will be when 90 EFS events have occurred.
Part A and Part B: Subject participation will include a Screening Phase, a Treatment Phase, 
and a Follow-up Phase. The Screening Phase will be up to 28 days prior to start of study therapy 
in Part A or up to 28 days prior to randomization in Part B. The Treatment Phase begins with
start of study therapy (Part A) or randomization (Part B) and continues until the 
End-of-Treatment 
Visit. 
The 
Follow-up 
Phase 
begins 
immediately 
following 
the 
End-of-Treatment Visit, and continues until death, loss to follow up, consent withdrawal for 
study participation, or study end, whichever occurs first. Subjects will receive study treatment 
until treatment failure, relapse from CR/CRi, or death, unless discontinued early because of 
unacceptable toxicity, or other reasons specified in Section 10.2. The median time to response in 
a Phase 3 study of DACOGEN was 4.3 months.6 Additional responses were noted after 
4 months. For this study, it is recommended that for subjects who do not have evidence of 
treatment failure to continue decitabine treatment. Subjects in Arm 1 may discontinue one of the 
study agents (decitabine or talacotuzumab) because of unacceptable toxicity and continue 
treatment with the other agent until treatment failure, relapse from CR/CRi, or death, unless 
discontinued early because of unacceptable toxicity.
All study evaluations will be conducted according to the Time and Events Schedule Tables 1A,
1B,1C and 1D. Disease evaluations will include clinical presentation, peripheral blood, and bone 
marrow assessments. Disease status will be evaluated according to the modified “Response 
Criteria in AML” (Section 9.2.1.1).9 During the Treatment Phase, safety evaluations will include 
adverse event monitoring, vital sign measurements, physical examinations, clinical laboratory 
parameters (hematology and chemistry), and Eastern Cooperative Oncology Group (ECOG) 
performance status. Additional blood samples will be drawn for assessment of pharmacokinetic 
and pharmacodynamics parameters and a pharmacogenomics blood sample will be collected to 
allow for exploratory biomarker activities. 
Study Evaluation Team (SET): A SET will monitor preliminary safety and study conduct data 
on an ongoing basis during the study for Part A. The SET will consist of selected investigators, 
sponsor medical monitors, the sponsor’s statistician, and the sponsor’s clinical pharmacologist, 
or their designees. The scope of this safety review will be detailed in the SET Charter. Decisions 
regarding DLT determination, dose de-escalation, changes in the timing of pharmacokinetic or 
pharmacodynamic sampling, exploration of alternative schedule(s), cycle duration, or other study 
conduct recommendations, will be made by the SET and documented in a SET decision 
document and distributed to investigators. The Institutional Review Board (IRB) will be notified 
before implementation of any SET decision, if required. This document will be provided in the 
sponsor’s instruction manual and retained in the study master file and in the study center’s files.
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During Part A, the SET will review all available data upon completion of the 14-day period 
following talacotuzumab treatment (Cycle 1) to determine DLTs, and subsequently, will confirm
the RP2D. Additionally, accumulated safety data will be reviewed for subjects in Part A who are 
receiving combination therapy prior to the start of Part B. The following data will be reviewed as 
available: study compliance (including drug exposure as applicable), adverse event and safety
profile, PK, and PD. The SET recommendations will be documented in a SET recommendations 
document and distributed to investigators. 
Independent Data Monitoring Committee: An Independent Data Monitoring Committee 
(IDMC) will be established to evaluate safety and efficacy data collected during Part B of the 
study.
The IDMC will conduct a safety review of accumulated data from Part A and Part B when 
approximately 20 subjects from Part B (10 subjects from each arm) have been enrolled and 
followed for at least 1 month to assess the safety and tolerability of the combination regimen. 
The IDMC will also be responsible for reviewing the formal efficacy interim analyses as 
described in Section 11.2, and make recommendations for the study conduct. An IDMC charter
will describe the policies and procedures.
Independent Central Review: In addition to evaluations by investigators, disease status will be 
reviewed and determined by an independent central review in a blinded fashion. A charter will 
describe the policies and procedures in detail.
Note: After review of the data from Interim Analysis #2, the IDMC informed the Sponsor that 
the futility criterion for OS was met and that the CR rate did not meet per-protocol defined 
statistical significance. Given the lack of efficacy advantage of talacotuzumab + decitabine 
versus decitabine alone, the incidence of infusion-related reactions, and the complexities with 
premedications for drug administration, the benefit/ risk ratio is not favorable to continue 
treatment with talacotuzumab. The IDMC recommended closure of enrollment to the study and 
that subjects receiving talacotuzumab + decitabine should discontinue talacotuzumab treatment 
and may continue decitabine alone, according to Principal Investigator decision and subject 
agreement. All subjects will continue to be followed for survival and subsequent anti-cancer 
therapy. During the treatment phase with decitabine, subjects will be monitored for serious 
adverse events.
The end of study data collection is defined as when 270 deaths have occurred or 6 months after 
the last subject is enrolled, whichever occurs first. At that time, follow up of subjects will end. 
Subjects who are continuing to derive benefit from decitabine treatment as assessed by their 
investigator may continue to receive decitabine; during this period, only serious adverse events 
will be monitored and entered into the Company safety repository as described under 
Amendment 7.
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3.2.
Study Design Rationale
Rationale for Single Agent Talacotuzumab Monotherapy in Part A
Studies with CSL362 identified 9 mg/kg as the RP2D. Talacotuzumab is produced in a different 
cell line with a different process compared with the Phase 1 study (CSLCT-AML-11-73) 
CSL362 drug product. To confirm the safety and RP2D of talacotuzumab, a safety run-in period
of talacotuzumab at 9 mg/kg will be evaluated first as monotherapy in Part A of this study.
Rationale for DACOGEN
Decitabine is an appropriate comparator in this study as it is approved for the treatment of this 
AML population in the European Union (EU) and 21 other countries (as of November 2014) and 
is a treatment option recommended in treatment guidelines such as the National Comprehensive 
Cancer Network.9,28
The proposed schedule of decitabine administered at a dose of 20 mg/m2 body surface area by IV 
infusion over 1 hour repeated daily for 5 consecutive days (ie, 5 doses per treatment cycle) is
outlined in more detail in the prescribing information. The total daily dose of decitabine must not 
exceed 20 mg/m2 and the total dose per treatment cycle must not exceed 100 mg/m2. 
Rationale for Dose of Talacotuzumab
Safety: The talacotuzumab dose and schedule for this study was planned using CSL362 results 
from a Phase 1 study (CSLCT-AML-11-73). CSL362 has been deemed safe and well tolerated as 
no AE ≥CTCAE Grade 3 has occurred in 9 subjects dosed at 9 mg/kg every 14 days in the 
CSL-sponsored Phase 1 study. Despite the initially observed adverse event of severe (CTCAE 
Grade 3) infusion-related reaction at low doses, no subject at the 9-mg/kg dose level experienced 
a severe infusion related reaction after the institution of mandatory pre-medication and a 
prolonged infusion time to 3 hours. 
Pharmacokinetics: With CSL362, the 9 mg/kg dose exhibits predictable PK above the nonlinear 
pharmacokinetic range where higher clearance and shorter half-life was observed at lower doses. 
Additionally, the half-life of 4 to 5 days supports the every 14-day dosing frequency. At 
9 mg/kg, the trough concentration of CSL362 from the majority of subjects is expected to exceed 
the estimated concentration needed to saturate the CD123 target as measured by the peripheral 
marker monocytes. This dose is selected to ensure sustained target saturation throughout the 
dosing period, particularly considering that 1 of the therapeutic targets is anticipated to be the 
leukemic stem cell niche in the bone marrow. 
Pharmacodynamics: For CSL362, the pharmacodynamic pattern and kinetics of biomarkers, 
including basophils, pDC cells, NK cells, monocytes, etc. are generally comparable regardless of 
the cycle number. Aside from CD123 expressing cell types, CSL362 at 9 mg/kg does not seem to 
significantly affect other cells, or only affect transiently with return to baseline expected within 
3 days, as in the case of NK cells. In summary, 9 mg/kg every 2 weeks is a safe dose within the 
linear PK dose range that is expected to provide adequate exposure and sustained target 
saturation throughout the dosing interval for both peripheral and bone marrow blasts and LSCs. 
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Rationale for Talacotuzumab Dose in Combination with DACOGEN
Decitabine has a safety profile that allows for its use as an outpatient therapy for elderly and 
physically impaired patients with AML.25 Treatment with decitabine is associated with 
myelosuppression and adverse events related to myelosuppression (ie, thrombocytopenia, 
anemia, neutropenia, and febrile neutropenia) which are however common in both treated and 
untreated patients with AML.15 Decitabine administered at the recommended dose (20 mg/m2) 
and schedule (Days 1 to 5) currently is being tested in combination with a variety of 
experimental compounds.25,26 The safety and PK data obtained for CSL362 in the ongoing Phase 
1 study support the proposed combination regimen with decitabine using full doses of both 
agents. The safety profiles of both agents are considerably different. While treatment with 
decitabine may exacerbate the myelosuppression frequently observed in patients with AML, no 
impact on normal hematopoiesis was observed in AML patients in CR exposed to increasing 
doses of CSL362. This Phase 1 safety observation supports the scientific hypothesis that CD123 
is differentially expressed on normal hematopoietic stem cells and LSCs. Therefore, by 
specifically targeting the LSCs and the emerging leukemic blast cells, the addition of 
talacotuzumab may not lead to an aggravation of the myelosuppression or extension of the time 
of hematopoietic recovery observed
in AML patients receiving decitabine. Lastly, 
pharmacokinetic drug-drug interaction between decitabine and talacotuzumab is not expected 
given the different absorption, distribution, metabolism, and excretion (ADME) properties and 
metabolic pathways utilized by these agents. 
Rationale for Randomization
In Part B, subjects will be randomized to receive either decitabine + talacotuzumab (Arm 1) or 
decitabine alone (Arm 2). Randomization will minimize bias in the assignment of subjects to 
treatment groups, to increase the likelihood that known and unknown subject attributes 
(eg, demographic and baseline characteristics) are evenly balanced across treatment groups, and 
to enhance the validity of statistical comparisons across treatment groups. Additionally, 
enrollment into the treatment arms is stratified by baseline ECOG performance status score 
(0-1 versus 2) and type of AML (de novo versus secondary), prognostic factors known to affect 
clinical outcomes.9
After Interim Analysis #2, enrollment to the study was closed. Subjects receiving talacotuzumab 
+ decitabine (Arm 1) stopped talacotuzumab treatment and were allowed to continue to receive 
decitabine alone, according to Principal Investigator decision and subject agreement. This was 
based on an IDMC review that noted a lack of efficacy advantage of talacotuzumab + decitabine 
versus decitabine alone, the incidence of infusion-related reactions, and the complexities with 
premedications for drug administration that made the benefit/ risk ratio not favorable to continue 
treatment with talacotuzumab. 
Rationale for Primary Endpoints
For this Phase 2/3 study, CR rate and OS are chosen as the 2 primary endpoints for the reason 
that a higher CR rate would be an early and clinically meaningful measure of efficacy and an 
improvement in OS would demonstrate the broadest and most meaningful measure of treatment 
benefit.32
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Rationale for Biomarker Evaluation
Biomarker samples will be collected to evaluate the mechanism of action of the combination of
decitabine + talacotuzumab, to establish the threshold of CD123 expression needed for clinical
response, and to help explain inter-individual variability in clinical outcomes or to identify 
population subgroups that respond differently to decitabine + talacotuzumab or decitabine alone. 
Rationale for Pharmacodynamic Marker Evaluation
Previous CSL362 pre-clinical and clinical studies in subjects with AML demonstrated that 
CD123-positive pDC and basophils are reliable cellular pharmacodynamic markers for CSL362 
activity.3,33 These cells were completely depleted within hours of CSL362 infusion and depletion 
was sustained for ≥ 15 days at doses ≥ 3.0 mg/kg. Natural killer cells are critical to the 
mechanism of action of talacotuzumab (CSL362) and quantification may reveal an association 
with clinical response. Natural killer cell counts are reduced in the first few hours after dosing 
but stabilized at Day 3 and thereafter, indicating that this fluctuation may be caused by NK cell
redistribution.33
Rationale for Assessment of CD123 Expression
CD123 is expressed in AML blasts and LSCs in a large percentage of AML patients 
(75-89%).14,17,27 The percentage of CD123+ leukemic blasts at diagnosis has been correlated 
with a poor response to intensive chemotherapy.36 In a study by Ehninger,10 78% of newly 
diagnosed AML patients had AML blasts that were positive for CD123 expression. The cutoff 
for positive flow measurements in this study was set to >10, based on the geometric mean 
fluorescence intensities (MFIs) of CD123 in blasts in relation to the MFIs of lymphocytes 
(considered negative for CD123).10
Rationale for Minimal Residual Disease Assessment
Assessment of minimal residual disease (MRD) is becoming an important evaluation to 
determine the depth of response beyond clinical CR in AML and other hematologic 
malignancies,13 and it has been shown that MRD assessment adds prognostic value beyond both 
karyotype and specific gene mutations.2,18
Rationale for Immunophenotyping
The activity of talacotuzumab depends on its ability to engage its target (CD123) and recruit 
effector cells of the immune system for cell killing. Therefore, the ultimate activity of this agent 
depends not only on expression of the target by AML blasts and LSCs, but also on the fitness of 
the host immune system. Therefore, we will determine the state of the host’s immune system. In 
addition, the biomarker plan will attempt to address the effect of decitabine on the host immune 
system, with particular attention to NK effector cell number and function.
4.
SUBJECT POPULATION
The screening period for eligible subjects for this study will be performed within 28 days before 
the first dose of study therapy (Part A) or within 28 days before randomization (Part B).
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The inclusion and exclusion criteria for enrolling subjects in this study are described in the 
following 2 subsections. If there is a question about the inclusion or exclusion criteria below, the 
investigator must consult with the appropriate sponsor representative and resolve any issues
before enrolling a subject in the study. Waivers are not allowed.
For a discussion of the statistical considerations of the number of subjects, refer to Section 11.3, 
Sample Size Determination.
4.1.
Inclusion Criteria
Each potential subject must satisfy all of the following criteria to be enrolled in the study. These 
criteria are applicable for both Part A and Part B of the study unless otherwise noted.
1
Criterion Modified per Amendment 1
1.1
1.2
Criterion Modified per Amendment 2
AML according to WHO 2008 criteria35 fulfilling all of the following criteria:
For Part A: 
Patients with AML (treatment naive or relapsed) for whom experimental therapy is 
appropriate (as assessed by their treating physician); 
For Part B:

≥75 years of age or

≥65 up to 75 years of age and have at least one of the following:
o
Congestive heart failure or ejection fraction ≤50%
o
Creatinine >2 mg/dL, dialysis or prior renal transplant
o
Documented pulmonary disease with lung diffusing capacity for carbon 
monoxide (DLCO) ≤65% of expected, or forced expiratory volume in 
1 second (FEV1) ≤65% of expected or dyspnea at rest requiring oxygen
o
ECOG performance status of 2
o
Prior or current malignancy that does not require concurrent treatment
o
Unresolved infection
o
Comorbidity that, in the Investigator’s opinion, makes the patient unsuitable 
for intensive chemotherapy and must be documented and approved by the 
Sponsor before randomization

De novo or secondary AML
(post myelodysplastic syndrome [MDS] or 
myeloproliferative neoplasm [MPN] or after leukemogenic chemotherapy); 

Previously untreated AML (except: emergency leukopheresis and/or hydroxyurea 
during the screening phase to control hyperleukocytosis but must be discontinued at 
least one day prior to start of study therapy);

Not eligible for an allogeneic hematopoietic stem cell transplantation.
2.
ECOG Performance Status score of 0, 1 or 2.
3.
Criterion Modified per Amendment 1
3.1
3.2
Criterion modified per Amendment 2
Criterion modified per Amendment 3
The following clinical laboratory values at screening:
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Hematology: 

Platelet count ≥ 10 x 109/L (with or without transfusions)

White blood cell count (WBC) ≤ 40 x 109/L (Note: leukopheresis or hydroxyurea is 
permitted to decrease WBC count but must be discontinued 1 day prior to start of study 
therapy)
Hepatic: 

Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤ 2.5 times 
ULN; for subjects with leukemic infiltration of the liver, AST and ALT ≤ 5 times ULN 
is permitted
Total Bilirubin ≤ 1.5 times ULN unless bilirubin rise is due to Gilbert’s syndrome or of 
non-hepatic origin
4.
A woman must be either:

Not of childbearing potential: postmenopausal (>45 years of age with amenorrhea for 
at least 12 months);

Of childbearing potential and practicing a highly effective method of birth control 
consistent with local regulations regarding the use of birth control methods for subjects 
participating in clinical studies for at least 3 months: eg, established use of oral,
injected or implanted hormonal methods of contraception; placement of an intrauterine 
device (IUD) or intrauterine system (IUS); barrier methods: condom with spermicidal 
foam/gel/film/cream/suppository or occlusive cap (diaphragm or cervical/vault caps) 
with spermicidal foam/gel/film/cream/suppository; male partner sterilization (the 
vasectomized partner should be the sole partner for that subject); true abstinence (when 
this is in line with the preferred and usual lifestyle of the subject)
Note: If the childbearing potential changes after start of the study (eg, woman who is 
not heterosexually active becomes active, premenarchal woman experiences menarche) 
a woman must begin a highly effective method of birth control, as described above.
5.
A woman of childbearing potential must have a negative serum (-human chorionic 
gonadotropin [-hCG]) or urine pregnancy test at screening. 
6.
A man who is sexually active with a woman of childbearing potential and has not had a 
vasectomy must agree to use a barrier method of birth control eg, either condom with 
spermicidal foam/gel/film/cream/suppository or partner with occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/suppository for at least 3 months 
after last study treatment.
7.
Each subject (or their legally acceptable representative) must sign an informed consent 
form (ICF) indicating that he or she understands the purpose of and procedures required for 
the study and are willing to participate in the study. 
4.2.
Exclusion Criteria
Any potential subject who meets any of the following criteria will be excluded from participating 
in the study. These criteria are applicable for both Part A and Part B of the study unless 
otherwise noted. 
1.
Acute promyelocytic leukemia with t(15;17), or its molecular equivalent (PML-RARα).
2.
For Part B only: Known leukemic involvement or clinical symptoms of leukemic 
involvement of the central nervous system.
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3.
Criterion Modified per Amendment 1
3.1
Subjects who received prior treatment with a hypomethylating agent. 
4.
For Part A only: Subjects who did not recover from all clinically significant toxicities 
(excluding alopecia and hematologic toxicities) of any previous surgery, radiotherapy, 
targeted therapy, or chemotherapy to less than or equal to Grade 1;
5.
Criterion modified per Amendment 1
5.1
5.2
Criterion Modified per Amendment 2
A diagnosis of other malignancy that requires concurrent treatment.
6
6.1.
Criterion Modified per Amendment 2
Any uncontrolled active systemic infection that requires treatment with IV antibiotics 
7.
Criterion Modified per Amendment 1
7.1
A history of human immunodeficiency virus (HIV) antibody positive or tests positive for 
HIV if tested at screening 
8.
8.1
Criterion Modified per Amendment 2
Active systemic hepatitis infection requiring treatment or other clinically active liver 
disease
9.
9.1
Criterion Modified per Amendment 2
Criterion modified per Amendment 3
Unstable angina 
10.
10.1
Criterion Removed per Amendment 2
11.
QTcF > 470 ms, or QTcF prolongation at screening deemed clinically relevant by the 
investigator
12.
Criterion modified per Amendment 1
12.1
12.2
Criterion Removed per Amendment 2
13.
Known allergies, hypersensitivity, or intolerance to talacotuzumab or decitabine or its 
excipients15,16
14.
14.1
Criterion Modified per Amendment 2
Any condition for which, in the opinion of the investigator, participation would not be in 
the best interest of the subject (eg, compromise the well-being) or physical limitations that 
could prevent, limit, or confound the protocol-specified assessments
15.
Major surgery, (eg, requiring general anesthesia) within 4 weeks before screening, or will 
not have fully recovered from surgery, or has surgery planned during the time the subject 
is expected to participate in the study
Note: subjects with planned surgical procedures to be conducted under local anesthesia 
may participate. In such cases, the investigator must notify the sponsor before 
randomization. 
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NOTE: Investigators should ensure that all study enrollment criteria have been met at screening. 
If a subject's clinical status changes (including any available laboratory results or receipt of 
additional medical records) after screening but before 1) Cycle 1 Day 1 for Part A or 2) 
randomization for Part B such that he or she no longer meets all eligibility criteria, then the 
subject should be excluded from participation in the study. Section 17.4, Source Documentation, 
describes the required documentation to support meeting the enrollment criteria.
4.3.
Prohibitions and Restrictions
Potential subjects must be willing and able to adhere to the following prohibitions and 
restrictions during the course of the study to be eligible for participation:
1.
Refer to Section 8 PRESTUDY AND CONCOMITANT THERAPY for details 
regarding prohibited and restricted therapy during the study.
2.
Agree to follow all requirements that must be met during the study as noted in the 
Inclusion and Exclusion Criteria (eg, contraceptive requirements).
5.
TREATMENT ALLOCATION AND BLINDING
Treatment Allocation
Procedures for Randomization and Stratification
Central randomization will be implemented in this study for Part B using an interactive web 
response system (IWRS). Subjects will be stratified by baseline ECOG performance status score 
(0-1 versus 2) and type of AML (de novo versus secondary) and then assigned randomly to 1 of 
2 treatment groups based on a computer-generated randomization schedule prepared before the 
study by or under the supervision of the sponsor.
After Interim Analysis #2, enrollment to the study was closed and therefore the IWRS was 
closed to randomization of new subjects.
Blinding
As this is an open study, blinding procedures are not applicable.
6.
DOSAGE AND ADMINISTRATION
6.1.
Dosing Schedule
6.1.1.
Part A
In Part A of the study dosing will occur as per Table 2 below.
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Table 2: 
Dosing Schedule for Part A
Cycle 1
Talacotuzumab
All subsequent cycles 
Study Day
1
2-14
1
2
3
4
5
6-7
8
9-21
22
23-28
Decitabine
(20 mg/m2)
X
X
X
X
X
Talacotuzumab
(9 mg/kg)
X
X
X
Cycles may be delayed due to recovery from toxicity or other causes. 
6.1.2.
Part B
In Part B of the study, subjects will receive study therapy according to the arm to which they are 
assigned. The start of each cycle is defined as the date of the first dose of decitabine. Cycles may 
be delayed due to recovery from toxicity or other causes. Study treatment continues until 
treatment failure, relapse from CR/CRi, unacceptable toxicity, death, or other reasons specified 
in Section 10.2.
In Arm 1, study therapy Cycle 1 will start with decitabine at a dose of 20 mg/m2 IV administered 
daily for five consecutive days followed by IV treatment with talacotuzumab (at the RP2D) on 
Days 8 and 22 (± 24 hours) of a 28-day cycle. Subsequent cycles of study therapy will follow the 
same dosing schedule as Cycle 1 as outlined in Table 3.
Table 3: 
Dosing Schedule for Part B - Arm 1 
All treatment cycles
Study Day
1
2
3
4
5
6-7
8
9-21
22
23-28
Decitabine
(20 mg/m2)
X
X
X
X
X
Talacotuzumab
(RP2D mg/kg)
X
X
Subjects assigned to Arm 2 will receive decitabine at a dose of 20 mg/m2 IV administered daily 
for five consecutive days. A Cycle of study therapy will be repeated every 28 days from the first 
dose of decitabine onwards. The dosing schedule for Arm 2 is outlined in Table 4.
Table 4: 
Dosing Schedule for Part B - Arm 2 
All treatment cycles
Study Day
1
2
3
4
5
6-28
Decitabine
(20 mg/m2)
X
X
X
X
X
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Investigators should be aware that for treatment with decitabine as monotherapy or in 
combination, it is recommended that subjects be treated for a minimum of 4 cycles; however, a 
complete or partial response may take longer than 4 cycles.
Study treatment is to continue until treatment failure, relapse from CR/CRi, or death, unless 
discontinued early because of unacceptable toxicity. Subjects in Arm 1 may discontinue 1 of the 
study treatments (decitabine or talacotuzumab) because of unacceptable toxicity and continue 
treatment the other agent until treatment failure, relapse from CR/CRi, or death, unless 
discontinued early because of unacceptable toxicity.
Following Amendment 6, enrollment to the study was closed and subjects receiving 
talacotuzumab + decitabine should discontinue talacotuzumab treatment and may continue to 
receive decitabine alone, according to Principal Investigator decision and subject agreement.
Following Amendment 7 and when 270 deaths have occurred or 6 months after the last subject is 
enrolled (whichever occurs first), follow up of subjects and data collection will end. Subjects 
who are continuing to derive benefit from decitabine treatment as assessed by their investigator 
may continue to receive decitabine; during this period, only serious adverse events will be 
monitored and entered into the Company safety repository.
6.2.
Decitabine
6.2.1.
Preparation and Administration of Decitabine
Decitabine will be supplied as a lyophilized powder in a single-dose vial of 50 mg per vial. 
Decitabine powder should be reconstituted as outlined in the prescribing information. Decitabine
will be administered at a dose of 20 mg/m2 by continuous IV infusion over 1 hour repeated daily 
for 5 days at the start of each cycle. The 5-Day decitabine treatment will be repeated every
28 days. 
6.2.2.
Decitabine: Premedication
As outlined in the prescribing information, subjects receiving decitabine may be premedicated 
with anti-emetic therapies according to institutional standards. 
6.2.3.
Decitabine Dose Modifications
Treatment with decitabine may be delayed for up to 28 days at the discretion of the investigator, 
if the subject experiences disease related complications such as myelosuppression-associated 
complications (such as: febrile neutropenia [temperature ≥38.5°C and absolute neutrophil count 
<1000/µL], active viral, bacterial or fungal infection [ie, requiring intravenous anti-infectives or 
extensive supportive care], hemorrhage [gastrointestinal, genito-urinary, pulmonary with 
platelets <25000/µL or any central nervous system hemorrhage]). The treatment with decitabine
may be resumed once these conditions have improved or have been stabilized with adequate 
treatment (anti-infective therapy, transfusions, or growth factors). If there is more than a 28-day 
dose delay, the subject may be permitted to continue treatment if the investigator believes it is in 
the best interest of the subject. Dose reduction is not recommended.
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In Arm 1, if a subject discontinues decitabine because of unacceptable toxicity, they should 
continue treatment with talacotuzumab alone.
6.3.
Talacotuzumab
6.3.1.
Preparation and Administration of Talacotuzumab
Talacotuzumab will be supplied as a lyophilized product containing 100 mg of active 
pharmaceutical ingredient (50 mg/mL after reconstitution with 2.0 mL sterile water for 
injection). 
The talacotuzumab dose administered will be dependent upon the subject’s weight at the Day 1 
assessment of each cycle. The talacotuzumab dose should be adjusted in case the subject’s 
weight changes by >10%. Talacotuzumab will be administered as a 250 mL IV infusion over 
approximately 305 minutes using an infusion pump. The talacotuzumab treatment will be 
administered per the dosing schedule described in Section 6.1.2. Subjects should be carefully 
observed during talacotuzumab infusions. Trained study staff at the clinic should be prepared to 
intervene in case any infusion reactions occur. Resuscitation equipment and other agents 
necessary to treat anaphylaxis must be readily available (eg, epinephrine, corticosteroids, 
intravenous antihistamines, bronchodilators, oxygen). Attention to staffing should be considered 
when multiple subjects will be dosed at the same time.
The rate of the talacotuzumab infusion is as follows:
First Four Cycles: Initiate the IV infusion at a rate of 10 mL/hr. In the absence of any infusion-
related reaction during the first 30 minutes, increase the infusion rate to 20 mL/hr for 30 minutes, 
if no infusion reaction is observed during this 30 minute period, increase the infusion rate to 
40 mL/hr for the next 30 minutes. If no infusion reaction is observed during this 30 minute 
period, increase the infusion rate to 60 ml/hr for the remainder of the infusion. The infusion rate 
should not exceed 60 mL/hr at any time. Subjects should be monitored for infusion reactions for 
one hour after completion of the talacotuzumab infusion.
Subsequent Cycles (after the first 4 cycles): If no infusion reaction is observed in the first 
4 cycles, initiate the IV infusion at a rate of 40 mL/hr for 30 minutes and if no infusion-related 
reactions are observed during this period increase the infusion rate by 40 mL/hr every 
30 minutes. The infusion rate should not exceed 150 mL/hr at any time. Subjects should be 
monitored for infusion reactions for 1 hour after completion of the talacotuzumab infusion.
If an infusion-related reaction is observed during the administration of talacotuzumab, then 
follow the procedures described in Section 6.3.4.
6.3.2.
Talacotuzumab: Premedication 
All subjects receiving talacotuzumab in the current study must receive premedication during the 
first 4 cycles, as outlined in Table 5. If no infusion-related reactions, independent of severity, are 
seen for 2 consecutive cycles during the first 4 cycles of talacotuzumab treatment, then 
premedication may be modified per investigator discretion after discussion with the Sponsor for
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Cycle 5 and subsequent talacotuzumab treatments. In the event an infusion-related reaction 
(independent of severity) occurs in subsequent talacotuzumab treatments, premedication needs to 
be reintroduced. If a subject has a medical condition or clinical need that precludes complete 
administration of premedications at any time, notification to and discussion with the Sponsor’s 
study physician is required. 
Table 5:
Premedication for Subjects Receiving Talacotuzumab
Part A and
Part B – Arm 1
Infusion-related 
Reaction
Mandatory Premedication2
Cycle 1- Cycle 4
Dexamethasone 8 mg PO (or equivalent) twice per day approx. 2 days 
prior to infusion and approx. 3 hrs prior to infusion 
Methylprednisolone (100 mg IV)1
approx. 1-2 hrs prior to infusion
Acetaminophen (paracetamol) 650 – 1000 mg IV or PO approx.1 hr 
prior to infusion
Antihistamines: diphenhydramine 25 – 50 mg IV or PO3 and cimetidine 
300 mg PO (or equivalent4) approx. 1 hr prior to infusion
Leukotriene inhibitor (montelukast 10 mg PO, or equivalent), approx.
1-2 hrs prior to infusion 
Cycle 5 +
Subsequent cycles
If Prior Event:
Dexamethasone 8 mg PO (or equivalent) twice per day approx. 2 days 
prior to infusion and approx. 3 hrs prior to infusion 
Methylprednisolone (100 mg IV)1
approx. 1-2 hrs prior to infusion
Acetaminophen (paracetamol) 650 – 1000 mg IV or PO approx.1 hr
prior to infusion
Antihistamines: diphenhydramine 25 – 50 mg IV or PO3 and cimetidine 
300 mg PO (or equivalent4) approx. 1 hr prior to infusion
Leukotriene inhibitor (montelukast 10 mg PO, or equivalent), approx.
1-2 hrs prior to infusion 
No Prior Event
for 2 
consecutive 
cycles:
Premedication may be modified per investigator discretion and after 
discussion with the Sponsor
1 If methylprednisolone is not available at the institution, consult with Sponsor regarding corticosteroid selection. 
Dose and frequency may be increased at the discretion of the investigator.
2 Additional doses of steroids prior to treatment with talacotuzumab may be given at the discretion of the 
investigator. 
3 Or similar sedating antihistamine per institutional standards; avoid the use of promethazine.
4 For example: famotidine 20 mg (PO or IV), ranitidine 150 mg PO or 50 mg IV, or nizatidine (150 mg PO) 
6.3.3.
Talacotuzumab Dosing Modifications
Refer to Section 6.3.4 for details on management of infusion-related reactions. 
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In Part B of the study, dose reduction of talacotuzumab is not permitted and dose delay is the 
primary method for managing talacotuzumab-related toxicities. 
A dose delay should occur if any of the following criteria is met even if the event in the opinion 
of the investigator is attributed to decitabine:

Febrile neutropenia;

Grade 3 or higher hemorrhagic event

Toxicity that in the opinion of the investigator, requires delay.
If the dose of talacotuzumab is delayed by more than 3 days, then the dose should be skipped. 
Administration may resume at the next planned dosing date. A missed dose will not be made up.
If there is more than a 28-day delay between doses, then the subject may be permitted to 
continue treatment if the investigator believes it is in the best interest of the subject. However, 
this must be approved by the Sponsor.
In Arm 1, if a subject discontinues talacotuzumab because of unacceptable toxicity, they should 
continue treatment with decitabine alone.
If a dose delay occurs, then pharmacokinetic and biomarker assessments should be performed on 
the actual administration day of talacotuzumab, not on the original scheduled administration day.
Dose reduction in Part A: Stepwise dose reductions described in the table below are permitted 
if requested and approved by the sponsor in the event of unacceptable toxicity defined as 
non-hematologic Grade ≥ 3 AE or Grade 4 hematologic toxicity lasting more than 14 days and 
not responsive to treatment and/or supportive care. 
Talacotuzumab dosing
0 
9 mg/kg
-1
6 mg/kg
-2
3 mg/kg
6.3.4.
Management of Potential Hypersensitivity/ Infusion-related Reactions
Subjects who experience treatment emergent adverse events during the IV infusion of 
talacotuzumab must be treated according to the investigator’s judgment and best clinical 
practice. The following guidelines may apply:

Subjects should be treated with acetaminophen, H1-antihistamine, or corticosteroids.
Intravenous saline may be indicated. For bronchospasm, urticaria, or dyspnea, subjects may
require H1-antihistamines, oxygen, corticosteroids, or bronchodilators. For hypotension,
subjects may require vasopressors.
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
In the event of a life-threatening infusion-related reaction (which may include pulmonary or
cardiac events), or anaphylactic reaction, talacotuzumab should be discontinued and no
additional talacotuzumab should be administered to the subject.
6.3.4.1.
Guidelines for the Interruption of Talacotuzumab Infusion due to 
Infusion-related Reaction
Infusion-Related Events of Grade 1 or Grade 2
If the investigator assesses a TEAE to be related to the talacotuzumab infusion, then the infusion 
should be paused. When the subject’s condition is stable, the infusion may be restarted at the 
investigator’s discretion. Upon restart, the infusion rate should be half of that used before the 
interruption. Subsequently, the infusion rate may be increased at the investigator’s discretion but 
should not exceed 60 mL/hr for Cycles 1 to 4 and 150 mL/hr for subsequent cycles at any time.
If the subject experiences a Grade 2 or higher event of laryngeal edema or a Grade 2 or higher 
event of bronchospasm that does not respond to systemic therapy and does not resolve within 
6 hours from the onset, then the subject must be withdrawn from treatment.
Infusion-Related Reactions of Grade 3 or Higher
For infusion-related TEAEs that are Grade 3, the talacotuzumab infusion must be stopped, and 
the subject must be observed carefully until resolution of the TEAE or until the intensity of the 
event decreases to Grade 1 or baseline, at which point the infusion may be restarted at the 
investigator’s discretion. Upon restart, the infusion rate should be half of that used before the 
interruption. Subsequently, the infusion rate may be increased at the investigator’s discretion but
should not exceed 60 mL/hr for Cycles 1 to 4 and 150 mL/hr for subsequent cycles at any time.
If the intensity of the TEAE returns to Grade 3 after restart of the infusion, then the procedure 
described in this section may be repeated at the investigator’s discretion. 
For infusion-related TEAEs that are Grade 4, the infusion should be stopped and treatment with
talacotuzumab will be discontinued for that subject.
7.
TREATMENT COMPLIANCE
Decitabine and talacotuzumab will be administered as IV infusions by qualified staff and the 
details of each administration will be recorded in the eCRF. Additional details are provided in 
the Site Investigational Product Procedures Manual.
Following Amendment 7 and when 270 deaths have occurred or 6 months after the last subject is 
enrolled (whichever occurs first), the eCRFs will be closed.
8.
PRESTUDY AND CONCOMITANT THERAPY
Prestudy therapies administered up to 28 days before the first dose of study drug (Part A) or 
28 days before randomization (Part B) must be recorded at screening. Prior systemic therapies for 
MDS or MPN administered before signing of the informed consent should be collected at screening. 
Concomitant therapies must be recorded throughout the study beginning with signing of the 
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Informed Consent Form and continuing until 30 days after the last dose of study drug. The 
sponsor must be notified in advance (or as soon as possible thereafter) of any instances in which 
prohibited therapies are administered.
Following Amendment 7 and when 270 deaths have occurred or 6 months after the last subject is 
enrolled (whichever occurs first), follow up of subjects and data collection will end. Subjects 
who are continuing to derive benefit from decitabine treatment as assessed by their investigator 
may continue to receive decitabine; during this period, only serious adverse events will be 
monitored and entered into the Company safety repository.
8.1.
Permitted Medications and Supportive Therapies
All concomitant medications for medical conditions other than AML are permitted, as clinically 
indicated. All supportive therapies, other than anticancer treatment needed for the management 
of subjects enrolled in this study, are encouraged.
The following medications and supportive therapies are examples of support therapies that are 
recommended during the study:

Short-term (<3 days) treatment with low doses of systemic corticosteroids when medically 
necessary for the control of acute symptoms or for premedication of talacotuzumab;

Prophylactic antibacterial, antifungal, or antiviral agents need to be used per institutional 
guidelines;

Growth factors are strongly recommended to be used for the treatment of febrile neutropenia 
(temperature ≥ 38.5°C and absolute neutrophil count < 1,000/µL) or an active bacterial or 
fungal infection (ie, requiring intravenous anti-infectives or extensive supportive care) in 
neutropenic subjects. Growth factors need to also be used to prevent treatment delay due to 
neutropenia.

Red blood cell and platelet transfusions per institutional guidelines.
8.2.
Prohibited Therapies
The following medications are prohibited during the study:

Concurrent systemic corticosteroids except for short-term treatment and mandatory 
premedication;

Plasmapheresis, cytoreduction by hydroxyurea or other concurrent anticancer therapy. Of 
note: treatment with hydroxyurea and plasmapheresis has to be discontinued prior to start of 
study therapy; 

Any investigational agent; and

Any live attenuated vaccination.
8.3.
Subsequent Antineoplastic Therapies
Administration of any other antineoplastic therapy, for reasons other than treatment failure
(defined in Section 9.2.1.1) or relapse from CR/CRi, is strongly discouraged until treatment 
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failure or relapse is established. After treatment failure or relapse is established, subsequent 
therapy is permitted at the investigator’s discretion. Subsequent therapy (including start date, end 
date, and best response) should be documented in the appropriate section of the eCRF.
9.
STUDY EVALUATIONS
Following Amendment 6, which incorporated the IDMC’s recommendations to close enrollment 
to the study and discontinue talacotuzumab treatment for subjects receiving talacotuzumab + 
decitabine and offer to continue decitabine alone, all subjects will continue to be followed for 
survival and subsequent anti-cancer therapy. During the treatment phase with decitabine, 
subjects will be monitored for serious adverse events.
Following Amendment 7 and when 270 deaths have occurred or 6 months after the last subject is 
enrolled (whichever occurs first), follow up of subjects and data collection will end. Subjects 
who are continuing to derive benefit from decitabine treatment as assessed by their investigator 
may continue to receive decitabine; during this period, only serious adverse events will be 
monitored and entered into the Company safety repository.
9.1.
Study Procedures
9.1.1.
Overview
The Time and Events Schedules: Tables 1A, 1B, 1C, 1D, 2A, and 2B summarize the frequency 
and timing of efficacy, pharmacokinetic, immunogenicity, pharmacodynamic, biomarker, 
pharmacogenomic, patient-reported outcomes, and safety measurements applicable to this study.
Every effort should be made to keep subjects on the study schedule as planned from Study 
Day 1. At each visit, study assessments should be completed before study drug administration. 
All PRO assessments should be conducted/completed before any tests, procedures, or other 
consultations to prevent influencing subject perceptions but prior to and on the day of the actual 
study drug administration.
Post-baseline disease evaluations may be conducted 7 days from the scheduled visit date, if 
necessary. At the following visit, the subject should return to the original planned schedule. 
Additional serum or urine pregnancy tests may be performed, as determined necessary by the 
investigator or required by local regulation, to establish the absence of pregnancy at any time 
during the subject's participation in the study.
Medical resource utilization data will be collected. Refer to Section 9.8 for details.
Assuming a study duration of 6 cycles, the total blood volume to be collected from each subject 
will be approximately 336 mLs for subjects participating in Part A, 541 mLs for subjects 
participating in Part B Arm 1 (decitabine + talacotuzumab) and 387 mLs for subjects 
participating in Part B Arm 2 (decitabine only). Repeat or unscheduled samples may be taken for 
safety reasons or for technical issues with the samples.
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9.1.2.
Screening Phase
The signed informed consent form (ICF) must be obtained before any study-specific procedures 
are performed. The Screening Phase begins when the first screening assessment is conducted 
(that was not performed as part of the subject’s standard of care). During the Screening Phase, 
eligibility criteria will be reviewed and a complete clinical evaluation will be performed as 
specified in Time and Events Schedule Tables 1A and 1B. Screening procedures will be 
performed within 28 days before first dose (Part A) or within 28 days before randomization 
(Part B). 
9.1.3.
Open-Label Treatment Phase
Details of the procedures performed during the Treatment Phase are outlined in the Time and 
Events Schedule Tables 1A, 1B, and 1C. For Part A, treatment will start on Day 1 with an IV 
infusion of talacotuzumab and proceed as described in Section 6.1. Subjects will continue on 
study and receive open label talacotuzumab in combination with decitabine in Part A until 
treatment failure, relapse from CR/CRi, unacceptable toxicity, death or other reasons specified in 
Section 10.2.
For Part B, treatment with study drug should start within 3 days after randomization and continue
until treatment failure, relapse from CR/CRi, unacceptable toxicity, death, or other reasons 
specified in Section 10.2. 
All subjects in Part A and Part B will be closely monitored for adverse events, laboratory 
abnormalities, and disease status. Clinical evaluations and laboratory studies may be repeated 
more frequently, if clinically indicated. If treatment failure or relapse from CR/CRi occurs, then 
the subject will complete the End-of-Treatment Visit and enter the Follow-up Phase. Subjects 
randomized into the decitabine + talacotuzumab arm can discontinue 1 drug (decitabine or 
talacotuzumab); while continuing treatment with the other drug.
End of Treatment
All subjects should have an End-of-Treatment Visit, unless a subject withdraws consent for study 
participation or is lost to follow up. The End-of-Treatment Visit is to occur within 30 days
(+/- 7 days) after the last dose of study drug. Every effort should be made to conduct the 
End-of-Treatment Visit before the subject starts subsequent treatment. 
9.1.4.
Follow-up Phase
The Follow-up Phase will begin once a subject has completed the End-of-Treatment Visit. 
Subjects who discontinue before treatment failure or relapse from CR/CRi must continue to have 
disease evaluations according to the Time and Events Schedule Tables 1A, 1B, and 1C. Subjects 
with unresolved drug-related adverse events of Grade 3 or higher as well as ongoing drug-related
serious adverse events (SAEs) will be followed until event resolution. After treatment failure or 
relapse is documented, only subsequent anticancer therapy, concomitant therapy to treat a 
continuing drug-related adverse events (AE) ≥ Grade 3 or serious adverse event (SAE), survival 
status, and other malignancies will continue to be collected. If this information is obtained via 
telephone contact, then written documentation of the communication must be available for 
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review in the source documents. If the subject has died, then the date and cause of death will be 
collected and documented on the eCRF.
End of Study
The end of study data collection is defined as when 270 deaths have occurred or 6 months after 
the last subject is enrolled, whichever occurs first. At that time, follow up of subjects will end. 
Subjects who are continuing to derive benefit from decitabine treatment as assessed by their 
investigator may continue to receive decitabine; during this period, only serious adverse events 
will be monitored and entered into the Company safety repository as described under 
Amendment 7.
9.1.5.
Disease Evaluation and Clinical Cutoff
Disease evaluations will be performed for each subject per the Time and Events Schedule Tables
1A and 1B until treatment failure, relapse from CR/CRi, or until the study has reached the 
clinical cutoff for OS or EFS, whichever occurs first. If the study continues enrollment to 
400 subjects then the clinical cut-off for the final analysis of OS is when 270 subjects have died. 
If study enrollment stops with approximately 120 subjects, the clinical cut-off for the final 
analysis of EFS is when 90 EFS events have occurred. Enrollment was terminated after Interim 
Analysis #2 and the study will end 6 months after the last subject was enrolled.
9.2.
Efficacy
9.2.1.
Evaluations
Disease assessments based on bone marrow evaluations, peripheral blood counts, and clinical 
presentation will be conducted per the Time and Events Schedule Tables 1A, 1B, and 1C at the 
local laboratory. Cytogenetics will be evaluated at the local site.
In Part B, bone marrow aspirates will be collected every 2 cycles. All treatment decisions will be 
based on local assessments. Additionally, slides will be sent to a central laboratory for analysis 
of the percentage of leukemic blast cells. A portion of the bone marrow aspirate specimen will 
also be sent in the appropriate medium for MRD status. Bone marrow biopsy material is not 
required, unless an aspirate sample cannot be obtained (dry tap).
9.2.1.1.
Disease Status 
Subjects will be assessed for disease status according to the “Response Criteria in AML”9 with a 
modification by the Sponsor for treatment failure (Table 6). The modification is necessary 
because the original criteria were intended for evaluation of standard induction therapy with 
3 days of an anthracycline and 7 days of cytarabine (3+7) or therapies of comparable intensity.
If treatment failure is suspected due to clinical indications or increased peripheral blast counts,
then a bone marrow sample must be obtained to confirm treatment failure as defined below. In 
the case of overt leukostasis, uncontrollable coagulopathy, or new extramedullary leukemia 
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requiring immediate action and a bone marrow sample cannot be obtained, the sponsor must be 
consulted to confirm treatment failure for the subject.
For this study, treatment failure is defined as >25% absolute increase in the bone marrow blast 
count from baseline to the present assessment (eg, from 20% to 46%) on bone marrow aspirate 
(or biopsy in case of dry tap).
Stable disease is defined as response that does not qualify for a complete or partial response and 
does not meet the criteria for treatment failure.
The sponsor must be notified before subjects discontinue study treatment. Before subjects 
discontinue the Treatment Phase due to treatment failure or relapse from CR/CRi, sites will 
document treatment failure or relapse as soon as possible and within 48 hours. The primary 
reason for discontinuation of study treatment is to be recorded in the eCRF. For all subjects, the 
Sponsor should be informed as soon as treatment failure or relapse from CR/CRi is confirmed.
Discontinuation criteria for all subjects must be reviewed and confirmed by the Sponsor prior to 
discontinuation.
Based on investigator’s disease assessments across all cycles of treatment, overall best response 
during the entire study will be derived by the Sponsor. For an overall best response of stable 
disease, disease stabilization must have lasted for at least 8 weeks.
Table 6: 
Response Assessments
Category
Definition
Complete response (CR)1
Bone marrow blasts <5%; absence of blasts with Auer rods; absence of 
extramedullary disease; absolute neutrophil count >1.0 × 109/L (1000/μL); 
platelet count >100 × 109/L (100 000/μL); independence of red cell transfusions 
CR with incomplete recovery 
(CRi)2
All CR criteria except for residual neutropenia (<1.0 × 109/L [1000/μL]) or 
thrombocytopenia (<100 × 109/L [100 000/μL]) 
Morphologic leukemia-free 
state3
Bone marrow blasts <5%; absence of blasts with Auer rods; absence of 
extramedullary disease; no hematologic recovery required 
Partial response (PR)
Relevant in the setting of Phase 1 and 2 clinical trials only; all hematologic 
criteria of CR; decrease of bone marrow blast percentage to 5% to 25%; and 
decrease of pretreatment bone marrow blast percentage by at least 50% 
Cytogenetic CR (CRc)4
Reversion to a normal karyotype at the time of morphologic CR (or CRi) in cases 
with an abnormal karyotype at the time of diagnosis; based on the evaluation of 
20 metaphase cells from bone marrow 
Molecular CR (CRm)5
No standard definition; depends on molecular target
Relapse6
Bone marrow blasts ≥5%; or reappearance of blasts in the blood; or development 
of extramedullary disease 
Treatment failure7
>25% absolute increase in the bone marrow blast count from baseline to the 
present assessment (eg, from 20% to 46%) on bone marrow aspirate (or biopsy in 
case of dry tap)
Stable disease8
Does not qualify for a complete or partial response and has no evidence of
treatment failure.
Source: Dohner 20109 with modification by Sponsor for treatment failure
Definitions of response criteria are based primarily on those given by Cheson 1990.5
1
All criteria need to be fulfilled; marrow evaluation should be based on a count of 200 nucleated cells in an 
aspirate with spicules; if ambiguous, consider repeat exam after 5 to 7 days; flow cytometric evaluation may help 
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to distinguish between persistent leukemia and regenerating normal marrow; a marrow biopsy should be 
performed in cases of dry tap, or if no spicules are obtained; no minimum duration of response required.
2
The criterion of CRi is of value in protocols using intensified induction or double induction strategies, in which 
hematologic recovery is not awaited, but intensive therapy will be continued. In such protocols, CR may even 
not be achieved in the cycle of the entire treatment plan. In these instances, the overall response rate should 
include CR and CRi patients. Some patients may not achieve complete hematologic recovery upon longer 
observation times.
3
This category may be useful in the clinical development of novel agents within phase 1 clinical trials, in which a 
transient morphologic leukemia-free state may be achieved at the time of early response assessment.
4
Four studies showed that failure to convert to a normal karyotype at the time of CR predicts inferior outcome.
5
As an example, in core binding factor (CBF) AML low-level PCR-positivity can be detected in patients even in 
long-term response. Normalizing to 104 copies of ABL1 in accordance with standardized criteria, transcript 
levels below 12 to 10 copies appear to be predictive for long-term response.
6
In cases with low blast percentages (5-10%), a repeat marrow should be performed to confirm relapse. 
Appearance of new dysplastic changes should be closely monitored for emerging relapse. In a patient who has 
been recently treated, dysplasia or a transient increase in blasts may reflect a chemotherapy effect and recovery 
of hematopoiesis. Cytogenetics should be tested to distinguish true relapse from therapy-related MDS/AML.
7, 8 Modified by Sponsor to meet the need for subjects in this study who are not candidates for conventional 
intensive induction chemotherapy.
9.3.
Pharmacokinetics and Immunogenicity
9.3.1.
Evaluations
For all subjects participating in the study, pharmacokinetic samples to determine plasma
concentrations of decitabine and serum concentrations of talacotuzumab will be obtained 
according to the Time and Events Schedule Tables 2A and 2B. 
Venous blood samples (approximate 7.5 mL per sample) will be collected to determine serum 
concentration of talacotuzumab and the serum will be divided into 4 aliquots of approximate 
equal volume (1 aliquot for pharmacokinetic analysis, 1 aliquot for antibodies to talacotuzumab
analysis [when appropriate], and 2 aliquots as backup). If needed, samples collected for 
determining serum concentrations of talacotuzumab in this study may be used for determining 
immunogenicity, further characterization of immunogenicity, such as the ability of anti-drug 
antibodies to neutralize the effect of talacotuzumab, address questions about drug characteristics 
that may arise at a later time point, or evaluation of safety or efficacy aspects that address 
concerns arising during or after the study period. Venous blood samples (approximate 0.5 mL 
per sample) will be collected to determine plasma concentration of decitabine. Genetic analyses 
will not be performed on these samples, and subject confidentiality will be maintained. 
The exact dates and times of blood sampling must be recorded. Refer to the Laboratory Manual 
for sample collection, handling, and shipping requirements. Collected samples must be stored 
under the specified and controlled conditions for the temperatures indicated in the Laboratory 
Manual.
9.3.2.
Analytical Procedures
Serum samples will be analyzed to determine concentrations of talacotuzumab and generation of 
antibodies to talacotuzumab (immunogenicity) using validated immunoassay methods by or 
under the supervision of the sponsor’s bioanalytical facility as indicated by the Time and Events 
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Schedule Tables 2A and 2B. If needed, interim analyses of the serum talacotuzumab
concentrations from Part A may be conducted. All bioanalytical results from the interim analysis 
will be considered final and these samples will not be re-assayed at the end of the study.
Plasma samples will be analyzed to determine the concentration of decitabine using a validated 
LC/MS/MS method by or under the supervision of the sponsor’s bioanalytical facility. The 
complete bioanalytical report, describing the assay methodologies and results, will be included as 
an appendix to the pharmacokinetic report which is contained within the integrated study report.
9.3.3.
Pharmacokinetic Parameters
Plasma concentrations of decitabine and serum concentrations of talacotuzumab will be 
measured and resulting concentration over time data will be summarized by treatment. 
Population PK models will be explored and developed if data are sufficient from this study. If 
sufficient data are available, the pharmacokinetic parameters such as the ones listed below for 
talacotuzumab may be calculated.
AUCt1-t2
Area under the concentration-time curve between time t1
and t2
CL
total systemic clearance of drug after IV administration
Cmax
maximum observed concentration
Cmin
minimum observed concentration
V
volume of distribution
Pharmacokinetic samples to determine the plasma concentration of decitabine and the serum 
concentration of talacotuzumab will be obtained from all applicable subjects in the study as 
described in Time and Events Tables 2A and 2B.
9.3.4.
Immunogenicity Assessments
For all subjects in Part A and those randomized to receive decitabine + talacotuzumab in Part B, 
venous blood samples will be drawn to assess the generation of antibodies to talacotuzumab
(immunogenicity), as specified in the Time and Events Schedule Tables 2A and 2B. 
Additionally, blood samples to assess immunogenicity should be collected at the final visit for 
subjects who discontinue treatment or withdrawn from the study. Subjects who discontinue 
treatment in Part B will also be asked to return for an immunogenicity evaluation during the 
Follow-up Phase. 
All samples collected for immunogenicity analysis will be evaluated for talacotuzumab serum 
concentration to ensure appropriate interpretation of immunogenicity data. At each time point, 
immunogenicity and serum talacotuzumab concentration analyses will be performed on aliquots 
from the same blood draw and no additional sampling is required. Procedures for sample 
collection, preparation, identification, storage, and shipment will be provided in the Laboratory 
Manual or equivalent document. 
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Serum samples will be screened for antibodies binding to talacotuzumab and serum titer will also 
be determined from confirmed positive samples using validated assay methods by or under the 
supervision of the sponsor. Other immunogenicity analyses (eg, assessment of neutralizing 
capabilities) may be performed to further characterize the immune responses that are generated. 
Any time an infusion-related reaction is observed or reported during the study, a blood sample 
should be drawn for determination of antibodies to talacotuzumab. Talacotuzumab serum 
concentration will also be determined from the same infusion-related reaction sample for the 
purpose of interpreting immunogenicity data. These samples will be stored and evaluated if 
deemed necessary. If the infusion-related reaction results in treatment discontinuation, then 
subjects should undergo all scheduled safety and efficacy evaluations. Samples collected for the 
analysis of talacotuzumab immunogenicity/serum concentration may additionally be used to 
evaluate safety or efficacy aspects that address concerns arising during or after the study period 
or for the evaluation of relevant biomarkers by the sponsor or sponsor’s designee. 
9.4.
Pharmacokinetic/Pharmacodynamic Evaluations
If sufficient data are available, pharmacokinetic/pharmacodynamic modeling may be performed, 
including exploring the relationship between serum concentrations of talacotuzumab and 
biomarkers, PD markers, or endpoints of clinical efficacy. If these analyses are performed, the 
details and results will be presented in a separate report.
9.5.
Biomarkers
Biomarker analyses are dependent upon the availability of appropriate biomarker assays and may 
be deferred or not performed if, during or at the end of the study, it becomes clear that the 
analysis will have no scientific value, or if there are not enough samples or not enough 
responders to allow for adequate biomarker evaluation. In the event the study is terminated early 
or shows poor clinical efficacy, completion of biomarker assessments is based on justification 
and intended utility of the data. Samples for biomarker evaluations will be collected as specified 
in the Time and Events Schedule Tables 2A and 2B.
9.5.1.
Assessment of Pharmacodynamic Markers (Part A and Part B)
Changes in cell numbers of cellular biomarkers (basophils, pDCs, monocytes, NK cells and 
eosinophils) as well as CD123 expression and receptor occupancy will be measured by flow 
cytometry or other similar technologies. 
9.5.2.
Assessment of CD123 Expression (Part B)
CD123 expression and density will be determined in AML blasts and LSCs in bone marrow and 
blood by flow cytometry at a central laboratory and may be compared with other methods such 
as reverse transcriptase – quantitative polymerase chain reaction (RT-qPCR), CD123 expression 
may be followed when bone marrow aspirates or blood samples are obtained for clinical 
assessment of CR or CRi and upon treatment failure or relapse from CR/CRi, and at End-Of-
Treatment to evaluate changes in CD123 expression in the myeloid blast and LSC population 
with talacotuzumab treatment (Time and Events Schedule Table 1B and 1C).
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9.5.3.
Minimal Residual Disease Assessment (Part B)
Minimal residual disease assessments will be performed on bone marrow aspirates and may be 
compared with assessments in whole blood collected at time points as specified in the Time and 
Events Table 1B. The objective is to compare MRD in subjects from both arms who achieve a 
CR or CRi response. Minimal residual disease negativity is defined as less than 1 blast or 
leukemic stem cell in 10,000 leukocytes (MRD level <104). Flow cytometry will be utilized as 
the primary method of MRD analysis, and when available, may be compared to other molecular 
approaches such as PCR
or next-generation sequencing (NGS) of specific genomic 
abnormalities.
9.5.4.
Immunophenotyping (Part B)
Bone marrow aspirates (as available per Time and Events Schedule Table 1B) or whole blood 
may
be utilized for immunophenotyping (performed by flow cytometry or mass 
cytometry/CyTOF) which includes analyses of NK cells, T cells, and B cells as well as other 
potential immune cell subpopulations. The main mechanism of action of talacotuzumab is 
ADCC through NK cell activation; therefore, NK cell counts and activation will be assessed by 
flow cytometry (Time and Events Schedules Tables 1B, 2A, and 2B). Patients receiving 
decitabine will be analyzed pre- and post-decitabine treatment for NK cell number and activity in 
an attempt to address the effect of decitabine on NK cell function (Time and Events Schedules 
Tables 2A and 2B). Subjects in Part A will only be assessed for NK cell activity and cell 
numbers by flow cytometry (Time and Events Schedule Table 2A). To investigate whether an 
immune fitness signature can be developed utilizing either flow cytometry or genomic profiling, 
whole blood samples may also be subjected to RNA profiling (RNA-seq, gene expression 
profiling), or methylation assessment to evaluate novel technologies for immune profiling in 
bone marrow and whole blood, and to compare these methodologies to standard flow cytometry
or CyTOF. These assessments will be evaluated for association with clinical outcome. 
9.5.5.
Cytokine Analysis
Samples (blood) for cytokine analysis will be collected as described in the Time and Events 
Schedule 2B.
Infusion-related reactions occur with the administration of talacotuzumab. Cytokine analysis will 
be performed to determine the association of cytokines with infusion-related reactions and to 
help gain an understanding of the mechanism of these reactions.
9.6.
Pharmacogenomic (DNA and RNA) Evaluations (Part B)
DNA or RNA samples will be used for research related to talacotuzumab (CSL362) and/or 
decitabine or AML. They may also be used to develop tests/assays related to talacotuzumab 
(CSL362) and/or decitabine and AML. Pharmacogenomic research may consist of the analysis of 
one or more candidate genes or of the analysis of genetic markers throughout the genome in 
relation to talacotuzumab or AML clinical endpoints. 
More specifically, myeloid specific genomic profiling may be done employing a panel of genes 
with known myeloid mutations such as NPM1, FLT3-ITDD, DNMT3a, TET2, IDH1/2 that will 
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be sequenced and analyzed in correlation to prognosis and response to talacotuzumab or 
decitabine treatment. Additional analyses may be conducted if it is hypothesized that this may 
help resolve issues with the clinical data.
Gene expression and DNA methylation analyses may be analyzed on bone marrow aspirates 
and/or peripheral blood samples at baseline and post decitabine exposure if deemed necessary to 
evaluate the decitabine
effect in combination with talacotuzumab. Single nucleotide 
polymorphism (SNPs) associated with ADCC or NK-cell activity may be evaluated if warranted 
based on additional clinical data.
9.7.
Patient-reported Outcomes
9.7.1.
FACT-Leu
The FACT-Leu, a self-administered PRO measure, will be used in this study. It will enable the 
evaluation of a subject’s perceptions of health-related quality of life. 
The FACT-Leu is a 44-item, self-reported leukemia-specific measure that is used to 
quantitatively assess an individual’s perception of how the disease affects their day-to-day life. It 
includes 5 subscales, ie, physical well-being, social/family well-being, emotional well-being, 
functional well-being, and leukemia-specific concerns. All FACT-Leu subscale and aggregated 
scores showed high internal consistency and high test-retested reliability.4 A sample of the 
FACT-Leu containing representative questions is provided in Attachment 1.
9.7.2.
EQ-5D-5L
The EQ-5D-5L is a generic measure of health status. For purposes of this study, the EQ-5D-5L 
will be used to generate utility scores for use in cost effective analyses. The EQ-5D-5L is a 
5 item questionnaire that assesses 5 domains including mobility, self-care, usual activities, 
pain/discomfort and anxiety/depression plus a visual analog scale rating “health today” with 
anchors ranging from 0 (worst imaginable health state) to 100 (best imaginable health state).7,22
The scores for the 5 separate questions are categorical and cannot be analyzed as cardinal 
numbers. However, the scores for the 5 dimensions are used to compute a single utility score 
ranging from zero (0.0) to 1 (1.0) representing the general health status of the individual. A 
sample of the EQ-5D-5L that contains representative questions is provided in Attachment 2.
9.8.
Medical Resource Utilization 
Medical resource utilization data, associated with medical encounters, will be collected in the 
CRF by the investigator and study-site personnel for all subjects throughout the study. 
Protocol-mandated procedures, tests, and encounters are excluded. The data collected may be 
used to conduct exploratory economic analyses and will include:

Duration of hospitalization (total days length of stay, including duration by wards; 
eg, intensive care unit)

Outpatient medical encounters and treatments (including physician or emergency room 
visits, selected tests and procedures, and medications)
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9.9.
Safety Evaluations
Details regarding the Independent Data Monitoring Committee are provided in Section 11.12.
Any clinically relevant changes occurring during the study must be recorded on the Adverse 
Event section of the eCRF. Any clinically significant abnormalities persisting at the end of the 
study/early withdrawal will be followed by the investigator until resolution or until a clinically 
stable endpoint is reached. The study will include the following evaluations of safety and 
tolerability according to the time points provided in the Time and Events Schedule Tables 1A,
1B, 1C, and 1D:
Adverse Events
Adverse events will be reported by the subject (or, when appropriate, by a caregiver, surrogate, 
or the subject's legally acceptable representative) from the time a signed and dated informed 
consent form is obtained. Adverse events will be reported until 30 days after the last dose of 
study drug. During the Follow-up Phase, any adverse events of Grade 3 or higher that are 
considered related to study drug, as well as related serious adverse events, should be followed 
until resolution or until a clinically stable endpoint is reached. Adverse events will be followed 
by the investigator as specified in Section 12, Adverse Event Reporting.
Following Amendment 7 and when 270 deaths have occurred or 6 months after the last subject is 
enrolled (whichever occurs first), follow up of subjects and data collection will end. Subjects 
who are continuing to derive benefit from decitabine treatment as assessed by their investigator 
may continue to receive decitabine; during this period, only serious adverse events will be 
monitored and entered into the Company safety repository.
Clinical Laboratory Tests
Blood samples for serum chemistry and hematology will be collected as specified in the Time 
and Events Schedule Tables 1A and 1B and 1C. Additional clinical laboratory tests may be 
performed as indicated by the overall clinical condition of the subject or if abnormalities warrant 
more frequent monitoring. Hematology and serum chemistry laboratory evaluations may be 
repeated as clinically indicated. The investigator must review the laboratory results, document 
this review, and record any clinically relevant changes occurring during the study in the adverse 
event section of the eCRF. The laboratory reports must be filed with the source documents.
Screening laboratory results must be available to the investigator for evaluation before the first 
dose of study drug on Day 1 of Cycle 1.
The following tests will be performed by the local laboratory:

Hematology Panel
-hemoglobin
-absolute white blood cell (WBC) count
-platelet count
-absolute monocyte count
-absolute basophil count
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-absolute eosinophil count
-absolute neutrophil count
-absolute lymphocyte count
- peripheral blast count

Coagulation: 
-activated partial thromboplastin time (aPTT)
-International normalized ratio (INR) or prothrombin time (PT)

Serum Chemistry Panel
-sodium
-aspartate aminotransferase (AST)
-potassium
-alanine aminotransferase (ALT)
-magnesium
-alkaline phosphatase
-creatinine
-calcium
-total bilirubin
-blood urea nitrogen (BUN)
-phosphate
-uric acid

Serum -hCG or urine pregnancy testing for women of childbearing potential only
(screening only) or if clinically indicated or required by local regulations.
Electrocardiogram (ECG)
Electrocardiogram will be performed for all subjects during screening as indicated in the Time 
and Events Tables 1A and 1B. Abnormalities noted at screening should be included in the 
medical history. During the collection of ECGs, subjects should be in a quiet setting without 
distractions (eg, television, cell phones). Subjects should rest in a supine position for at least 
5 minutes before ECG collection and should refrain from talking or moving arms or legs. If 
blood sampling or vital sign measurement is scheduled for the same time point as ECG 
recording, then the procedures should be performed in the following order: ECG(s), vital signs, 
blood draw. 
In Part A, QTcF will be assessed at the time of screening and in the Open-Label Treatment Phase 
if clinically required. If QTcF is >470 milliseconds, refer to the Time and Events Schedule 
Tables 1A,1B, and 1C for additional assessment procedures. 
In Part B, ECG monitoring for subjects in Arm 1 will occur during screening and on Cycle 1 Day 
8 and Day 22 after the talacotuzumab IV infusion, then every 2 cycles thereafter on Day 22 after 
the talacotuzumab IV infusion and at EOT. For subjects in Arm 2, ECG monitoring will occur 
during screening and on Cycle 1 Day 5 after the decitabine IV infusion and then every 2 cycles 
thereafter on Day 5 after the decitabine IV infusion and at EOT.
Multi Gated Acquisition (MUGA) Scan/ Echocardiography
Baseline left ventricular ejection fraction (LVEF) measured by (MUGA or echocardiogram) 
must be assessed and be within institutional limits for subjects to be eligible for this study and 
may be repeated throughout the study when clinically indicated and at EOT. When the exam is 
repeated, the same measurement modality should be used.
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Vital Signs
Temperature, heart rate, blood pressure will be recorded according to the Time and Events
Schedule Tables 1A and 1B. Blood pressure and heart rate measurements should be preceded by 
at least 5 minutes of rest in a quiet setting without distractions (eg, television, cell phones).
Physical Examination
A full physical examination will be performed at screening. Subsequently, a directed physical 
examination (including all organ systems that were previously abnormal or involved with disease 
and documentation of any clinically relevant abnormalities in any organ) will be performed at the 
timepoints specified in the Time and Events Schedule Tables 1A, 1B, and 1C. Any changes that 
are clinically significant will be recorded on the AE page. Height will be measured at Screening 
only; weight will be measured prior to the start of each cycle and at the EOT.
ECOG Performance Status
The ECOG Performance Status scale will be used to grade changes in the subject’s daily living 
activities. The ECOG Performance Status scale is provided in Attachment 3. The frequency of 
ECOG Performance Status assessment is provided in the Time and Events Schedule Tables 1A
and 1B.
9.10.
Sample Collection and Handling
The actual dates and times of sample collection must be recorded in the eCRF or laboratory 
requisition form. When applicable, blood samples should be collected from the arm contralateral 
to the drug infusion arm. If blood samples are collected via an indwelling cannula, an appropriate 
amount (1 mL) of serosanguineous fluid slightly greater than the dead space volume of the lock 
will be removed from the cannula and discarded before each blood sample is taken. Refer to the 
Time and Events Schedule Tables 2A and 2B for the timing and frequency of all sample 
collections.
For samples collected for the central laboratory, sample dates and times must be recorded on the 
laboratory requisition form. Further instructions for the collection, handling, storage, and 
shipment of samples are found in the laboratory manual that will be provided. Collection, 
handling, storage, and shipment of samples must be under the specified, and where applicable, 
controlled temperature conditions as indicated in the laboratory manual.
10.
DISCONTINUATION OF STUDY TREATMENT/ WITHDRAWAL FROM STUDY
10.1.
Completion
A subject will be considered to have completed the study if he or she has finished all 
protocol-specified procedures, has not been lost to follow up, and has not withdrawn consent for 
study participation before the end of study data collection. In addition, subjects who die prior to 
the end of study data collection will be considered to have completed. Subjects in the Follow-up 
Phase will be considered to have completed the study when the end of study data collection has 
been reached (270 deaths have occurred or 6 months after the last subject is enrolled, whichever 
occurs first; see Section 9.1.4). Following Amendment 7, follow up of subjects and data 
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collection will end. Subjects who are continuing to derive benefit from decitabine treatment as 
assessed by their investigator may continue to receive decitabine; during this period, only serious 
adverse events will be monitored and entered into the Company safety repository.
10.2.
Discontinuation of the Treatment Phase
If a subject's study treatment must be discontinued before the end of the treatment regimen, then
this will not result in automatic withdrawal of the subject from the study. A subject’s 
participation in the Treatment Phase will be discontinued if any of the following occur:

The subject experiences treatment failure (defined in Section 9.2.1.1) or relapse from 
CR/CRi;

The subject experiences unacceptable toxicity (In Arm 1, subjects may discontinue 1 drug 
while continuing treatment with the other drug);

The subject experiences a severe infusion reaction with cardiovascular collapse;

The subject initiates treatment with a prohibited medication;

The investigator or sponsor believes (eg, that for safety or tolerability reasons such as an 
adverse event) it is in the best interest of the subject to discontinue treatment;

The subject becomes pregnant; or

The subject (or the subject’s legally acceptable representative) withdraws consent for 
administration of study treatment. 
Before subjects discontinue the Treatment Phase due to treatment failure or relapse from 
CR/CRi, sites will document treatment failure or relapse as soon as possible and within 48 hours. 
The primary reason for discontinuation of study treatment is to be recorded in the eCRF. For all 
subjects, the Sponsor should be informed as soon as treatment failure or relapse from CR/CRi is 
confirmed and all treatment discontinuations will be reviewed for approval by the Sponsor.
After discontinuation from the Treatment Phase, all subjects in both treatment groups should 
have an End-of-Treatment Visit and enter the Follow-up Phase. Follow-up assessments should 
continue as specified in the Time and Events Schedules (Tables 1A,1B, 1C, and 1D). 
10.3.
Withdrawal From the Study
A subject will be withdrawn from the study for any of the following reasons:

Lost to follow-up

Withdrawal of consent

The study investigator or Sponsor, for any reason, stops the study or stops the subject’s 
participation in the study
If a subject is lost to follow-up, every reasonable effort must be made by the study site personnel 
to contact the subject and determine the reason for discontinuation/withdrawal. The measures 
taken to follow up must be documented.
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When a subject withdraws before completing the study, the reason for withdrawal is to be 
documented in the eCRF and in the source document. Study drug assigned to the withdrawn 
subject may not be assigned to another subject. Subjects who withdraw will not be replaced. If a 
subject withdraws from the study, then the assessments outlined in the End-of-Treatment Visit 
should be obtained.
10.4.
Withdrawal From the Use of Samples in Future Research
The subject may withdraw consent for use of samples for research (refer to Section 16.2.5, 
Long-Term Retention of Samples for Additional Future Research). In such a case, samples will 
be destroyed after they are no longer needed for the clinical study. Details of the sample 
retention for research are presented in the main ICF.
11.
STATISTICAL METHODS
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general 
description of the statistical methods to be used to analyze the efficacy and safety data is outlined 
below. Specific details will be provided in the Statistical Analysis Plan.
11.1.
Subject Information
The primary analysis population will be the all-randomized population, which will include all 
subjects in Part B. Safety will be evaluated for all subjects who have received at least 1 dose of 
study drug in Part A or Part B. The pharmacokinetic analyses will be performed on the 
pharmacokinetic evaluable population. Continuous variables will be summarized using 
descriptive statistics such as mean, standard deviation, and range. Categorical variables will be 
summarized using frequency tables.
11.2.
Interim and Final Analyses
Safety reviews will be performed in Part A and Part B. The safety assessments by the Study 
Evaluation Team (SET) in Part A will occur prior to the initiation of Part B. This will include 
available PK and PD data from both single agent talacotuzumab and the combination of 
decitabine + talacotuzumab. In addition, a safety review by the IDMC of the accumulative data 
will be performed when approximately 20 subjects (10 subjects from each arm) have been 
enrolled in Part B and followed for at least 1 month to assess the safety and tolerability of the 
combination treatment. This review will also include all safety, PK, and PD data available from 
Part A.
Part B of the study includes an interim analysis based on response rates of CR and CR+CRi that 
will occur after approximately 80 subjects (40 subjects per arm) have been randomized and 
followed for at least 4 months. The results of this interim analysis will be used to guide if the 
study continues enrollment to the pre-specified 400 subjects or stops enrollment. Enrollment will 
continue during the interim analysis; it is estimated that approximately 120 subjects will have 
been randomized by the time the results of the first interim analysis are available. 
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The statistical criteria to guide the decision making will be based on the difference (Δ) in 
response rate between the 2 treatment arms (decitabine + talacotuzumab minus decitabine alone) 
as the following:

If ΔCR ≥15% or Δ(CR+CRi) ≥25%, then the study may continue enrollment to 
400 subjects; 

If ΔCR <15% and Δ(CR+CRi) <25%, then the study may stop enrollment at 
approximately 120 subjects. 
The IDMC will use the above response rate criteria as well as the totality of the data to guide the 
recommendation regarding enrollment continuation to 400 subjects or stopping enrollment at this 
interim analysis. The final decision will be made by the Sponsor based on the IDMC 
recommendation, totality of the data, and other development considerations.
If the study continues enrollment to 400 subjects, then the overall Type 1 error of 0.05 (2-sided) 
will be allocated between the primary endpoints of CR rate and OS using a gate-keeping 
procedure as described below:

There will be a formal statistical testing for superiority for CR at the interim analysis of 
80 subjects with 2-sided α=0.001. The final analysis of CR (in terms of formal statistical 
hypothesis testing) will take place after 160 subjects have been randomized and followed for 
4 months (to occur at the same time as the 1st interim analysis of OS) with 2-sided α=0.009. 
The study and collection of response data continue after the final CR analysis regardless of 
the outcome of the analysis.

Overall 2-sided α=0.04 for OS; and if the final analysis of CR achieves statistical 
significance, then α=0.009 allocated to this CR analysis can be reclaimed by OS analysis, ie, 
OS can be tested at the overall level of 0.049.

The 2 interim analyses and final analysis for OS will utilize the O’Brien-Fleming 
α-spending procedure.
If the study stops enrollment after the first interim analysis, then the clinical cut-off will be when 
90 EFS events have occurred. The analyses of these 120 subjects will be exploratory with EFS as 
the primary outcome of interest.
The overall statistical inference of the study can be summarized as in Table 7.
Table 7:
Overall Statistical Inference
Enrollment, 
No. of 
Subjects
Analysis
Clinical Cutoff
2-Sided α
40 subjects 
per arm
Interim analysis of CR 
and CR+CRi to 
determine enrollment 
continuation
4 months after 40 subjects per arm
are randomized
0.001
Continue to 
approx. 400
CR final analysis
4 months after 160 subjects are 
randomized
0.009
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OS interim analysis No.1 
At the time of final CR analysis
0.0002
OS interim analysis No.2
180 deaths
0.0088/0.0116a
OS final analysis
270 deaths
0.0372/0.0454a
Stop with 
approx. 120
EFS final analysisb
90 EFS events
NA
a If CR final analysis reaches statistical significance
b Exploratory without formal statistical hypothesis testing
11.3.
Sample Size Determination
Part A:
Approximately 6 subjects will be enrolled in Part A of the study in order to confirm the RP2D of 
talacotuzumab for Part B.
Part B:
The first interim analysis to guide the decision for study continuation will occur after 
approximately 80 subjects (40 subjects per arm) have been randomized and followed for at least 
4 months; the operating characteristics of the criteria are shown in Table 8.
Table 8:
Study Continuation Decision Rule, Operating Characteristics 
Sample size
40/arm
Enrollment may continue to approximately 400 subjects
CR ≥15% or (CR+CRi) ≥25%
Enrollment may stop with approximately 120 subjects
CR <15% and (CR+CRi) <25%
False positive error ratea
0.04
False negative error rateb
0.10
a Decision for enrollment to approximately 400 subjects, assuming true effect of decitabine alone and decitabine +
talacotuzumab are the same: CR=15%, CR+CRi=25%
b Decision for stopping enrollment with approximately 120 subjects, assuming true effect of decitabine alone: 
CR=15%, CR+CRi=25%, and true effect of decitabine + talacotuzumab: CR=40%, CR+CRi=55%
=difference in response rate, decitabine + talacotuzumab minus decitabine alone
If the study continues enrollment to 400 subjects, both primary endpoints (CR rate and OS) will 
be powered for 80% with overall α allocation of 0.01 and 0.04, respectively (Table 9).
If the study stops enrollment after the first interim analysis, it is expected that approximately 
120 subjects would have been randomized to the study. In this case, the primary focus will be 
exploratory to assess if there is a clinically relevant improvement in EFS for decitabine + 
talacotuzumab-treated subjects compared with subjects treated with decitabine alone. Assuming 
median EFS of 4 months for the decitabine alone arm, an improvement of 2.8 months in the 
talacotuzumab + decitabine arm (or hazard ratio HR=0.59) is considered clinically meaningful. 
For this purpose, 90 EFS events will provide 80% power to rule out a HR=1.0 (no difference in 
EFS between the 2 treatment arms) using a 90% confidence interval. If 120 subjects are recruited 
in 15 months, it is estimated that 90 EFS events will occur 5 months after the last subject is 
randomized.
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Overall power and sample size determinations are summarized in Table 9.
Table 9:
Sample Size Determination
Endpoint(s)
Effect Size,
Decitabine + Talacotuzumab
vs. Decitabine alone
Power
Overall
2-side α
Total No. 
of Events
Total 
Sample 
Size
Primary: CR Rate
40% vs. 15%
80%
0.01
160
Primary: OS
Median 11.4 vs. 8.0 months
Hazard ratio=0.70
80%
0.04
270
400
Secondary: EFS
Median 6.8 vs.4.0 months
Hazard ratio=0.59
80%
90% CIa
90
120
a If enrollment stops with approximately 120 subjects, analysis of EFS is exploratory with hazard ratio estimate and 
corresponding 90% confidence interval (CI).
11.4.
Efficacy Analyses
Kaplan-Meier estimates of time to events, including OS and EFS will be presented, along with a 
stratified (by baseline ECOG performance status and type of AML) log-rank test comparing the 
2 treatment arms. Median OS along with corresponding 95% confidence intervals (CIs) will be 
obtained from the Kaplan-Meier estimates. Cox’s regression
(stratified by baseline 
ECOG performance status and type of AML) will be applied to obtain the hazard ratio estimate 
and the corresponding 95% CI. Additional Cox’s regression may be performed to include 
appropriate baseline prognostic variables.
Number and percent of subjects who have CR, CR+CRi, and CR plus MRD negative CRi will be 
calculated and compared between the 2 treatment arms using Fisher’s exact test. Time to 
response and duration of response will also be summarized for subjects who have CR, CR+CRi, 
and CR plus MRD negative CRi.
Descriptive analysis will be performed for RFS.
Statistical analyses will be performed for all randomized subjects, as well as for subgroups 
defined by important baseline or disease characteristics, including CD123 status. Additional 
efficacy analyses may be performed to include appropriate data from Part A.
11.5.
Pharmacokinetic Analyses
Pharmacokinetic analyses will be performed on the pharmacokinetic-evaluable population, 
defined as subjects who have received at least 1 dose of talacotuzumab or decitabine and have at 
least 1 post-infusion sample available. 
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Data will be listed for all subjects with available talacotuzumab or decitabine concentrations. 
Subjects will be excluded from the PK analysis if their data do not allow for accurate assessment 
of the PK (eg, incomplete administration of the study agent). All analyte concentrations below 
the lowest quantifiable concentration and any missing data will be labeled as such in the 
concentration data presentation. Concentrations below the lowest quantifiable concentration will 
be treated as zero in the summary statistics. All subjects and samples excluded from the analysis 
will be clearly documented in the study report. 
Descriptive statistics, including mean, standard deviation, coefficient of variation (%CV), 
median, minimum, and maximum, will be used to summarize decitabine plasma concentrations 
and talacotuzumab serum concentrations at each sampling time point. If appropriate, 
pharmacokinetic parameters of talacotuzumab such as Cmin, Cmax, AUCt1-t2, CL, and V may be 
calculated. Graphical exploration of data may be performed if deemed useful.
Population PK analysis of decitabine and talacotuzumab will be explored. If sufficient data are 
available, then population pharmacokinetic analysis of plasma concentration x time data of 
decitabine or serum concentration x time data of talacotuzumab will be performed using 
nonlinear mixed-effects modeling. Data may be combined with those of other studies to support 
a relevant structural model. In addition, available subject characteristics (eg, demographics, 
laboratory data, etc.) may be tested as potential influential covariates affecting PK parameters. If 
the population pharmacokinetic analysis is conducted, then details will be given in a population 
pharmacokinetic analysis plan and the results of the analysis will be presented in a separate 
report.
11.6.
Immunogenicity Analyses
The incidence of antibodies to talacotuzumab (immunogenicity) will be summarized for all 
subjects who receive at least 1 dose of talacotuzumab and have appropriate samples for detection 
of antibodies to talacotuzumab.
A listing of subjects who are positive for antibodies to talacotuzumab will be provided. The 
maximum titers of antibodies to talacotuzumab will be summarized for subjects who are positive 
for antibodies to talacotuzumab.
Other immunogenicity analyses may be performed to further characterize the immune responses 
that are generated.
11.7.
Pharmacokinetic/Pharmacodynamic Analyses
If sufficient data are available, then the relationship between serum concentrations of 
talacotuzumab or plasma concentrations of decitabine, and PD markers, biomarkers or endpoints 
of clinical efficacy could be explored using population approaches (eg, non-linear mixed effects 
approaches). Details and results of such analysis will be presented in a separate report. 
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11.8.
Biomarker Analyses
Biomarker studies are designed to identify markers predictive of response (or resistance) to 
talacotuzumab. Analyses will be stratified by clinical covariates or molecular subgroups using 
the appropriate statistical methods (eg, parametric or non-parametric, univariate or multivariate, 
analysis of variance [ANOVA], or survival analysis, depending on the endpoint). Correlation of 
baseline expression levels or changes in expression levels with clinical parameters will identify 
responsive (or resistant) subgroups in addition to immune cells, genes and pathways attenuated 
following treatment with talacotuzumab. 
Basophils and pDCs, as potential pharmacodynamic measures, will be listed, tabulated, and 
where appropriate, plotted. Subjects may be grouped by cohort, dose, or clinical response. Data 
from CD123 expression will be used as prognostic factors for clinical outcomes to explore if 
potential thresholds can be established for future subject selection. Results of biomarker and 
pharmacodynamic analyses may be presented in a separate report. Planned analyses are based on 
the availability of clinically valid assays and may be deferred if emerging study data show no 
likelihood of providing useful scientific information.
11.9.
Pharmacogenomic Analyses
All pharmacogenomic measures will be listed, tabulated, and where appropriate, plotted. 
Correlation of response and pharmacogenomics measures will be explored. Results may be 
presented in a separate report. Planned analyses are based on the availability of clinically valid 
assays and may be deferred if emerging study data show no likelihood of providing useful 
scientific information.
11.10. Patient-reported Outcomes and Medical Resource Utilization
FACT-Leu and EQ-5D-5L scores will be summarized at each time point. Medical resource 
utilization will be descriptively summarized by treatment group. Duration of hospitalization 
(total days length of stay, including duration by wards; eg, intensive care unit), frequencies of 
outpatient medical encounters and treatments will be calculated and tabulated.
11.11. Safety Analyses
Adverse Events
The verbatim terms used in the eCRF by investigators to identify adverse events will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA). Toxicities will be graded for 
severity according to NCI-CTCAE, version 4.03. All reported adverse events with onset during 
the treatment phase (ie, treatment-emergent adverse events, and adverse events that have 
worsened since baseline) will be included in the analysis. For each adverse event, the percentage 
of subjects who experience at least 1 occurrence of the given event will be summarized by 
treatment group.
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Specifically, the following will be summarized:

All adverse events;

Grade 3 or higher adverse events;

Serious adverse events;

Adverse events leading to discontinuation of treatment;

Adverse events leading to death; and

Adverse events of special interest. 
Summaries, listings, datasets, or subject narratives may be provided, as appropriate, for those 
subjects who die, who discontinue treatment due to an adverse event, or who experience a severe 
or a serious adverse event.
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test. Reference ranges and markedly 
abnormal results (specified in the Statistical Analysis Plan) will be used in the summary of 
laboratory data. Descriptive statistics will be calculated for each laboratory analyte at baseline. 
Parameters with predefined National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI-CTCAE) toxicity grades will be summarized. Change from baseline to the 
worst adverse event grade experienced by the subject during the study will be provided as shift 
tables.
Electrocardiogram (ECG)
Electrocardiogram data will be presented by descriptive analysis only.
Vital Signs
Descriptive statistics of heart rate and supine blood pressure (systolic and diastolic) values and 
changes from baseline will be summarized. The percentage of subjects with clinically important 
changes from baseline will be summarized.
11.12.
Independent Data Monitoring Committee 
An IDMC, consisting of at least 2 clinicians and 1 statistician who are independent experts 
otherwise not participating in the study, will be established to review efficacy and safety results 
at the planned interim analyses. After the interim review, they will make recommendations 
regarding the continuation or stopping of the study. Study investigators and the sponsor’s study 
team will not have access to the blinded data provided to the IDMC.
In addition, the IDMC will review safety data after the first 20 subjects have been followed for at 
least 1 month in Part B. The details will be provided in a separate IDMC charter.
12.
ADVERSE EVENT REPORTING
Timely, accurate, and complete reporting and analysis of safety information from clinical studies 
are crucial for the protection of subjects, investigators, and the sponsor, and are mandated by 
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regulatory agencies worldwide. The sponsor has established Standard Operating Procedures in 
conformity with regulatory requirements worldwide to ensure appropriate reporting of safety 
information; all clinical studies conducted by the sponsor or its affiliates will be conducted in 
accordance with those procedures.
Method of Detecting Adverse Events and Serious Adverse Events
Care will be taken not to introduce bias when detecting adverse events or serious adverse events. 
Open-ended and nonleading verbal questioning of the subject is the preferred method to inquire 
about adverse event occurrence. For some studies, subjects are not always able to provide valid 
verbal responses to open ended questions. In these circumstances, caregivers or guardians would
provide information regarding adverse event occurrence. 
Solicited Adverse Events
Solicited adverse events are predefined local and systemic events for which the subject is 
specifically questioned.
Unsolicited Adverse Events
Unsolicited adverse events are all adverse events for which the subject is specifically not 
questioned.
12.1.
Definitions
12.1.1.
Adverse Event Definitions and Classifications
Adverse Event
An adverse event is any untoward medical occurrence in a clinical study subject administered a 
medicinal (investigational or non-investigational) product. An adverse event does not necessarily 
have a causal relationship with the treatment. An adverse event can therefore be any unfavorable 
and unintended sign (including an abnormal finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational or non-investigational) product, whether or not 
related to that medicinal (investigational or non-investigational) product (Definition per 
International Conference on Harmonisation [ICH]). This includes any occurrence that is new in 
onset or aggravated in severity or frequency from the baseline condition, or abnormal results of 
diagnostic procedures, including laboratory test abnormalities. Note: The sponsor collects 
adverse events starting with the signing of the ICF (refer to Section 12.3.1, All Adverse Events, 
for time of last adverse event recording).
Serious Adverse Event
A serious adverse event based on ICH and EU Guidelines on Pharmacovigilance for Medicinal 
Products for Human Use is any untoward medical occurrence that at any dose:

Results in death
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
Is life-threatening
(The subject was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe.)

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect

Is a suspected transmission of any infectious agent via a medicinal product

Is Medically Important*
*Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
also appropriate in other situations, such as important medical events that may not be 
immediately life threatening or result in death or hospitalization but may jeopardize the subject 
or may require intervention to prevent one of the other outcomes listed in the definition above. 
These should usually be considered serious.
If a serious and unexpected adverse event occurs for which there is evidence suggesting a causal 
relationship between the study drug and the event (eg, death from anaphylaxis), the event must 
be reported as a serious and unexpected suspected adverse reaction even if it is a component of 
the study endpoint (eg, all-cause mortality).
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An adverse event is considered unlisted if the nature or severity is not consistent with the 
applicable product reference safety information. For talacotuzumab and decitabine, the 
expectedness of an adverse event will be determined by whether or not it is listed in the 
Investigator's Brochure.
Adverse Event Associated With the Use of the Drug
An adverse event is considered associated with the use of the drug if the attribution is possible, 
probable, or very likely by the definitions listed in Section 12.1.2.
12.1.2.
Attribution Definitions
Not Related
An adverse event that is not related to the use of the drug.
Doubtful
An adverse event for which an alternative explanation is more likely, eg, concomitant drug(s), 
concomitant disease(s), or the relationship in time suggests that a causal relationship is unlikely.
Possible
An adverse event that might be due to the use of the drug. An alternative explanation, 
eg, concomitant drug(s), concomitant disease(s), is inconclusive. The relationship in time is 
reasonable; therefore, the causal relationship cannot be excluded.
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Probable
An adverse event that might be due to the use of the drug. The relationship in time is suggestive 
(eg, confirmed by dechallenge). An alternative explanation is less likely, eg, concomitant 
drug(s), concomitant disease(s).
Very Likely
An adverse event that is listed as a possible adverse reaction and cannot be reasonably explained 
by an alternative explanation, eg, concomitant drug(s), concomitant disease(s). The relationship 
in time is very suggestive (eg, it is confirmed by dechallenge and rechallenge).
12.1.3.
Severity Criteria
The severity assessment for an adverse event or serious adverse event should be completed using 
the NCI CTCAE Version 4.03. Any adverse event or serious adverse event not listed in the NCI 
CTCAE Version 4.03 will be graded according to investigator clinical judgment by using the 
standard grades as follows:
Grade 1 (Mild): Awareness of symptoms that are easily tolerated, causing minimal discomfort 
and not interfering with everyday activities.
Grade 2 (Moderate): Sufficient discomfort is present to cause interference with normal activity.
Grade 3 (Severe): Extreme distress, causing significant impairment of functioning or 
incapacitation. Prevents normal everyday activities.
Grade 4: Life-threatening of disabling adverse event
Grade 5: Death related to the adverse event
The investigator should use clinical judgment in assessing the severity of events not directly 
experienced by the subject (eg, laboratory abnormalities).
12.2.
Special Reporting Situations
Safety events of interest on a sponsor study drug that may require expedited reporting and/or 
safety evaluation include, but are not limited to:

Overdose of a sponsor study drug

Suspected abuse/misuse of a sponsor study drug

Inadvertent or accidental exposure to a sponsor study drug

Medication error involving a sponsor product (with or without subject/patient exposure to 
the sponsor study drug, eg, name confusion)
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Special reporting situations should be recorded in the eCRF. Any special reporting situation that 
meets the criteria of a serious adverse event should be recorded on the serious adverse event page 
of the eCRF.
12.3.
Procedures
Following Amendment 6, which incorporated the IDMC’s recommendations to close enrollment 
to the study and discontinue talacotuzumab treatment for subjects receiving talacotuzumab + 
decitabine and offer to continue decitabine alone, all subjects will continue to be followed for 
survival and subsequent anti-cancer therapy. During the treatment phase with decitabine, 
subjects will be monitored for serious adverse events.
Following Amendment 7 and when 270 deaths have occurred or 6 months after the last subject is 
enrolled (whichever occurs first), follow up of subjects and data collection will end. Subjects 
who are continuing to derive benefit from decitabine treatment as assessed by their investigator 
may continue to receive decitabine; during this period, only serious adverse events will be 
monitored and entered into the Company safety repository.
12.3.1.
All Adverse Events
All adverse events and special reporting situations, whether serious or non-serious, will be 
reported from the time a signed and dated ICF is obtained until 30 days following the last dose of 
study drug. During the Follow-up Phase, adverse events of Grade 3 or higher that are considered 
related to study drug, as well as all related serious adverse events, should be followed until 
resolution.
Serious adverse events, including those spontaneously reported to the investigator within 30 days 
after the last dose of study drug, must be reported using the Serious Adverse Event Form. The 
sponsor will evaluate any safety information that is spontaneously reported by an investigator 
beyond the time frame specified in the protocol. Anticipated events will be recorded and reported 
as described in Attachment 4.
Treatment failure or relapse from CR/CRi should not be recorded as an adverse event or serious 
adverse event term; instead, signs and symptoms resulting from disease relapse/lack of efficacy 
will be reported if they fulfill the serious adverse event definition (refer to Section 12.1.1
Adverse Event Definitions and Classifications). Death should not be recorded as an adverse 
event or serious adverse event, but as the outcome of an adverse event. The adverse event that 
resulted in the death should be reported as a serious adverse event. All events that meet the 
definition of a serious adverse event will be reported as serious adverse events, regardless of 
whether they are protocol-specific assessments.
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All adverse events, regardless of seriousness, severity, or presumed relationship to study drug, 
must be recorded using medical terminology in the source document and the eCRF. Whenever 
possible, diagnoses should be given when signs and symptoms are due to a common etiology 
(eg, cough, runny nose, sneezing, sore throat, and head congestion should be reported as "upper 
respiratory infection"). Investigators must record in the eCRF their opinion concerning the 
relationship of the adverse event to study therapy. All measures required for adverse event 
management must be recorded in the source document and reported according to sponsor 
instructions.
The sponsor assumes responsibility for appropriate reporting of adverse events to the regulatory 
authorities. The sponsor will also report to the investigator (and the head of the investigational 
institute where required) all suspected unexpected serious adverse reactions (SUSARs). For 
anticipated events reported as individual serious adverse events the sponsor will make a 
determination of relatedness in addition to and independent of the investigator’s assessment. The 
sponsor will periodically evaluate the accumulating data and, when there is sufficient evidence 
and the sponsor has determined there is a reasonable possibility that the drug caused a serious 
anticipated event, they will submit a safety report in narrative format to the investigators (and the 
head of the investigational institute where required).
For all studies with an outpatient phase, including open-label studies, the subject must be 
provided with a "wallet (study) card" and instructed to carry this card with them for the duration 
of the study indicating the following:

Study number

Statement, in the local language(s), that the subject is participating in a clinical study

Investigator's name and 24-hour contact telephone number

Local sponsor's name and 24-hour contact telephone number (for medical staff only)

Site number

Subject number

Any other information that is required to do an emergency breaking of the blind
12.3.2.
Serious Adverse Events
All serious adverse events occurring during the study must be reported to the appropriate sponsor 
contact person by study-site personnel within 24 hours of their knowledge of the event.
Information regarding serious adverse events will be transmitted to the sponsor using the Serious 
Adverse Event Form, which must be completed and signed by a physician from the study site, 
and transmitted to the sponsor within 24 hours. The initial and follow-up reports of a serious 
adverse event should be made by facsimile (fax).
All serious adverse events that have not resolved by the end of the study, or that have not 
resolved upon discontinuation of the subject's participation in the study, must be followed until 
any of the following occurs:
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
The event resolves

The event stabilizes

The event returns to baseline, if a baseline value/status is available

The event can be attributed to agents other than the study drug or to factors unrelated to 
study conduct

It becomes unlikely that any additional information can be obtained (subject or health care 
practitioner refusal to provide additional information, lost to follow-up after demonstration 
of due diligence with follow-up efforts)
Suspected transmission of an infectious agent by a medicinal product will be reported as a 
serious adverse event. Any event requiring hospitalization (or prolongation of hospitalization) 
that occurs during the cycle of a subject's participation in a study must be reported as a serious 
adverse event, except hospitalizations for the following:

Hospitalizations not intended to treat an acute illness or adverse event (eg, social reasons 
such as pending placement in long-term care facility)

Surgery or procedure planned before entry into the study (must be documented in the 
eCRF). Note: Hospitalizations that were planned before the signing of the ICF, and where 
the underlying condition for which the hospitalization was planned has not worsened, will 
not be considered serious adverse events. Any adverse event that results in a prolongation of 
the originally planned hospitalization is to be reported as a new serious adverse event.
Treatment failure or relapse from CR/CRi should not be recorded as an adverse event or serious 
adverse event term; instead, signs and symptoms of clinical sequelae resulting from treatment 
failure or relapse will be reported if they fulfill the serious adverse event definition (refer to
Section 12.1.1, Adverse Event Definitions and Classifications).
12.3.3.
Pregnancy
All initial reports of pregnancy must be reported to the sponsor by the study-site personnel
within 24 hours of their knowledge of the event using the appropriate pregnancy notification 
form. Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, and ectopic pregnancy) are considered serious adverse events and must be reported 
using the Serious Adverse Event Form. Any subject who becomes pregnant during the study 
must be promptly withdrawn from the study and discontinue further study treatment. Follow-up 
information regarding the outcome of the pregnancy and any postnatal sequelae in the infant will 
be required.
Because the effect of the study drug on sperm is unknown, pregnancies in partners of male subjects 
included in the study will be reported as noted above.
12.4.
Contacting Sponsor Regarding Safety
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding safety issues or questions regarding the study are listed on the Contact Information 
page(s), which will be provided as a separate document.
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13.
PRODUCT QUALITY COMPLAINT HANDLING
A product quality complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, quality, 
durability, or reliability of a product, including its labeling or package integrity. A PQC may have 
an impact on the safety and efficacy of the product. Timely, accurate, and complete reporting and 
analysis of PQC information from studies are crucial for the protection of subjects, investigators, 
and the sponsor, and are mandated by regulatory agencies worldwide. The sponsor has 
established procedures in conformity with regulatory requirements worldwide to ensure 
appropriate reporting of PQC information; all studies conducted by the sponsor or its affiliates 
will be conducted in accordance with those procedures.
13.1.
Procedures
All initial PQCs must be reported to the sponsor by the study-site personnel within 24 hours after 
being made aware of the event. If the defect is combined with a serious adverse event, the 
study-site personnel must report the PQC to the sponsor according to the serious adverse event 
reporting timelines (refer to Section 12.3.2, Serious Adverse Events). A sample of the suspected 
product should be maintained for further investigation if requested by the sponsor.
13.2.
Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding product quality issues are listed on the Contact Information page(s), which will be 
provided as a separate document.
14.
STUDY DRUG INFORMATION
14.1.
Physical Description of Study Drug(s)
Talacotuzumab will be supplied as a lyophilized product containing 100 mg of active 
pharmaceutical ingredient (50 mg/mL after reconstitution with 2.0 mL sterile water for injection). 
It will be manufactured and provided under the responsibility of the sponsor. Decitabine will be 
supplied as a lyophilized powder in a single-dose vial of 50 mg per vial and provided by the 
sponsor. Decitabine powder should be reconstituted as outlined in the prescribing information.
14.2.
Packaging
The investigational supplies will be uniquely packaged to assure that they are appropriately 
managed throughout the supply chain process.
14.3.
Labeling
Study drug labels will contain information to meet the applicable regulatory requirements.
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14.4.
Preparation, Handling, and Storage
Study drug will be supplied to the study sites. All talacotuzumab vials must be stored at 
controlled temperatures ranging from 36°F to 46°F (2°C to 8°C) and protected from exposure to 
light. Decitabine is supplied as a lyophilized preparation. Each 20 mL vial containing 50 mg 
decitabine should be stored at or below 25 °C.
Refer to the Site Investigational Product Manual for additional guidance on study drug preparation,
handling, and storage.
14.5.
Drug Accountability
The investigator is responsible for ensuring that all study drug received at the site is inventoried 
and accounted for throughout the study. The study drug administered to the subject must be 
documented on the drug accountability form. All study drug will be stored and disposed of 
according to the sponsor's instructions. Study-site personnel must not combine contents of the 
study drug containers.
Study drug must be handled in strict accordance with the protocol and the container label, and 
must be stored at the study site in a limited-access area or in a locked cabinet under appropriate 
environmental conditions. Unused study drug must be available for verification by the sponsor's 
study site monitor during on-site monitoring visits. The return to the sponsor of unused study 
drug will be documented on the drug return form. When the study site is an authorized 
destruction unit and study drug supplies are destroyed on-site, this must also be documented on 
the drug return form.
Potentially hazardous materials such as used ampules, needles, syringes, and vials containing 
hazardous liquids should be disposed of immediately in a safe manner and therefore will not be 
retained for drug accountability purposes. The immediate destruction of these drug supplies 
should be documented in the drug accountability records on site. 
Study drug should be dispensed under the supervision of the investigator or a qualified member 
of the study-site personnel, or by a hospital/clinic pharmacist. Study drug will be supplied only 
to subjects participating in the study. Study drug may not be relabeled or reassigned for use by 
other subjects. The investigator agrees neither to dispense the study drug from, nor store it at, 
any site other than the study sites agreed upon with the sponsor.
Following Amendment 7 and when 270 deaths have occurred or 6 months after the last subject is 
enrolled (whichever occurs first), follow up of subjects and data collection will end. Subjects 
who are continuing to derive benefit from decitabine treatment as assessed by their investigator 
may continue to receive decitabine; during this period, only serious adverse events will be 
monitored and entered into the Company safety repository.
15.
STUDY-SPECIFIC MATERIALS
The investigator will be provided with the following supplies:
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
Investigator Brochures

Pharmacy manual/study site investigational product manual

Laboratory manual

Patient-reported outcomes (PRO) questionnaires and user manuals

Interactive web response system (IWRS) Manual

Electronic data capture (eDC) Manual

Sample ICF

NCI CTCAE version 4.03
16.
ETHICAL ASPECTS
16.1.
Study-Specific Design Considerations
This is the first study of the combination of decitabine + talacotuzumab. These 2 agents are 
expected to have non-overlapping toxicity profiles; decitabine is primarily myelosuppressive 
while the most frequently reported toxicity from administration of talacotuzumab is infusion 
reactions. Additionally, the administration of the 2 agents is sequential and staggered which 
decreases the likelihood of toxicities due to direct interactions of the combination. 
Pharmacokinetic drug interactions are not anticipated because ADME properties of a nucleoside 
analog (decitabine) are different from those of a monoclonal antibody (talacotuzumab). The 
sponsor will evaluate the available safety of the combination of talacotuzumab and decitabine 
tested during Part A before proceeding to Part B. 
Part B, the randomized portion of this study, will start after the RP2D for talacotuzumab is 
confirmed in Part A. Part B will use talacotuzumab at the RP2D + decitabine prior to the 
complete evaluation of safety for talacotuzumab + decitabine in Part A. The rationale for starting 
Part B is that randomization will provide a more informative safety analysis of the combination 
than that of the single-arm design of Part A. Furthermore, an IDMC will be formed to monitor 
safety and analyze efficacy. A comprehensive safety review of all available data from Part A and 
Part B will be conducted by the IDMC when approximately 10 subjects from each arm of Part B 
have been followed for 1 month. The sponsor, in collaboration with the IDMC, can amend the 
protocol, if needed, based on the results of those reviews. The IDMC will also analyze efficacy 
data, and if necessary, protect subjects from being exposed to an ineffective treatment.
After review of the data from Interim Analysis #2, the IDMC informed the Sponsor that the 
futility criterion for OS was met and that the CR rate did not meet per-protocol defined statistical 
significance. Given the lack of efficacy advantage of talacotuzumab + decitabine versus 
decitabine alone, the incidence of infusion-related reactions, and the complexities with 
premedications for drug administration, the benefit/ risk ratio is not favorable to continue 
treatment with talacotuzumab. The IDMC recommended closure of enrollment to the study and 
that subjects receiving talacotuzumab + decitabine should discontinue talacotuzumab treatment 
and may continue decitabine alone, according to Principal Investigator decision and subject 
agreement. All subjects will continue to be followed for survival and subsequent anti-cancer 
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therapy. During the treatment phase with decitabine, subjects will be monitored for serious 
adverse events.
Following Amendment 7 and when 270 deaths have occurred or 6 months after the last subject is 
enrolled (whichever occurs first), follow up of subjects and data collection will end. Subjects 
who are continuing to derive benefit from decitabine treatment as assessed by their investigator 
may continue to receive decitabine; during this period, only serious adverse events will be 
monitored and entered into the Company safety repository.
Infusion-related reactions have been reported with CSL362 in a Phase 1 study. Subjects in the 
current study will be monitored closely for safety. Premedication for prevention of 
infusion-related reactions will be mandatory prior to dosing for the first 4 cycles. If no infusion-
related reactions, independent of severity, are seen for 2 consecutive cycles during the first 
4 cycles of talacotuzumab treatment, then premedication may be modified per investigator 
discretion after discussion with the Sponsor for Cycle 5 and subsequent talacotuzumab 
treatments.
Potential subjects will be fully informed of the risks and requirements of the study and, during the 
study, subjects will be given any new information that may affect their decision to continue 
participation. They will be told that their consent to participate in the study is voluntary and may be 
withdrawn at any time with no reason given and without penalty or loss of benefits to which they 
would otherwise be entitled. Only subjects who are fully able to understand the risks, benefits, and 
potential adverse events of the study, and provide their consent voluntarily will be enrolled.
The volume of blood to be drawn is considered to be acceptable for subjects participating in a 
cancer clinical study and reasonable over the time frame of the study.29
16.2.
Regulatory Ethics Compliance
16.2.1.
Investigator Responsibilities
The investigator is responsible for ensuring that the study is performed in accordance with the 
protocol, current ICH guidelines on Good Clinical Practice (GCP), and applicable regulatory and 
country-specific requirements. Good Clinical Practice is an international ethical and scientific 
quality standard for designing, conducting, recording, and reporting studies that involve the 
participation of human subjects. Compliance with this standard provides public assurance that 
the rights, safety, and well-being of study subjects are protected, consistent with the principles 
that originated in the Declaration of Helsinki, and that the study data are credible.
16.2.2.
Independent Ethics Committee or Institutional Review Board
Before the start of the study, the investigator (or sponsor where required) will provide the
Independent Ethics Committee/ Institutional Review Board (IEC/IRB) with current and complete 
copies of the following documents (as required by local regulations):

Final protocol and, if applicable, amendments

Sponsor-approved ICF (and any other written materials to be provided to the subjects)
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Investigator's Brochure (or equivalent information) and amendments/addenda

Sponsor-approved subject recruiting materials

Information on compensation for study-related injuries or payment to subjects for 
participation in the study, if applicable

Investigator's curriculum vitae or equivalent information (unless not required, as 
documented by the IEC/IRB)

Information regarding funding, name of the sponsor, institutional affiliations, other potential 
conflicts of interest, and incentives for subjects

Any other documents that the IEC/IRB requests to fulfill its obligation
This study will be undertaken only after the IEC/IRB has given full approval of the final 
protocol, amendments (if any, excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct, unless required locally), the ICF, applicable 
recruiting materials, and subject compensation programs, and the sponsor has received a copy of 
this approval. This approval letter must be dated and must clearly identify the IEC/IRB and the 
documents being approved.
During the study the investigator (or sponsor where required) will send the following documents 
and updates to the IEC/IRB for their review and approval, where appropriate:

Protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct)

Revision(s) to ICF and any other written materials to be provided to subjects

If applicable, new or revised subject recruiting materials approved by the sponsor

Revisions to compensation for study-related injuries or payment to subjects for participation 
in the study, if applicable

New edition(s) of the Investigator's Brochure and amendments/addenda

Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at 
least annually)

Reports of adverse events that are serious, unlisted/unexpected, and associated with the 
study drug

New information that may adversely affect the safety of the subjects or the conduct of the 
study

Deviations from or changes to the protocol to eliminate immediate hazards to the subjects

Report of deaths of subjects under the investigator's care

Notification if a new investigator is responsible for the study at the site

Development Safety Update Report and Line Listings, where applicable

Any other requirements of the IEC/IRB
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For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct), the amendment and applicable ICF revisions 
must be submitted promptly to the IEC/IRB for review and approval before implementation of 
the change(s).
At least once a year, the IEC/IRB will be asked to review and reapprove this study where 
required. 
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB 
about the study completion (if applicable, the notification will be submitted through the head of 
investigational institution).
16.2.3.
Informed Consent
Each subject (or a legally acceptable representative) must give written consent according to local 
requirements after the nature of the study has been fully explained. The ICF(s) must be signed 
before performance of any study-related activity. The ICF(s) that is/are used must be approved 
by both the sponsor and by the reviewing IEC/IRB and be in a language that the subject can read 
and understand. The informed consent should be in accordance with principles that originated in 
the Declaration of Helsinki, current ICH and GCP guidelines, applicable regulatory 
requirements, and sponsor policy.
Before enrollment in the study, the investigator or an authorized member of the study-site 
personnel must explain to potential subjects or their legally acceptable representatives the aims, 
methods, reasonably anticipated benefits, and potential hazards of the study, and any discomfort 
participation in the study may entail. Subjects will be informed that their participation is 
voluntary and that they may withdraw consent to participate at any time. They will be informed 
that choosing not to participate will not affect the care the subject will receive for the treatment 
of his or her disease. Subjects will be told that alternative treatments are available if they refuse 
to take part and that such refusal will not prejudice future treatment. Finally, they will be told 
that the investigator will maintain a subject identification register for the purposes of long-term 
follow up if needed and that their records may be accessed by health authorities and authorized 
sponsor personnel without violating the confidentiality of the subject, to the extent permitted by 
the applicable law(s) or regulations. By signing the ICF the subject or legally acceptable 
representative is authorizing such access, including permission to obtain information about his or 
her survival status, and agrees to allow his or her study physician to recontact the subject for the 
purpose of obtaining consent for additional safety evaluations, if needed, and subsequent 
disease-related treatments, or to obtain information about his or her survival status.
The subject or legally acceptable representative will be given sufficient time to read the ICF and 
the opportunity to ask questions. After this explanation and before entry into the study, consent 
should be appropriately recorded by means of either the subject's or his or her legally acceptable 
representative's personally dated signature. After having obtained the consent, a copy of the ICF
must be given to the subject.
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Where local regulations require, a separate ICF may be used for the required DNA component of 
the study.
If the subject or legally acceptable representative is unable to read or write, an impartial witness 
should be present for the entire informed consent process (which includes reading and explaining 
all written information) and should personally date and sign the ICF after the oral consent of the 
subject or legally acceptable representative is obtained.
16.2.4.
Privacy of Personal Data
The collection and processing of personal data from subjects enrolled in this study will be 
limited to those data that are necessary to fulfill the objectives of the study. These data must be 
collected and processed with adequate precautions to ensure confidentiality and compliance with 
applicable data privacy protection laws and regulations. Appropriate technical and organizational 
measures to protect the personal data against unauthorized disclosures or access, accidental or 
unlawful destruction, or accidental loss or alteration must be put in place. Sponsor personnel 
whose responsibilities require access to personal data agree to keep the identity of subjects 
confidential.
The informed consent obtained from the subject (or his or her legally acceptable representative) 
includes explicit consent for the processing of personal data and for the investigator/institution to 
allow direct access to his or her original medical records (source data/documents) for study-
related monitoring, audit, IEC/IRB review, and regulatory inspection. This consent also 
addresses the transfer of the data to other entities and to other countries.
The subject has the right to request through the investigator access to his or her personal data and 
the right to request rectification of any data that are not correct or complete. Reasonable steps 
will be taken to respond to such a request, taking into consideration the nature of the request, the 
conditions of the study, and the applicable laws and regulations.
Exploratory DNA, pharmacodynamics, biomarker, pharmacokinetics, and immunogenicity 
research is not conducted under standards appropriate for the return of data to subjects. In 
addition, the sponsor cannot make decisions as to the significance of any findings resulting from 
exploratory research. Therefore, exploratory research data will not be returned to subjects or 
investigators, unless required by law or local regulations. Privacy and confidentiality of data 
generated in the future on stored samples will be protected by the same standards applicable to 
all other clinical data.
16.2.5.
Long-Term Retention of Samples for Additional Future Research
Samples collected in this study may be stored for up to 15 years (or according to local 
regulations) for additional research. Samples will only be used to understand the function of
talacotuzumab and decitabine, to understand the biology of AML, to understand differential drug 
responders, and to develop tests/assays related to talacotuzumab and decitabine. The research 
may begin at any time during the study or the post-study storage period. 
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Stored samples will be coded throughout the sample storage and analysis process and will not be 
labeled with personal identifiers. Subjects may withdraw their consent for their samples to be 
stored for research (refer to Section 10.4, Withdrawal From the Study (Withdrawal From the Use 
of Samples in Future Research).
16.2.6.
Country Selection
This study will only be conducted in those countries where the intent is to launch or otherwise 
help ensure access to the developed product if the need for the product persists, unless explicitly 
addressed as a specific ethical consideration in Section 16,
Study-Specific Design 
Considerations.
17.
ADMINISTRATIVE REQUIREMENTS
17.1.
Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment 
by the sponsor. All protocol amendments must be issued by the sponsor, and signed and dated by 
the investigator. Protocol amendments must not be implemented without prior IEC/IRB 
approval, or when the relevant competent authority has raised any grounds for non-acceptance, 
except when necessary to eliminate immediate hazards to the subjects, in which case the 
amendment must be promptly submitted to the IEC/IRB and relevant competent authority. 
Documentation of amendment approval by the investigator and IEC/IRB must be provided to the 
sponsor. When the change(s) involves only logistic or administrative aspects of the study, the 
IRB (and IEC where required) only needs to be notified.
During the course of the study, in situations where a departure from the protocol is unavoidable, 
the investigator or other physician in attendance will contact the appropriate sponsor 
representative (see Contact Information page(s) provided separately). Except in emergency 
situations, this contact should be made before implementing any departure from the protocol. In 
all cases, contact with the sponsor must be made as soon as possible to discuss the situation and 
agree on an appropriate course of action. The data recorded in the eCRF and source documents 
will reflect any departure from the protocol, and the source documents will describe this 
departure and the circumstances requiring it.
17.2.
Regulatory Documentation
17.2.1.
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities 
in each respective country, if applicable. A study may not be initiated until all local regulatory 
requirements are met.
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17.2.2.
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study drug to the 
study site:

Protocol and amendment(s), if any, signed and dated by the principal investigator

A copy of the dated and signed (or sealed, where appropriate per local regulations), written 
IEC/IRB approval of the protocol, amendments, ICF, any recruiting materials, and if 
applicable, subject compensation programs. This approval must clearly identify the specific 
protocol by title and number and must be signed (or sealed, where appropriate per local 
regulations) by the chairman or authorized designee.

Name and address of the IEC/IRB, including a current list of the IEC/IRB members and 
their function, with a statement that it is organized and operates according to GCP and the 
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, 
from the IEC/IRB, a general statement may be substituted for this list. If an investigator or a 
member of the study-site personnel is a member of the IEC/IRB, documentation must be 
obtained to state that this person did not participate in the deliberations or in the 
vote/opinion of the study.

Regulatory authority approval or notification, if applicable

Signed and dated statement of investigator (eg, Form FDA 1572), if applicable

Documentation of investigator qualifications (eg, curriculum vitae)

Completed investigator financial disclosure form from the principal investigator, where 
required

Signed and dated clinical trial agreement, which includes the financial agreement

Any other documentation required by local regulations
The following documents must be provided to the sponsor before enrollment of the first subject:

Completed investigator financial disclosure forms from all subinvestigators

Documentation of subinvestigator qualifications (eg, curriculum vitae)

Name and address of any local laboratory conducting tests for the study, and a dated copy of 
current laboratory normal ranges for these tests, if applicable

Local 
laboratory 
documentation 
demonstrating 
competence 
and 
test 
reliability 
(eg, accreditation/license), if applicable
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17.3.
Subject Identification, Enrollment, and Screening Logs
The investigator agrees to complete a subject identification and enrollment log to permit easy 
identification of each subject during and after the study. This document will be reviewed by the 
sponsor study-site contact for completeness.
The subject identification and enrollment log will be treated as confidential and will be filed by 
the investigator in the study file. To ensure subject confidentiality, no copy will be made. All 
reports and communications relating to the study will identify subjects by subject identification
and date of birth. In cases where the subject is not randomized into the study, the date seen and 
date of birth will be used.
The investigator must also complete a subject screening log, which reports on all subjects who 
were seen to determine eligibility for inclusion in the study.
17.4.
Source Documentation
At a minimum, source documents consistent in the type and level of detail with that commonly 
recorded at the study site as a basis for standard medical care, must be available for the 
following: subject identification, eligibility, and study identification; study discussion and date of 
signed informed consent; dates of visits; results of safety and efficacy parameters as required by 
the protocol; record of all adverse events and follow-up of adverse events; concomitant 
medication; drug receipt/dispensing/return records; study drug administration information; and 
date of study completion and reason for early discontinuation of study drug or withdrawal from 
the study, if applicable. In addition, the author of an entry in the source documents should be 
identifiable.
Specific details required as source data for the study and source data collection methods will be 
reviewed with the investigator before the study and will be described in the monitoring 
guidelines (or other equivalent document).
Subject- and investigator-completed scales and assessments designated by the sponsor (eg, PRO 
assessments) will be recorded and will be considered source data.
The minimum source documentation requirements for Section 4.1, Inclusion Criteria and 
Section 4.2, Exclusion Criteria that specify a need for documented medical history are as 
follows:

Referral letter from treating physician or

Complete history of medical notes at the site

Discharge summaries
Inclusion and exclusion criteria not requiring documented medical history must be verified at a 
minimum by subject interview or other protocol required assessment (eg, physical examination, 
laboratory assessment) and documented in the source documents.
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An electronic source system may be utilized, which contains data traditionally maintained in a 
hospital or clinic record to document medical care (eg, electronic source documents) as well as 
the clinical study-specific data fields as determined by the protocol. This data is electronically 
extracted for use by the sponsor. If the electronic source system is utilized, references made to 
the CRF in the protocol include the electronic source system but information collected through 
the electronic source system may not be limited to that found in the CRF. Data in this system 
may be considered source documentation.
17.5.
Case Report Form Completion
Case report forms are prepared and provided by the sponsor for each subject in electronic format. 
All CRF entries, corrections, and alterations must be made by the investigator or authorized 
study-site personnel. The investigator must verify that all data entries in the CRF are accurate 
and correct.
The study data will be transcribed by study-site personnel from the source documents onto an 
electronic CRF, if applicable. Study-specific data will be transmitted in a secure manner to the 
sponsor.
Worksheets may be used for the capture of some data to facilitate completion of the CRF. Any 
such worksheets will become part of the subject's source documentation. Data must be entered 
into CRFs in English. The CRF must be completed as soon as possible after a subject visit, and 
the forms should be available for review at the next scheduled monitoring visit.
All subjective measurements (eg, pain scale information or other questionnaires) will be 
completed by the same individual who made the initial baseline determinations whenever 
possible.
If necessary, queries will be generated in the eDC tool. If corrections to a CRF are needed after 
the initial entry into the CRF, this can be done in either of the following ways:
•
Investigator and study- site personnel can make corrections in the eDC tool at their own 
initiative or as a response to an auto query (generated by the eDC tool).
•
Sponsor or sponsor delegate can generate a query for resolution by the investigator and 
study-site personnel.
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17.6.
Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study sites, review of protocol procedures with the investigator and 
study-site personnel before the study, periodic monitoring visits by the sponsor. Written 
instructions will be provided for collection, handling, storage, and shipment of samples. 
Guidelines for eCRF completion will be provided and reviewed with study-site personnel before 
the start of the study. The sponsor will review eCRF for accuracy and completeness during 
on-site monitoring visits and after transmission to the sponsor; any discrepancies will be resolved 
with the investigator or designee, as appropriate. After upload of the data into the study database 
they will be verified for accuracy and consistency with the data sources.
17.7.
Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all eCRFs 
and all source documents that support the data collected from each subject, as well as all study 
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a 
Clinical Trial, and all study documents as specified by the applicable regulatory requirement(s). 
The investigator/institution will take measures to prevent accidental or premature destruction of 
these documents.
Essential documents must 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 product. These documents will be 
retained for a longer period if required by the applicable regulatory requirements or by an 
agreement with the sponsor. It is the responsibility of the sponsor to inform the 
investigator/institution as to when these documents no longer need to be retained.
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will 
accept the responsibility. The sponsor must be notified in writing of the name and address of the 
new custodian. Under no circumstance shall the investigator relocate or dispose of any study 
documents before having obtained written approval from the sponsor.
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any 
documentation relating to this study, the investigator/institution must permit access to such 
reports.
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17.8.
Monitoring
The sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will 
record dates of the visits in a study site visit log that will be kept at the study site. The first 
post-initiation visit will be made as soon as possible after enrollment has begun. At these visits, 
the monitor will compare the data entered into the eCRFs with the source documents (eg, 
hospital/clinic/physician’s office medical records). The nature and location of all source 
documents will be identified to ensure that all sources of original data required to complete the 
eCRF are known to the sponsor and study-site personnel and are accessible for verification by 
the sponsor study-site contact. If electronic records are maintained at the study site, the method 
of verification must be discussed with the study-site personnel. 
Direct access to source documentation (medical records) must be allowed for the purpose of 
verifying that the data recorded in the eCRF are consistent with the original source data. Findings 
from this review of eCRF and source documents will be discussed with the study-site personnel. 
The sponsor expects that, during monitoring visits, the relevant study-site personnel will be 
available, the source documentation will be accessible, and a suitable environment will be 
provided for review of study-related documents. The monitor will meet with the investigator on a 
regular basis during the study to provide feedback on the study conduct.
17.9.
Study Completion/Termination
17.9.1.
Study Completion/ End of Study
The end of study data collection is defined as when 270 deaths have occurred or 6 months after 
the last subject is enrolled, whichever occurs first. At that time, follow up of subjects will end. 
Subjects who are continuing to derive benefit from decitabine treatment as assessed by their 
investigator may continue to receive decitabine; during this period, only serious adverse events 
will be monitored and entered into the Company safety repository as described under 
Amendment 7.
17.9.2.
Study Termination
The sponsor reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A
study site is considered closed when all required documents and study supplies have been 
collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or 
local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of subjects by the investigator
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Status: Approved, Date: 31 October 2017   

Discontinuation of further study drug development
17.10. On-Site Audits
Representatives of the sponsor's clinical quality assurance department may visit the study site at 
any time during or after completion of the study to conduct an audit of the study in compliance 
with regulatory guidelines and company policy. These audits will require access to all study 
records, including source documents, for inspection. Subject privacy must, however, be 
respected. The investigator and study-site personnel are responsible for being present and 
available for consultation during routinely scheduled study-site audit visits conducted by the 
sponsor or its designees. 
Similar auditing procedures may also be conducted by agents of any regulatory body, either as 
part of a national GCP compliance program or to review the results of this study in support of a 
regulatory submission. The investigator should immediately notify the sponsor if he or she has
been contacted by a regulatory agency concerning an upcoming inspection.
17.11. Use of Information and Publication
All information, including but not limited to information regarding talacotuzumab and decitabine
or the sponsor's operations (eg, patent application, formulas, manufacturing processes, basic 
scientific data, prior clinical data, formulation information) supplied by the sponsor to the 
investigator and not previously published, and any data, including pharmacogenomic or 
exploratory biomarker research data, generated as a result of this study, are considered 
confidential and remain the sole property of the sponsor. The investigator agrees to maintain this 
information in confidence and use this information only to accomplish this study, and will not 
use it for other purposes without the sponsor's prior written consent.
The investigator understands that the information developed in the study will be used by the 
sponsor in connection with the continued development of talacotuzumab and decitabine, and thus 
may be disclosed as required to other clinical investigators or regulatory agencies. To permit the 
information derived from the clinical studies to be used, the investigator is obligated to provide 
the sponsor with all data obtained in the study.
The results of the study will be reported in a Clinical Study Report generated by the sponsor and 
will contain data from all study sites that participated in the study as per protocol. Recruitment 
performance or specific expertise related to the nature and the key assessment parameters of the 
study will be used to determine a coordinating investigator. Results of pharmacogenomics or 
exploratory biomarker analyses performed after the Clinical Study Report has been issued will 
be reported in a separate report and will not require a revision of the Clinical Study Report. 
Study subject identifiers will not be used in publication of results. Any work created in 
connection with performance of the study and contained in the data that can benefit from 
copyright protection (except any publication by the investigator as provided for below) shall be 
the property of the sponsor as author and owner of copyright in such work.
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Consistent with Good Publication Practices and International Committee of Medical Journal 
Editors guidelines, the sponsor shall have the right to publish such primary (multicenter) data 
and information without approval from the investigator. The investigator has the right to publish 
study site-specific data after the primary data are published. If an investigator wishes to publish 
information from the study, a copy of the manuscript must be provided to the sponsor for review 
at least 60 days before submission for publication or presentation. Expedited reviews will be 
arranged for abstracts, poster presentations, or other materials. If requested by the sponsor in 
writing, the investigator will withhold such publication for up to an additional 60 days to allow 
for filing of a patent application. In the event that issues arise regarding scientific integrity or 
regulatory compliance, the sponsor will review these issues with the investigator. The sponsor 
will not mandate modifications to scientific content and does not have the right to suppress 
information. For multicenter study designs and substudy approaches, secondary results generally 
should not be published before the primary endpoints of a study have been published. Similarly, 
investigators will recognize the integrity of a multicenter study by not submitting for publication 
data derived from the individual study site until the combined results from the completed study
have been submitted for publication, within 12 months of the availability of the final data (tables, 
listings, graphs), or the sponsor confirms there will be no multicenter study publication. 
Authorship of publications resulting from this study will be based on the guidelines on 
authorship, such as those described in the Uniform Requirements for Manuscripts Submitted to 
Biomedical Journals, which state that the named authors must have made a significant
contribution to the design of the study or analysis and interpretation of the data, provided critical 
review of the paper, and given final approval of the final version.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and/or disclose the existence of and the results of clinical studies as 
required by law.
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REFERENCES
1.
Badger C, Davis J, et al. Biodistribution and Dosimetry following Infusion of Antibodies Labeled with Large 
Amounts of 13II1. Cancer Research 1991; 51, 5921-5928.
2.
Buccisano F, Maurillo L, Spagnoli A, et al. Cytogenetic and molecular diagnostic characterization combined to 
postconsolidation minimal residual disease assessment by flow cytometry improves risk stratification in adult 
acute myeloid leukemia. Blood 2010;116:2295-2303.
3.
Busfield SJ, Biondo M, Wong M, et al. Targeting of acute myeloid leukemia in vitro and in vivo with an anti-
CD123 mAb engineered for optimal ADCC. Leukemia. 2014;1-9. 
4.
Cella D, Jensen S, Webster K, et al. Measuring health-related quality of life in leukemia: the functional 
assessment of cancer therapy–leukemia (FACT-Leu) questionnaire. Value in Health. 2012;15:1051–1058.
5.
Cheson BD, Cassileth PA, Head DR et al, Report of the National Cancer Institute-sponsored workshop on 
definitions of diagnosis and response in acute myeloid leukemia. J Clin Oncol 1990;8:813-819.
6.
DACO-016 Clinical Study Report. Randomized Phase 3 trial of decitabine versus patient’s choice with 
physician’s advice of either supportive care or low-dose cytarabine for the treatment of older patients with 
newly diagnosed acute myeloid leukemia. 4 April 2011.
7.
De Charro F, Rabin R. EQ-5D-5L from the EuroQol group: an update. QOL Newsletter, 2000;25:6-7.
8.
D’Incalci M, Covey JM, Zaharko DS, Kohn KW. DNA Alkali-labile Sites Induced by Incorporation of 5-Aza-
2'-deoxycytidine into DNA of Mouse Leukemia L1210 Cells. Cancer Res 1985;45:3197-3202.
9.
Dohner H, Estey EH, Amadori S, et al. Diagnosis and management of acute myeloid leukemia in adults: 
recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood. 
2010;115:453-474. 
10.
Ehninger A, Kramer M, Rollig C, et al. Distribution and levels of cell surface expression of CD33 and CD123 
in acute myeloid leukemia. Blood Cancer J. 2014;4:e218. 
11.
Guzman ML, Allan JN. Concise Review: Leukemia stem cells in personalized medicine. Stem Cells. 
2014;32:844-851. 
12.
Hercus TR, Dhagat U, Kan WLT, et al. Signalling by the c family of cytokines. Cytokine & Growth Factor 
Rev. 2013;24:189-201. 
13.
Hourigan CS, Karp JE. Minimal residual disease in acute myeloid leukaemia. Nat Rev Clin Oncol 2013;
doi:10.1038/nrclinonc.2013.100. 
14.
Hwang K, Park C-J, Jang S, et al. Flow cytometric quantification and immunophenotyping of leukemic stem 
cells in acute myeloid leukemiaAnn Hematol 2012;91:1541-1546.
15.
Investigator’s Brochure: JNJ-30979754 DACOGEN (decitabine for Injection) March 2015.
16.
Investigator’s Brochure: JNJ-56022473(CSL362) April 2015.
17.
Jordan CT, Upchurch D, Szilvassy SJ, et al. The interleukin-3 receptor alpha chain is a unique marker for 
human acute myelogenous leukemia stem cells. Leukemia. 2000;14:1777-1784.
18.
Jourdan E, Boissel N, Chevret S, et al. Prospective evaluation of gene mutations and minimal residual disease 
in patients with core binding factor acute myeloid leukemia. Blood 2013; doi:10.1182/blood-2012-10-462879.
19.
Kantarjian H, Oki Y, Garcia-Manero G, et al. Results of a randomized study of 3 schedules of low-dose 
decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia. Blood 
2007;109:52-57.
20.
Kantarjian H, Ravandi F, O’Brien S, et al. Intensive chemotherapy does not benefit most older patients (age 70 
years or older) with acute myeloid leukemia. Blood 2010;116:4422-4429.
21.
Kantarjian HM, Thomas XG, Dmoszynska A, et al. Multicenter, Randomized, Open-Label, Phase III Trial of 
Decitabine Versus Patient Choice, With Physician Advice, of Either Supportive Care or Low-Dose Cytarabine 
for the Treatment of Older Patients With Newly Diagnosed Acute Myeloid Leukemia. J Clin Oncol 
2012;30:2670-2677.
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Status: Approved, Date: 31 October 2017   
22.
Kind P, Dolan P, Gudex C, Williams A. Variations in population health status: results from a United Kingdom 
national questionnaire survey. BMJ 1998;316:736-741.
23.
Kopp LM, Ray A, Denman CJ, et al. Decitabine has a biphasic effect on natural killer cell viability, phenotype, 
and function under proliferative conditions. Molecular Immunology 2013;54:296-301.
24.
Kuykendall JR. 5-azacytidine and decitabine monotherapies of myelodysplastic disorders. Ann Pharmacother 
2005;39:1700-1709.
25.
Malik P, Cashen AF. Decitabine in the treatment of acute myeloid leukemia in elderly patients. Cancer 
management and Research 2014;6:53-61.
26.
Montalban-Bravo G, Garcia-Manero G. Novel drugs for older patients with acute myeloid leukemia. Leukemia 
2014;1-10, doi:10.1038/leu.2014.244.
27.
Munoz L, Nomdedeu JF, Lopez O, et al. Interleukin-3 receptor a chain (CD123) is widely expressed in 
hematologic malignancies. Haematologica 2001;86:1261-1269.
28.
National Comprehensive Cancer Network (NCCN) Guidelines Acute Myeloid Leukemia version 1.2015.
29.
POLICY: Guidelines for Limits of Blood Drawn for Research Purposes in the Clinical Center at 
https://irb.research.chop.edu/sites/default/files/documents/g_nih_blooddraws.pdf. accessed 08 June 2016
30.
Qiu S, Jia Y, Xing H, et al. N-cadherin and Tie2 positive CD34+CD38-CD123+ leukemic stem cell 
populations can develop acute myeloid leukemia more effectively in NOD/SCID mice. Leukemia Res. 
2014;38:632-637. 
31.
Schmiedel BJ, Arelin V, Gruenebach K, et al. Azacytidine impairs NK cell reactivity while decitabine 
augments NK cell responsiveness toward stimulation. Int J Cancer 2011;128:2911-2922.
32.
Smith BD, Karp JE. What Are the Endpoints of Therapy for Acute Leukemias? Old Definitions and New 
Challenges. Clin Lymphoma Myeloma. 2009; 9(Suppl 3): S296–S301.
33.
Smith BD, Roboz GJ, Walter RB, et al. Abstract 120 First-in Man, Phase 1 Study of CSL362 (Anti-IL3Rα / 
Anti-CD123 Monoclonal Antibody) in Patients with CD123+ Acute Myeloid Leukemia (AML) in CR at High 
Risk for Early Relapse. American Society for Hematology meeting 2014.
34.
Testa U, Riccioni R, Militi S, et al. Elevated expression of IL-3Rα in acute myelogenous leukemia is 
associated with enhanced blast proliferation, increased cellularity, and poor prognosis. Blood. 2002;100:2980-
2988.
35.
Vardiman JW, Thiele J, Arber DA, et al. The 2008 revision of the World Health Organization (WHO) 
classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood. 
2009;114:937-951.
36.
Vergez F, Green AS, Tamburini J, et al. High levels of CD34+CD38low/-CD123+ blasts are predictive of an 
adverse outcome in acute myeloid leukemia: a GOELAMS study. Haematologica. 2011;96:1792-1798. 
37.
Wang JCY, Dick JE. Cancer stem cells: lessons from leukemia. Trends in Cell Biology. 2005;15:494-501.
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Attachment 1: Sample FACT-Leu (Version 4)
Below is a list of statements that other people with your illness have said are important. Please 
circle or mark one number per line to indicate your response as it applies to the past 
7 days.
PHYSICAL WELL-BEING
Not at 
all
A little 
bit
Some-
what
Quite
a bit
Very 
much
GP
1
I have a lack of energy......................................
0
1
2
3
4
GP
2
I have nausea.....................................................
0
1
2
3
4
GP
3
Because of my physical condition, I have 
trouble meeting the needs of my family............
0
1
2
3
4
GP
4
I have pain.........................................................
0
1
2
3
4
GP
5
I am bothered by side effects of treatment........
0
1
2
3
4
GP
6
I feel ill..............................................................
0
1
2
3
4
GP
7
I am forced to spend time in bed.......................
0
1
2
3
4
SOCIAL/FAMILY WELL-BEING
Not at 
all
A little 
bit
Some-
what
Quite
a bit
Very 
much
GS
1
I feel close to my friends...................................
0
1
2
3
4
GS
2
I get emotional support from my family...........
0
1
2
3
4
GS
3
I get support from my friends ...........................
0
1
2
3
4
GS
4
My family has accepted my illness...................
0
1
2
3
4
GS
5
I am satisfied with family communication 
about my illness ................................................
0
1
2
3
4
GS
6
I feel close to my partner (or the person who 
is my main support) ..........................................
0
1
2
3
4
Q1
Regardless of your current level of sexual 
activity, please answer the following question. If 
you prefer not to answer it, please mark this box    
and go to the next section.
GS
7
I am satisfied with my sex life..........................
0
1
2
3
4
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Status: Approved, Date: 31 October 2017   
Please circle or mark one number per line to indicate your response as it applies to the past 
7 days.
EMOTIONAL WELL-BEING
No
t at 
all
A 
little 
bit
Some-
what
Quit
e a 
bit
Very 
muc
h
GE
1
I feel sad .........................................................................
0
1
2
3
4
GE
2
I am satisfied with how I am coping with my illness.....
0
1
2
3
4
GE
3
I am losing hope in the fight against my illness.............
0
1
2
3
4
GE
4
I feel nervous..................................................................
0
1
2
3
4
GE
5
I worry about dying........................................................
0
1
2
3
4
GE
6
I worry that my condition will get worse .......................
0
1
2
3
4
FUNCTIONAL WELL-BEING
Not 
at 
all
A little 
bit
Some
-what
Quite
a bit
Very 
muc
h
GF1
I am able to work (include work at home)..........
0
1
2
3
4
GF2
My work (include work at home) is fulfilling ....
0
1
2
3
4
GF3
I am able to enjoy life .........................................
0
1
2
3
4
GF4
I have accepted my illness ..................................
0
1
2
3
4
GF5
I am sleeping well ...............................................
0
1
2
3
4
GF6
I am enjoying the things I usually do for fun......
0
1
2
3
4
GF7
I am content with the quality of my life right 
now......................................................................
0
1
2
3
4
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Status: Approved, Date: 31 October 2017   
Please circle or mark one number per line to indicate your response as it applies to the past 
7 days.
ADDITIONAL CONCERNS
Not at 
all
A little 
bit
Some-
what
Quite
a bit
Very 
much
BRM3
I am bothered by fevers (episodes of high 
body temperature)...........................................
0
1
2
3
4
P2
I have certain parts of my body where I 
experience pain...............................................
0
1
2
3
4
BRM2
I am bothered by the chills .............................
0
1
2
3
4
ES3
I have night sweats .........................................
0
1
2
3
4
LEU1
I am bothered by lumps or swelling in 
certain parts of my body (e.g., neck, 
armpits, or groin)............................................
0
1
2
3
4
TH1
I bleed easily...................................................
0
1
2
3
4
TH2
I bruise easily..................................................
0
1
2
3
4
HI12
I feel weak all over .........................................
0
1
2
3
4
BMT6
I get tired easily..............................................
0
1
2
3
4
C2
I am losing weight ..........................................
0
1
2
3
4
C6
I have a good appetite.....................................
0
1
2
3
4
An7
I am able to do my usual activities.................
0
1
2
3
4
N3
I worry about getting infections .....................
0
1
2
3
4
LEU5
I feel uncertain about my future health...........
0
1
2
3
4
LEU6
I worry that I might get new symptoms of 
my illness........................................................
0
1
2
3
4
BRM9
I have emotional ups and downs ....................
0
1
2
3
4
LEU7
I feel isolated from others because of my 
illness or treatment .........................................
0
1
2
3
4
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Status: Approved, Date: 31 October 2017   
Attachment 2: Sample EQ-5D-5L
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Talacotuzumab (JNJ-56022473)
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Status: Approved, Date: 31 October 2017   
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Talacotuzumab (JNJ-56022473)
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Status: Approved, Date: 31 October 2017   
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Clinical Protocol 56022473AML2002 Amendment 7
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Status: Approved, Date: 31 October 2017   
Attachment 3: ECOG Performance Status Score
ECOG PERFORMANCE STATUS*
Grade ECOG
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of 
a light or sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up 
and about more than 50% of waking hours
3
Capable of only limited selfcare, confined to bed or chair more than 50% of waking 
hours
4
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair
5
Dead
* As published in Am. J. Clin. Oncol.:
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity 
And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982.
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Status: Approved, Date: 31 October 2017   
Attachment 4: Anticipated Events
Anticipated Event
An anticipated event is an adverse event (serious or non-serious) that commonly occurs as a consequence 
of the underlying disease or condition under investigation (disease related) or background regimen.
For the purposes of this study the following events will be considered anticipated events:
Disease Based:

Thrombocytopenia

Anemia

Febrile neutropenia

Leukopenia

Pneumonia

Sepsis

Urinary tract infection

Broncopneumonias

Bacteremia

Pyrexia

Asthenia

Fatigue

Dyspnea

Cardia dysrhythmias (i.e., atrial fibrillation)
Population Based:

Congestive heart failure
Reporting of Anticipated Events
All adverse events will be recorded in the CRF regardless of whether considered to be anticipated events 
and will be reported to the sponsor as described in Section 12.3.1, All Adverse Events. Any anticipated 
event that meets serious adverse event criteria will be reported to the sponsor as described in 
Section 12.3.2, Serious Adverse Events. These anticipated events are exempt from expedited reporting as 
individual single cases to Health Authorities. However if based on an aggregate review, it is determined 
that an anticipated event is possibly related to study drug, the sponsor will report these events in an 
expedited manner.
Anticipated Event Review Committee (ARC)
An Anticipated Event Review Committee (ARC) will be established to perform reviews of pre-specified 
anticipated events at an aggregate level. The ARC is a safety committee within the sponsor’s organization 
that is independent of the sponsor’s study team. The ARC will meet to aid in the recommendation to the 
sponsor’s study team as to whether there is a reasonable possibility that an anticipated event is related to 
the study drug.
Statistical Analysis
Details of statistical analysis of anticipated events, including the frequency of review and threshold to 
trigger an aggregate analysis of anticipated events will be provided in a separate Anticipated Events 
Safety Monitoring Plan (ASMP).
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INVESTIGATOR AGREEMENT
NCT02472145

SAP_001.pdf: 
1 
Janssen Research & Development 
 
 
Statistical Analysis Plan 
 
 
 
A Randomized Phase2/3 Study of DACOGEN® (Decitabine) Plus JNJ-56022473 (Anti 
CD123) Versus DACOGEN (Decitabine) Alone in Patients with AML who are not 
Candidates for Intensive Chemotherapy 
 
Protocol JNJ56022473AML2002; Phase 2/3 
 
 JNJ-56022473 
 
 
Final 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date: 
16 March 2018 
Prepared by: 
Janssen Research & Development 
 
Confidentiality Statement 
The information in this document contains trade secrets and commercial information that are privileged or confidential and may 
not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the information 
is disclosed must be informed that the information is privileged or confidential and may not be further disclosed by them. These 
restrictions on disclosure will apply equally to all future information supplied to you that is indicated as privileged or confidential.
NCT02472145


JNJ-56022473  
 
 
 
Statistical Analysis Plan JNJ56022473AML2002  
2 
TABLE OF CONTENTS 
TABLE OF CONTENTS ............................................................................................................................... 2 
1. 
INTRODUCTION .................................................................................................................................. 4 
2. 
STUDY ENDPOINTS ........................................................................................................................... 4 
2.1. 
Primary Endpoints ............................................................................................................................ 4 
2.2. 
Secondary and Exploratory Endpoints (Part B) ............................................................................... 4 
3. 
SUMMARY OF STUDY DESIGN ........................................................................................................ 4 
4. 
DETERMINATION OF SAMPLE SIZE – STUDY PART B ................................................................. 7 
5. 
GENERAL DESCRIPTIONS AND DEFINITIONS ............................................................................... 8 
5.1. 
Summaries of Part A Data ............................................................................................................... 8 
5.2. 
Subject Populations (Part B) ............................................................................................................ 8 
5.3. 
Study Phases ................................................................................................................................... 9 
5.4. 
Convention of Time Computations ................................................................................................... 9 
5.5. 
Baseline Value ................................................................................................................................. 9 
5.6. 
Major Protocol Deviation .................................................................................................................. 9 
5.7. 
Cytogenetic Risk .............................................................................................................................. 9 
5.8. 
Prior and Concomitant Medications ................................................................................................. 9 
5.9. 
Disease Status per Central Review and Investigator’s Assessment ............................................... 9 
5.10. 
MRD Negativity .............................................................................................................................. 10 
5.11. 
Patient-Reported Outcomes .......................................................................................................... 10 
5.11.1. 
FACT-Leu ................................................................................................................................... 10 
5.11.2. 
EQ-5D-5L .................................................................................................................................... 10 
5.12. 
Interim Analyses ............................................................................................................................. 11 
5.13. 
Subgroups ...................................................................................................................................... 11 
5.14. 
Dose Intensity ................................................................................................................................ 11 
5.15. 
Treatment-Emergent Adverse Events ............................................................................................ 11 
5.16. 
Adverse Events of Special Interest ................................................................................................ 11 
6. 
PLANNED ANALYSES ..................................................................................................................... 12 
6.1. 
Subject Disposition ......................................................................................................................... 12 
6.2. 
Major Protocol Deviations .............................................................................................................. 12 
6.3. 
Demographics and Baseline Characteristics ................................................................................. 12 
6.4. 
Prior and Concomitant Medications ............................................................................................... 12 
6.5. 
Medical History ............................................................................................................................... 12 
6.6. 
Extent of Exposure ......................................................................................................................... 12 
6.7. 
Efficacy ........................................................................................................................................... 12 
6.7.1. 
Primary Efficacy Endpoints ......................................................................................................... 13 
6.7.1.1. 
Complete Response .................................................................................................... 13 
6.7.1.2. 
Overall Survival ........................................................................................................... 13 
6.7.2. 
Secondary and Exploratory Efficacy Endpoints ......................................................................... 13 
6.7.2.1. 
Event‐Free Survival ..................................................................................................... 13 
6.7.2.2. 
Overall Response ......................................................................................................... 13 
6.7.2.3. 
CR plus MRD‐Negative CRi .......................................................................................... 14 
6.7.2.4. 
Time to Response ........................................................................................................ 14 
6.7.2.5. 
Duration of Response .................................................................................................. 14 
6.7.2.6. 
Minimal Residual Disease ........................................................................................... 14 
6.7.2.7. 
Patient‐Reported Outcomes ....................................................................................... 14 
6.7.3. 
Transfusion Frequency as an Exploratory Efficacy Endpoint ..................................................... 15 
6.8. 
Safety ............................................................................................................................................. 15 
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6.8.1. 
Adverse Events ........................................................................................................................... 15 
6.8.2. 
Clinical Laboratory Tests ............................................................................................................ 15 
6.8.3. 
Electrocardiogram ....................................................................................................................... 16 
6.8.4. 
Vital Signs ................................................................................................................................... 16 
7. 
REFERENCES ................................................................................................................................... 16 
 
 
 
 
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1. 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to describe the procedures and the statistical 
methods that will be used to analyze and report results for study JNJ-56022473-AML-2002. 
JNJ-56022473-AML-2002 is an open-label, 2-part, multicenter, Phase 2/3 study to evaluate the 
safety and clinical efficacy of a combination of decitabine and talacotuzumab (JNJ-56022473) in 
subjects with acute myeloid leukemia (AML) who are suitable for experimental therapy (Part A) 
and in subjects with untreated AML who are not eligible for intense induction chemotherapy or 
hematopoietic stem cell transplantation (Part B).  
2. 
STUDY ENDPOINTS 
2.1. 
Primary Endpoints 
Part A: Safety 
Part B: Complete Remission (CR) rate and overall survival (OS)  
2.2. 
Secondary and Exploratory Endpoints (Part B)  
Secondary endpoints to be summarized in the clinical study report include the following: 
 
Event-free survival (EFS), defined as the time from randomization to treatment failure, 
relapse from CR or CR with incomplete blood count recovery (CRi), or death from any 
cause, whichever occurs first. Treatment failure is defined as >25% absolute increase in 
the bone marrow blast count from baseline to the present assessment. 
 
Overall response rate (ORR, CR + CRi) 
 
Rate of CR plus minimal residual disease (MRD) negative CRi 
 
Time to response, defined for subjects who achieved a best response of CR or CRi as time 
from randomization to achieving the best response 
 
Duration of response, defined for subjects who achieved a best response of CR or CRi as 
time from achieving CR or CRi to relapse 
 
MRD negativity 
 
Patient-reported outcomes (PROs) using the FACT-Leu (FACT-Leu Subscale, Trial 
Outcome Index, Physical Function, Functional Well-being, FACT-Leu Total Score, 
Emotional Well-being, Social/Family Function) and EQ-5D-5L (index score and Visual 
Analogue Scale [VAS] score). 
 
Safety 
Transfusion frequency will be an exploratory endpoint to be summarized in the clinical study 
report. 
3. 
SUMMARY OF STUDY DESIGN 
 
 
 
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Part A: 
Six subjects will be enrolled in Part A and receive 1 dose of talacotuzumab at 9 mg/kg on Day 1 
as a 180-minute IV infusion. Dose-limiting toxicities (DLTs) will be assessed during the DLT 
evaluation period (Cycle 1; 14 days). 
Pharmacokinetic and pharmacodynamic assessments will be conducted during the 8-day 
talacotuzumab evaluation period. Upon completion of dosing, there will be a review of all 
available study data by a Study Evaluation Team (SET) to confirm the recommended phase 2 dose 
of 9 mg/kg talacotuzumab. 
Subjects in Part A will continue on study (remaining in Part A) and start subsequent cycles of the 
combined study therapy with decitabine until treatment failure, relapse from CR/CRi, or death. 
Part B: 
Upon confirmation of the recommended phase 2 dose in Part A, Part B of the study will start. 
Subjects will be randomized in a 1:1 ratio to receive either decitabine + talacotuzumab or 
decitabine alone. Randomization will be stratified by baseline ECOG performance status (0-1 
versus 2) and type of AML (de novo versus secondary). 
In addition to evaluations by investigators, disease status will also be centrally reviewed and 
determined by an Independent Review Committee (IRC) in a blinded fashion. 
Part B of the study will have 3 interim analyses. The first interim analysis will occur after 
approximately 80 subjects (40 subjects per arm) have been randomized and followed for at least 4 
months. Guided by predefined statistical criteria based on CR and CR+CRi rates, the study will 
either continue enrollment to the full pre-specified Phase 3 sample size of 400 subjects or 
discontinue enrollment. The statistical criteria to guide the decision making will be based on the 
difference (Δ) in response rates between the 2 treatment arms (decitabine + talacotuzumab minus 
decitabine alone) as the following: 
 
If ΔCR ≥15% or Δ(CR+CRi) ≥25%, then the study may continue enrollment to 400 
subjects  
 
If ΔCR <15% and Δ(CR+CRi) <25%, then the study may stop enrollment at 
approximately 120 subjects 
EFS and available safety, PK, PD, MRD, and biomarker data will also be reviewed at the time of 
this first interim analysis. 
If the enrollment continues to 400 subjects (approximately 200 subjects per arm), the pre-specified 
design elements are: 
 
A second interim analysis will occur after 160 subjects (approximately 80 subjects per 
arm) have been randomized and followed for at least 4 months; this is the final analysis 
for CR rate and the first interim analysis for OS. The study will not be stopped on the 
basis of the CR rate results. 
 
A third interim analysis (ie, the second interim analysis of OS) will be conducted when 
180 deaths have occurred. 
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 
The final analysis of OS will take place when 270 deaths have occurred. 
If the study stops enrollment after the first interim analysis based on the pre-specified criteria, it is 
expected that approximately 120 subjects will have been randomized. These subjects will continue 
to be followed. The clinical cutoff in this case will be when 90 EFS events have occurred. 
Overall type I error of 0.05 (2-sided) will be allocated between the 2 primary endpoints CR rate 
and OS using a gate keeping procedure as described below: 
 
There will be a formal statistical testing for superiority for CR rate at the first interim 
analysis of 80 subjects with 2-sided α=0.001. The final analysis of CR rate (in terms of 
formal statistical hypothesis testing) will take place after 160 subjects have been 
randomized and followed for at least 4 months (to occur at the same time as the 1st interim 
analysis of OS) with 2-sided α=0.009. The study and collection of response data continue 
after the final CR analysis regardless of the outcome of the analysis. 
 
Overall 2-sided α=0.04 for OS; if the final analysis of CR rate achieves statistical 
significance, then α=0.009 allocated to this CR analysis can be reclaimed by the OS 
analysis, ie, OS can be tested at the overall level of 0.049. 
 
The 2 interim analyses and final analysis for OS will utilize the O’Brien-Fleming  
α-spending procedure. 
Statistical inferences including efficacy stopping boundaries (in terms of nominal α-value) for all 
planned interim and final analyses (2 primary endpoints, CR rate and OS) are shown in Table 1. 
Table 1: 
Overall Statistical Inference 
Analysis 
Description 
Clinical Cutoff 
2-Sided α 
IA.1 
CR and CR+CRi 
4 months after 80 subjects (40/arm) are 
randomized 
0.001 
IA.2 
CR final analysis 
4 months after 160 subjects are randomized 
0.009 
OS interim 
analysis No. 1 
0.0002 
IA.3 
OS interim 
analysis No. 2 
180 deaths 
0.0088 / 0.0116a 
Finalb 
OS final analysis 
270 deaths 
0.0372 / 0.0454a 
a If CR rate reaches statistical significance. 
b Final analysis will be carried out by Sponsor. 
 
An Independent Data Monitoring Committee (IDMC) will be established to evaluate safety and 
conduct the planned efficacy interim analyses. Upon completion of the first interim analysis, the 
IDMC requested a futility analysis of OS at the time of the second interim analysis. Survival data 
at the time of the second interim analysis will include approximately 100 deaths, which is 37% of 
the total 270 deaths planned at the final analysis. The futility boundary, in terms of the observed 
hazard ratio, is chosen to be 0.95. If the observed hazard ratio at the time of the secondary interim 
analysis is ≥0.95, the OS result will be considered futile. Detailed characteristics of the futility 
criterion are described in a separate IDMC statistical analysis plan. This futility analysis was not 
pre-planned in the study protocol, hence is considered ad hoc. 
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The OS outcome met the futility criteria at the time of the second interim analysis; thereafter upon 
IDMC’s recommendation, patient recruitment was terminated, treatment with talacotuzumab was 
discontinued, and treatment with decitabine may continue. 
Analyses described in this document include all data from all randomized subjects up to the clinical 
cutoff that is defined as 6 months after the last subject was randomized. 
4. 
DETERMINATION OF SAMPLE SIZE – STUDY PART B 
The first interim analysis to guide the decision for study continuation will occur after 
approximately 80 subjects (approximately 40 subjects per arm) have been randomized and 
followed for at least 4 months. The operating characteristics of the criteria are shown in Table 2. 
Table 2: 
Study Continuation Decision Rule, Operating Characteristics 
Sample size 
40/arm 
Enrollment may continue to approximately 400 subjects 
CR ≥15% or (CR+CRi) ≥25% 
Enrollment may stop with approximately 120 subjects 
CR <15% and (CR+CRi) <25% 
False positive error ratea 
0.04 
False negative error rateb 
0.10 
a Decision for enrollment to approximately 400 subjects, assuming true effect of decitabine alone and 
decitabine+talacotuzumab are the same: CR=15%, CR+CRi=25% 
b Decision for stopping enrollment with approximately 120 subjects, assuming true effect of decitabine alone: 
CR=15%, CR+CRi=25%, and true effect of decitabine+talacotuzumab: CR=40%, CR+CRi=55% 
=difference in response rate, decitabine+talacotuzumab minus decitabine alone 
If the study continues enrollment to 400 subjects, both primary endpoints (CR rate and OS) will 
be powered for 80% with overall α allocation of 0.01 and 0.04, respectively (Table 3). 
If the study stops enrollment after the first interim analysis it is expected that approximately 
120 subjects would have been randomized to the study. In this case, the primary focus will be 
exploratory to assess if there is a clinically relevant improvement in EFS for decitabine + 
talacotuzumab-treated subjects compared with subjects treated with decitabine alone. Assuming 
median EFS of 4 months for the decitabine alone arm, an improvement of 2.8 months in the 
talacotuzumab + decitabine arm (or hazard ratio HR=0.59) is considered clinically meaningful. 
For this purpose, 90 EFS events will provide 80% power to rule out a HR=1.0 (no difference in 
EFS between the 2 treatment arms) using a 90% confidence interval. 
Overall power and sample size determinations are summarized in Table 3. 
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Table 3: 
Sample Size Determination 
 
 
Endpoint(s) 
Effect Size, 
Decitabine+Talacotuzumab 
vs. Decitabine alone 
 
 
Power 
 
Overall 
2-side α 
 
Total No. 
of Events 
Total 
Sample 
Size 
Primary: CR Rate 
40% vs. 15% 
80% 
0.01 
 
160 
Primary: OS 
Median 11.4 vs. 8.0 months 
Hazard ratio=0.70 
80% 
0.04 
270 
400 
Secondary: EFS 
Median 6.8 vs.4.0 months 
Hazard ratio=0.59 
80% 
90% CIa 
90 
120 
a If enrollment stops with approximately 120 subjects, analysis of EFS is exploratory with hazard ratio estimate 
and corresponding 90% confidence interval (CI). 
5. 
GENERAL DESCRIPTIONS AND DEFINITIONS 
5.1. 
Summaries of Part A Data 
Safety data from Part A of the study will be summarized descriptively and separately from Part B 
data. 
5.2. 
Subject Populations (Part B) 
Intent-to-Treat (ITT): All subjects randomized into the study, grouped per treatment assigned by 
randomization, regardless of the actual treatment received. ITT will be used for summaries of 
disposition, demographics, baseline disease characteristics, and all efficacy analyses unless 
specified otherwise. 
Upon early termination of study recruitment after the second interim analysis, subjects’ disease 
status is no longer assessed by the IRC. For analyses of endpoints that depend on IRC assessment, 
only subjects in the ITT population who had IRC assessment will be included. Subjects who died 
before having data for IRC review will be included. 
Per-Protocol (PP): Subjects in the ITT population who received at least 1 complete dose of 
decitabine for the decitabine alone arm and at least 1 complete dose of talacotuzumab for the 
decitabine + talacotuzumab arm and have no major protocol deviations in terms of study entry 
criteria that by clinical judgement will have a potential to impact efficacy outcomes (see 
Section 6.6). The per-protocol population will be used for sensitivity analyses of the primary 
efficacy endpoints CR rate and OS. 
For analyses of endpoints that depend on IRC assessment, only subjects in the PP population who 
had IRC assessment will be included. Subjects who died before having data for IRC review will 
be included. 
Safety: All randomized subjects who received at least one dose of study medication, grouped 
according to actual treatment received. This population will be used for all summaries of safety 
and study drug exposure. 
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5.3. 
Study Phases 
Screening Phase: Before the first dose of study medication. 
Treatment Phase: Between the date of first dose of study medication and the date of the last dose 
of study medication plus 30 days. 
End of Treatment: Date of last dose of study medication plus 30 days. Assessments performed 
at the “end of treatment visit” will be included in this phase. 
Follow-up Phase: After end of treatment until the subject’s completion or withdraw from the 
study or study closeout. 
5.4. 
Convention of Time Computations 
By convention, one month equals to 30.4375 days and one year equals to 365.25 days. Duration 
in days between 2 time points will be calculated as (end date – start date + 1). 
5.5. 
Baseline Value 
The last non-missing value collected on or before the day of randomization. 
5.6. 
Major Protocol Deviation 
Major protocol deviations to be identified by the Sponsor prior to database lock are: 
 
Study entry criteria not met 
 
Received prohibited concomitant medication 
 
Study drug treatment deviation or crossover 
5.7. 
Cytogenetic Risk 
Cytogenetic risk (favorable, intermediate-I, intermediate-II, or adverse) will be determined by the 
Sponsor using collected cytogenetic data according to the criteria for AML diagnosis and 
management by European LeukemiaNet1. 
5.8. 
Prior and Concomitant Medications 
Medications administered prior to the first dose of study medication are considered prior 
medications. Concomitant therapies include those taken on or after first dose through 30 days after 
the last dose. 
5.9. 
Disease Status per Central Review and Investigator’s Assessment 
Disease status (including response) based on central review by the IRC will be the primary source 
for all pertinent analyses. Analyses based on investigator’s assessment will also be performed. Any 
major discordance between the 2 assessments affecting interpretation of study outcomes may be 
investigated. 
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5.10. MRD Negativity 
For subjects who achieved CR or CRi, a bone marrow sample will be taken and MRD status will 
be determined by flow cytometry. The leukemia-associated immunophenotype (LAIP) will be 
determined upon diagnosis, and will be tracked in each subject during treatment. If applicable, 
multiple LAIPs will be identified and tracked over time. MRD negativity will be defined as having 
less than 1 leukemic blast from an identified LAIP in 10,000 leukocytes. 
Upon early termination of study recruitment after the second interim analysis, MRD assessments 
are no longer performed. 
5.11. Patient-Reported Outcomes 
5.11.1. 
FACT-Leu 
The FACT-Leu is a 44-item2 self-reported measure used to quantitatively assess individuals’ 
perception of how the disease affects their daily life. It includes 5 subscales, ie, physical  
well-being (PWB), social/family well-being (SWB), emotional well-being (EWB), functional 
well-being (FWB), and leukemia-specific concerns (LeuS). All FACT-Leu subscales and 
aggregated scores showed high internal consistency and high test-retested reliability. 
The FACT-G is considered appropriate for use with subjects with any form of cancer, and has also 
been used and validated in other chronic illness conditions. The additional items of the FACT-Leu 
and LeuS allow for constructing a leukemia subscale. The subject is asked to rate the scale items 
as it applies to the past 7 days, on a 5-point scale (0=not at all, 1=a little bit, 2=somewhat, 3=quite 
a bit, 4=very much). Negatively stated items will be reversed by subtracting the response from 4. 
After reversing the proper items, items are summed to a total to generate a score on a (sub) scale3,4. 
 
FACT-Leu trial outcome index (TOI) = PWB + FWB + LeuS 
 
FACT-G total score = PWB + SWB + EWB + FWB 
 
FACT-Leu total score = PWB + SWB + EWB + FWB + LeuS 
5.11.2. 
EQ-5D-5L 
The EQ-5D-5L is a generic measure of health status. For purposes of this study, the EQ-5D-5L 
will be used to generate utility scores for use in cost effectiveness analyses. The EQ-5D-5L is a 5-
item questionnaire that assesses 5 domains including mobility, self-care, usual activities, 
pain/discomfort and anxiety/depression, plus a VAS rating “health today” with anchors ranging 
from 0 (worst imaginable health state) to 100 (best imaginable health state)5,6. The scores for the 
5 separate questions are categorical and cannot be analyzed as cardinal numbers. As such, the EQ-
5D Health Utility Index (HUI) will also be generated. The HUI is calculated from scores of the 
five health state domains and is scored between -1 (worst imaginable health state) and 1 (best 
imaginable health state), with 0 representing a health state equivalent to death. The United 
Kingdom weights will be used to generate patient utilities from the 5 dimensions of the  
EQ-5D-5L in this study. 
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5.12. Interim Analyses 
All interim analyses will be conducted by an external independent statistical group and reviewed 
by the IDMC. The IDMC procedures and interim analysis details are described in a separate IDMC 
charter and a statistical analysis plan, respectively. 
5.13. Subgroups 
Selected efficacy analyses will be performed for the following subgroups: 
 Age (<75, ≥75 years) 
 Gender (male, female) 
 Region (North American, Western Europe, rest of world) 
 Type of AML (de novo, secondary) 
 Cytogenetic risk (adverse, other) 
 Baseline ECOG performance status (0-1, 2) 
 Bone marrow blasts (≤50%, >50%) 
 Platelet (≤60, >60, 109/L) 
 WBC (≤4, >4, 109/L) 
5.14. Dose Intensity 
The unit for dose intensity calculation will be mg/m2/cycle for decitabine and mg/kg/cycle for 
talacotuzumab. Relative dose intensity is calculated as percent of intensity of received dose versus 
prescribed dose. 
5.15. Treatment-Emergent Adverse Events 
Treatment-emergent AEs are defined as those that occurred after the first dose of study drug 
through the last dose date + 30 days or the start of a subsequent anticancer therapy, whichever 
occurs earlier. Adverse events that occurred any time after the first dose of study drug during the 
study are also considered as treatment-emergent if they are study drug-related (ie, possible, 
probable, or very likely related to study drug). 
5.16. Adverse Events of Special Interest 
Adverse events of special interest are defined as the following: 
 Infusion-related reactions 
 Development of anti-drug antibodies (ADA) 
 Bleeding, with or without thrombocytopenia 
 Thrombotic events, including myocardial infarction (MI), cerebrovascular accident 
(CVA), and pulmonary embolism (PE) 
 Infections by severity and seriousness criteria, with and without neutropenia 
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 Febrile neutropenia 
6. 
PLANNED ANALYSES 
6.1. 
Subject Disposition 
Subject disposition will be summarized with the number and percent of the following: geographic 
region, ITT population, per-protocol population, safety population, study treatment ongoing, 
discontinued treatment and reason, completed the study, discontinued the study and reasons for 
discontinuation. 
6.2. 
Major Protocol Deviations 
Subjects with major protocol deviations will be summarized by each category of deviations (see 
Section 6.6). 
6.3. 
Demographics and Baseline Characteristics 
All demographic and baseline characteristics will be summarized for the ITT population by 
treatment arm and all subjects combined. 
Baseline clinical laboratory tests will be summarized for hematology and serum chemistry with 
NCI-CTCAE grade. 
6.4. 
Prior and Concomitant Medications 
Prior and concomitant medications will be coded to generic terms based on the World Health 
Organization (WHO) dictionary and will be summarized by Anatomical Therapeutic Chemical 
(ATC) class and drug generic term. Prior anticancer therapies include radiotherapy, surgery, 
chemotherapy, and systemic therapy. 
6.5. 
Medical History 
Number and percent of subjects who had abnormalities from their medical history will be 
summarized by System Organ Class (SOC), preferred terms (PT), and by treatment arm. 
6.6. 
Extent of Exposure 
Descriptive summaries include: total treatment duration in months, total number of cycles, total 
dose prescribed, total dose administrated, dose intensity, relative dose intensity, and cycle delay. 
For the combination treatment arm, summaries will be provided for each study drug and for the 
combination as a whole. 
 
Premedication for talacotuzumab will be summarized separately. 
6.7. 
Efficacy 
Unless specified otherwise, statistical inferences will be based on 2-sided p-values and 2-sided 
95% confidence intervals (CI). For stratified analyses, subjects’ strata recorded in the interactive 
web response system (IWRS) will be the data source. 
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6.7.1. 
Primary Efficacy Endpoints 
6.7.1.1. 
Complete Response 
Number and percent of subjects achieving CR will be presented by treatment arm. The odds ratio 
(decitabine + talacotuzumab vs. decitabine alone) will be reported along with the associated 95% 
CI based on a stratified logistic regression with treatment as the only covariate.  
The p-value will be based on a stratified Cochran-Mantel-Haenszel (CMH) test. Stratification 
factors are those used in randomization. Number of subjects achieving cytogenetic CR or 
molecular CR will be provided. 
A sensitivity analyses will be performed using the per-protocol population. 
Subgroup analysis will be performed and presented using a forest plot. 
6.7.1.2. 
Overall Survival 
Overall survival (in months) is defined as the time from randomization to death from any cause. 
For subjects who are not known to have died, survival time will be censored at the date last known 
to be alive. 
Number and percent of deaths will be provided. Kaplan-Meier estimates of the survival functions 
will be presented graphically. Median and 25th and 75th percentiles along with associated 95% CI 
will be provided. The p-value will be based on a stratified logrank test. The Hazard ratio 
(decitabine + talacotuzumab vs. decitabine alone) will be reported along with the associated 95% 
CI based on a stratified proportional hazard model with treatment as the only covariate. 
Stratification factors are those used in randomization. 
Two sensitivity analyses will be performed: (1) analysis using the per-protocol population; and (2) 
analysis censored at the time of first curative-intent subsequent therapy. 
Subgroup analysis will be performed and presented using forest plot. 
6.7.2. 
Secondary and Exploratory Efficacy Endpoints 
6.7.2.1. 
Event-Free Survival 
Event-free survival (EFS) is defined as the time from randomization to treatment failure, relapse 
from CR or CRi, or death from any cause, whichever occurs first. Subjects who did not reach any 
of these events will be censored at the last tumor assessment. 
EFS will be analyzed in the same fashion as that of overall survival. 
6.7.2.2. 
Overall Response 
Analyses similar to those for CR rate will be performed for overall response rate CR+CRi. In 
addition, number and percent of subjects whose best tumor response are morphologic leukemia-
free state (MLFS), partial response (PR), stable disease (SD), or treatment failure (TF) will also 
be provided. 
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6.7.2.3. 
CR plus MRD-Negative CRi 
Analyses similar to those for CR rate will be performed for CR plus MRD-negative CRi rate. 
6.7.2.4. 
Time to Response 
Time to response is defined as the time from randomization to achieving a best response of CR or 
CRi for subjects who achieved a response. Descriptive statistics will be summarized by treatment 
arm using the Kaplan-Meier method (with no censored observations). Time to best response of CR 
and time to CR plus MRD-negative CRi are similarly defined and will be summarized, 
respectively. 
6.7.2.5. 
Duration of Response 
Duration of response is defined for subjects who achieved a best response of CR or CRi as the 
time from achieving CR or CRi to relapse. Duration will be censored at the time of last tumor 
assessment for subjects who did not relapse. Duration of response will be summarized 
descriptively using the Kaplan-Meier method. Duration of response for best response of CR and 
best response of CR plus MRD-negative CRi are similarly defined and will be summarized, 
respectively. 
6.7.2.6. 
Minimal Residual Disease 
The following analyses will be performed for MRD by treatment arm: 
 For subjects who achieve CR, CRi, or MLFS, respectively, number and percent of subjects 
who achieve MRD negativity at time of achieving the response or at any time during the 
response 
 For all subjects of the ITT population, number and percent of subjects who achieve MRD 
negativity at the time of achieving CR or CRi, or at any time during CR or CRi. Subjects 
who do not achieve CR or CRi will be considered MRD positive in these analyses. 
Analyses similar to those for CR rate will be performed.  
6.7.2.7. 
Patient-Reported Outcomes 
Descriptive statistics (number of observations, mean, standard deviation, median, minimum, 
maximum) at baseline and each post-baseline time point will be reported by treatment group for 
each of the 9 PRO measures, including FACT-Leu subscale scores (PWB, SWB, EWB, FWB, and 
LeuS), FACT-Leu summary scores (TOI and FACT-Leu total score), EQ-5D-5L index score, and 
VAS. 
To compute each of the FACT-Leu subscale scores (PWB, SWB, EWB, FWB, and LeuS), there 
must be >50% non-missing items; otherwise the respective subscale score is considered missing, 
and the summary scores (TOI and FACT-Leu total score) containing the missing subscale score 
are also considered missing. 
Compliance rates, defined as the percent of the number of questionnaires received relative to the 
number expected per protocol-specified collection schedule, will be assessed by treatment group. 
Reasons for non-compliance will be explored. 
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6.7.3. 
Transfusion Frequency as an Exploratory Efficacy Endpoint 
Summaries will be provided for RBC and platelet transfusions separately. The number and percent 
of subjects who received transfusions from the date of randomization to 30 days after the last dose 
will be summarized by treatment arm. The total number of units transfused per subject, and 
exposure-adjusted transfusion rate will be summarized for each transfusion category by treatment 
arm. An exposure-adjusted transfusion rate (units per patient-month) is defined as (total number 
of units across all subjects) / (total patient-months across all subjects), where or each subject, 
patient-months is defined as [(last dose date + 30) – (randomization date) + 1] / 30.4375. 
6.8. 
Safety 
6.8.1. 
Adverse Events 
Adverse events are coded to SOC and PT terms using the Medical Dictionary for Regulatory 
Activities (MedDRA) coding system version 18.0 or higher. 
Severity of AEs will be graded on a scale of 1 to 5 according to the NCI Common Terminology 
Criteria for Adverse Events (NCI CTCAE version 4.0 or higher). Adverse events will be 
summarized by grade according to the worst grade experienced. 
Adverse events will be categorized and summarized according to their highest (worst) relationship 
to study medication. 
Summaries of treatment-emergent AEs will be provided as incidence tables (number of subjects 
experiencing an event) by treatment group, by SOC and PT, by NCI toxicity grade, by relationship 
to study drug, and by action taken. Tables will be sorted by frequency in incidence (the highest to 
lowest 
incidence). 
The 
same 
summary 
will 
be 
provided 
for 
serious 
AEs,  
drug-related serious AEs, AEs leading to treatment discontinuation, and AEs leading to death. 
For adverse events that are identified as special interest per Section 6.17, terms selected from 
standardized MedDRA queries (SMQs) and/or customized AE groupings that represent the clinical 
syndrome will be summarized. AEs of special interest, including infusion-related reactions, will 
be summarized by toxicity grade. 
The number and percent of subjects who die during the study and cause of death will be 
summarized by treatment arm. 
6.8.2. 
Clinical Laboratory Tests 
Selected hematologic and chemistry laboratory parameters will be descriptively summarized at 
each scheduled on-treatment evaluation by treatment group. Change from baseline will also be 
summarized. Mean value over time will be presented graphically. 
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A summary of the shifts in selected laboratory hematology and serum chemistry parameters from 
baseline to the worst toxicity grade during the study (from treatment start to 30 days after last dose 
or the end of treatment visit date, whichever is later) will be provided. 
6.8.3. 
Electrocardiogram 
QT prolongation (defined as QTcF >470) and other ECG abnormalities will be tabulated, 
displaying the number of subjects with abnormal findings. An abnormal finding is considered to 
be treatment-emergent if it occurred during treatment and up to 30 days after the last dose. 
6.8.4. 
Vital Signs 
Descriptive statistics of weight, heart rate, temperature and supine blood pressure (systolic and 
diastolic) values and changes from baseline will be descriptively summarized by treatment arm at 
each time point. 
7. 
REFERENCES 
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2. Cella D, Jensen SE, Webster K, Hongyan D, Lai JS, Rosen S, Tallman MS, Yount S (2012). 
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3. Yellen SB, Cella DF, Webster K, et al (1997). “Measuring Fatigue and other Anemia-Related 
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4. Cella DF, Tulsky DS, Gray G, et al (1993). “The Functional Assessment of Cancer Therapy 
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5. De Charro F, Rabin R (2000). “EQ-5D-5L from the EuroQol Group: an Update”. QOL 
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6. Kind P, Dolan P, Gudex C, et al (1998). “Variations in Population Health Status: Results from 
a United Kingdom National Questionnaire Survey”. Brit. Med. J., 316 (7133), pp 736–741. 
 
 
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