Conditions: Myelodysplastic Syndromes
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 34
Healthy volunteers: no

Brief summary:
The main purpose of the study is to evaluate the efficacy (transfusion independence \[TI\]) of talacotuzumab (JNJ-56022473) or daratumumab in transfusion-dependent participants with low or intermediate-1 risk Myelodysplastic Syndrome (MDS) whose disease has relapsed during treatment with or is refractory to Erythropoiesis-Stimulating Agent (ESAs).

Detailed description:
This is a multicenter, randomized (study drug assigned by chance), open-label (participants and researchers are aware of the treatment participants are receiving) study to evaluate the safety and efficacy of talacotuzumab or daratumumab. Approximately 60 participants (30 to receive talacotuzumab and 30 to receive daratumumab) will be enrolled and then assigned randomly on a 1:1 basis to receive either talacotuzumab or daratumumab. The study consists of: a Screening Phase of up to 28 days during which participant eligibility will be reviewed and approved by the sponsor prior to randomization, a Treatment Phase that will extend from the first dose on Cycle 1 Day 1 until study drug discontinuation, and a Post-treatment Follow up Phase beginning once the participant discontinues talacotuzumab or daratumumab. Study drugs will continue to be administered until disease progression, lack of response, unacceptable toxicity, withdrawal of consent, or study end. Safety will be monitored throughout the study. The talacotuzumab arm of the study is closed for enrollment.

Arms:
arm 1: Participants will receive talacotuzumab 9 milligram per kilogram (mg/kg) intravenously (IV) on Days 1 and 15 for all cycles. Each treatment cycle is of 28 days. The talacotuzumab arm of the study is closed for enrollment. arm 2: Participants will receive daratumumab 16 mg/kg IV on Days 1, 8, 15, and 22 for Cycles 1 and 2; on Days 1 and 15 for Cycles 3 to 6; and on Day 1 for all subsequent cycles. Each treatment cycle is of 28 days.

Interventions: intervention 1: Talacotuzumab intervention 2: Daratumumab
Intervention descriptions: intervention 1: Talacotuzumab 9 mg/kg will be administered as an IV infusion. intervention 2: Daratumumab 16 mg/kg will be administered as an IV infusion.

Protocol document:
Prot_000.pdf: 
1
Status: Approved, Date: 13 December 2018
Janssen Research & Development *
Clinical Protocol
A Phase 2 Proof-of-Concept Study to Separately Evaluate the Activity of Talacotuzumab 
(JNJ-56022473) or Daratumumab in Transfusion-Dependent Subjects with Low or 
Intermediate-1 Risk Myelodysplastic Syndromes (MDS) who are Relapsed or Refractory to 
Erythropoiesis-Stimulating Agent (ESA) Treatment
Protocol 56022473MDS2002; Phase 2
AMENDMENT 4
JNJ-56022473 (talacotuzumab)
JNJ-54767414 (daratumumab)
*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: 2016-003328-22
Status:
Approved
Date:
13 December 2018
Prepared by:
Janssen Research & Development, LLC  
EDMS number:
EDMS-ERI-128192930, 6.0
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.
NCT03011034


JNJ-56022473 (talacotuzumab) and JNJ-54767414 (daratumumab)
Clinical Protocol 56022473MDS2002 – Amendment 4
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Status: Approved, Date: 13 December 2018
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF ATTACHMENTS............................................................................................................................ 5
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 5
PROTOCOL AMENDMENTS....................................................................................................................... 6
SYNOPSIS.................................................................................................................................................. 10
TIME AND EVENTS SCHEDULE - TALACOTUZUMAB .......................................................................... 12
TIME AND EVENTS SCHEDULE - TALACOTUZUMAB PHARMACOKINETICS AND 
IMMUNOGENICITY ASSESSMENTS............................................................................................... 16
TIME AND EVENTS SCHEDULE – DARATUMUMAB ............................................................................. 16
TIME AND EVENTS SCHEDULE - DARATUMUMAB .............................................................................. 18
TIME AND EVENTS SCHEDULE - DARATUMUMAB PHARMACOKINETICS AND 
IMMUNOGENICITY ASSESSMENTS............................................................................................... 21
TIME AND EVENTS SCHEDULE – DARATUMUMAB - TABLE FOLLOWING AMENDMENT 4 ........... 21
ABBREVIATIONS ...................................................................................................................................... 22
1.
INTRODUCTION................................................................................................................................ 24
1.1.
Study Drugs ................................................................................................................................... 26
1.2.
Overall Rationale for the Study...................................................................................................... 26
2.
OBJECTIVES, ENDPOINTS, AND HYPOTHESISES ...................................................................... 27
2.1.
Objectives and Endpoints .............................................................................................................. 27
2.1.1.
Objectives ................................................................................................................................... 27
2.1.2.
Endpoints.................................................................................................................................... 28
2.2.
Hypothesis ..................................................................................................................................... 29
3.
STUDY DESIGN AND RATIONALE ................................................................................................. 29
3.1.
Overview of Study Design.............................................................................................................. 29
3.2.
Study Design Rationale.................................................................................................................. 31
3.3.
Dose Rationales for Talacotuzumab and Daratumumab............................................................... 32
4.
SUBJECT POPULATION.................................................................................................................. 32
4.1.
Inclusion Criteria ............................................................................................................................ 32
4.2.
Exclusion Criteria ........................................................................................................................... 34
4.3.
Prohibitions and Restrictions ......................................................................................................... 36
5.
TREATMENT ALLOCATION AND BLINDING................................................................................. 36
5.1.
Treatment Allocation ...................................................................................................................... 36
6.
DOSAGE AND ADMINISTRATION .................................................................................................. 36
6.1.
Dosing Schedule............................................................................................................................ 36
6.2.
Talacotuzumab............................................................................................................................... 37
6.2.1.
Preparation and Administration of Talacotuzumab .................................................................... 37
6.2.2.
Talacotuzumab: Premedication .................................................................................................. 38
6.2.3.
Talacotuzumab Dosing Modifications......................................................................................... 40
6.2.4.
Management of Talacotuzumab Hypersensitivity/Infusion-related Reactions............................ 40
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Clinical Protocol 56022473MDS2002 – Amendment 4
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Status: Approved, Date: 13 December 2018
6.2.4.1.
Guidelines for the Interruption of Talacotuzumab Infusion due to Infusion-related 
Reaction................................................................................................................................... 40
6.3.
Daratumumab ................................................................................................................................ 41
6.3.1.
Dosing Schedule......................................................................................................................... 41
6.3.2.
Preparation and Administration of Daratumumab ...................................................................... 41
6.3.3.
Daratumumab: Premedication.................................................................................................... 42
6.3.3.1.
Daratumumab: Postinfusion Medication.................................................................................. 43
6.3.4.
Daratumumab Dosing Delay and Modification ........................................................................... 44
6.3.5.
Daratumumab Toxicity Management.......................................................................................... 44
6.3.6.
Guidelines for Daratumumab Infusion-Related Reactions ......................................................... 45
7.
TREATMENT COMPLIANCE............................................................................................................ 46
8.
PRESTUDY AND CONCOMITANT THERAPY ................................................................................ 46
8.1.
Prestudy Therapy........................................................................................................................... 46
8.2.
Concomitant Medications............................................................................................................... 46
9.
STUDY EVALUATIONS .................................................................................................................... 47
9.1.
Study Procedures........................................................................................................................... 47
9.1.1.
Overview..................................................................................................................................... 47
9.1.2.
Screening Phase ........................................................................................................................ 48
9.1.3.
Open-Label Treatment Phase .................................................................................................... 48
9.1.4.
Posttreatment Phase (Follow-Up) .............................................................................................. 49
9.1.5.
Clinical Cutoff and End of Study................................................................................................. 49
9.2.
Efficacy Evaluations....................................................................................................................... 49
9.2.1.
Transfusions ............................................................................................................................... 49
9.2.2.
Hemoglobin Assessment............................................................................................................ 50
9.2.3.
Clinical Bone Marrow Assesment............................................................................................... 50
9.3.
Pharmacokinetics and Immunogenicity ......................................................................................... 50
9.3.1.
Sample Collection and Handling ................................................................................................ 50
9.3.2.
Analytical Procedures................................................................................................................. 51
9.3.3.
Pharmacokinetic Parameters ..................................................................................................... 51
9.3.4.
Immunogenicity Assessments (Antibodies to Talacotuzumab and Daratumumab)................... 51
9.4.
Biomarkers ..................................................................................................................................... 52
9.5.
Safety Evaluations ......................................................................................................................... 53
9.5.1.
Indirect Antiglobulin Test (IAT) ................................................................................................... 55
9.5.2.
Prophylaxis for Herpes Zoster Reactivation ............................................................................... 56
9.6.
Sample Collection and Handling.................................................................................................... 56
10.
SUBJECT COMPLETION/DISCONTINUATION OF STUDY TREATMENT/ WITHDRAWAL 
FROM THE STUDY ........................................................................................................................... 56
10.1.
Completion ..................................................................................................................................... 56
10.2.
Discontinuation of Study Treatment/Withdrawal from the Study ................................................... 56
10.3.
Withdrawal From the Use of Research Samples........................................................................... 57
11.
STATISTICAL METHODS................................................................................................................. 57
11.1.
Subject Information ........................................................................................................................ 57
11.2.
Sample Size Determination ........................................................................................................... 58
11.3.
Efficacy Analyses ........................................................................................................................... 58
11.4.
Pharmacokinetic Analyses............................................................................................................. 59
11.5.
Immunogenicity Analyses .............................................................................................................. 60
11.6.
Biomarker Analyses ....................................................................................................................... 60
11.7.
Pharmacokinetic/Pharmacodynamic Analyses.............................................................................. 60
11.8.
Safety Analyses ............................................................................................................................. 60
11.9.
Safety Review ................................................................................................................................ 61
12.
ADVERSE EVENT REPORTING ...................................................................................................... 61
12.1.
Definitions ...................................................................................................................................... 62
12.1.1.
Adverse Event Definitions and Classifications ........................................................................... 62
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Status: Approved, Date: 13 December 2018
12.1.2.
Attribution Definitions.................................................................................................................. 63
12.1.3.
Severity Criteria .......................................................................................................................... 64
12.2.
Special Reporting Situations.......................................................................................................... 64
12.3.
Procedures..................................................................................................................................... 65
12.3.1.
All Adverse Events...................................................................................................................... 65
12.3.2.
Serious Adverse Events ............................................................................................................. 66
12.3.3.
Pregnancy................................................................................................................................... 67
12.4.
Contacting Sponsor Regarding Safety........................................................................................... 67
13.
PRODUCT QUALITY COMPLAINT HANDLING.............................................................................. 67
13.1.
Procedures..................................................................................................................................... 68
13.2.
Contacting Sponsor Regarding Product Quality ............................................................................ 68
14.
STUDY DRUG INFORMATION......................................................................................................... 68
14.1.
Physical Description of Study Drug(s) ........................................................................................... 68
14.2.
Packaging ...................................................................................................................................... 68
14.3.
Labeling.......................................................................................................................................... 68
14.4.
Preparation, Handling, and Storage............................................................................................... 68
14.5.
Drug Accountability ........................................................................................................................ 69
15.
STUDY-SPECIFIC MATERIALS....................................................................................................... 69
16.
ETHICAL ASPECTS ......................................................................................................................... 70
16.1.
Study-Specific Design Considerations........................................................................................... 70
16.2.
Regulatory Ethics Compliance....................................................................................................... 71
16.2.1.
Investigator Responsibilities ....................................................................................................... 71
16.2.2.
Independent Ethics Committee or Institutional Review Board ................................................... 71
16.2.3.
Informed Consent ....................................................................................................................... 72
16.2.4.
Privacy of Personal Data ............................................................................................................ 73
16.2.5.
Long-Term Retention of Samples for Additional Future Research ............................................ 74
16.2.6.
Country Selection ....................................................................................................................... 74
17.
ADMINISTRATIVE REQUIREMENTS .............................................................................................. 74
17.1.
Protocol Amendments.................................................................................................................... 74
17.2.
Regulatory Documentation ............................................................................................................ 75
17.2.1.
Regulatory Approval/Notification ................................................................................................ 75
17.2.2.
Required Prestudy Documentation............................................................................................. 75
17.3.
Subject Identification, Enrollment, and Screening Logs ................................................................ 76
17.4.
Source Documentation................................................................................................................... 76
17.5.
Case Report Form Completion ...................................................................................................... 77
17.6.
Data Quality Assurance/Quality Control ........................................................................................ 77
17.7.
Record Retention ........................................................................................................................... 78
17.8.
Monitoring ...................................................................................................................................... 78
17.9.
Study Completion/Termination....................................................................................................... 79
17.9.1.
Study Completion/End of Study.................................................................................................. 79
17.9.2.
Study Termination....................................................................................................................... 79
17.10.
On-Site Audits ................................................................................................................................ 80
17.11.
Use of Information and Publication................................................................................................ 80
REFERENCES............................................................................................................................................ 82
INVESTIGATOR AGREEMENT ................................................................................................................. 96
NCT03011034


JNJ-56022473 (talacotuzumab) and JNJ-54767414 (daratumumab)
Clinical Protocol 56022473MDS2002 – Amendment 4
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Status: Approved, Date: 13 December 2018
LIST OF ATTACHMENTS
Attachment 1:
World Health Organization (WHO) Classification....................................................... 84
Attachment 2:
International Prognostic Scoring System (IPSS) for Myelodysplastic 
Syndrome ................................................................................................................... 85
Attachment 3:
Eastern Cooperative Oncology Group (ECOG) Performance Status Scale .............. 86
Attachment 4: 
NYHA Classification ................................................................................................... 87
Attachment 5:
Asthma Guidelines ..................................................................................................... 88
Attachment 6:
International Working Group (IWG) Response Criteria 2006..................................... 90
Attachment 7:
Conversion Table for Glucocorticosteroid Dose......................................................... 92
Attachment 8:
The Family of Antihistamine Medications................................................................... 93
Attachment 9:
Anticipated Events...................................................................................................... 94
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1:
Premedication for Subjects Receiving Talacotuzumab ............................................................ 39
Table 2:
Management of Talacotuzumab Infusion-related Reactions .................................................... 41
Table 3:
Daratumumab Infusion Rates ................................................................................................... 42
Table 4:
Premedication for Subjects Receiving Daratumumab.............................................................. 43
Table 5:
Daratumumab-Related Toxicity Management .......................................................................... 45
Table 6:
Management of Daratumumab Infusion-related Reactions...................................................... 46
Table 7:
Observed TI, 2-Sided Credible Interval, and Statistical Decision Criteria ................................ 59
FIGURES
Figure 1:
Schematic Overview of the Study............................................................................................. 30
NCT03011034


JNJ-56022473 (talacotuzumab) and JNJ-54767414 (daratumumab)
Clinical Protocol 56022473MDS2002 – Amendment 4
6
Status: Approved, Date: 13 December 2018
PROTOCOL AMENDMENTS
Protocol Version
Issue Date
Original Protocol
14 September 2016
Amendment 1
6 October 2016
Amendment 2
29 March 2017
Amendment 3
25 April 2017
Amendment 4
13 December 2018
Amendments are listed beginning with the most recent amendment.
Amendment 4 (13 December 2018)
The overall reason for the amendment To further clarify completion/end of study as the end of study data 
collection with continuation of daratumumab treatment according to the protocol for subjects continuing to derive 
benefit and to clarify that the monitoring of these subjects who continue to receive daratumumab according to the 
protocol will be for serious adverse events only.
Applicable Section(s)
Description of Change(s)
Rationale: To clarify the ‘end of study’ as the end of study data collection and to clarify that the monitoring of 
subjects who continue to receive daratumumab according to the protocol will be for serious adverse events only.
Synopsis: Overview of 
Study Design; Section 
3.1 Overview of Study 
Design; Section 9.1.5
Clinical Cutoff and 
End of Study; 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 subjects who 
are deriving benefit will continue to receive daratumumab according to the protocol
after study data collection ends. During this period after study data collection has 
ended, only serious adverse events will be monitored and only entered into the 
company safety repository.
Rationale: To clarify that the monitoring of subjects who continue to receive daratumumab according to the 
protocol will be for serious adverse events only.
Synopsis: Evaluations; 
Section 6.1 Dosing 
Schedule; Section 8.2 
Concomitant 
Medications; Section 9 
Study Evaluations; 
Section 9.5 Safety 
Evaluations; Section 
12.3.1 All Adverse 
Events; Section 16.1 
Study-Specific Design 
Considerations
Clarified that for subjects who are continuing to receive daratumumab according to the 
protocol and derive benefit from treatment, only serious adverse events will be 
monitored and only entered into the company safety repository.
Time And Events 
Schedule –
Daratumumab – Table 
Following Amendment 
4
Added the Time and Events Schedule (Time And Events Schedule – Daratumumab –
Table Following Amendment 4) with a note clarifying that for subjects who continue to 
receive daratumumab according to the protocol and derive benefit from the treatment 
after study data collection ends, only serious adverse events will be monitored and only 
entered into the company safety repository as of Amendment 4.
NCT03011034


JNJ-56022473 (talacotuzumab) and JNJ-54767414 (daratumumab)
Clinical Protocol 56022473MDS2002 – Amendment 4
7
Status: Approved, Date: 13 December 2018
Applicable Section(s)
Description of Change(s)
Section 7 Treatment 
Compliance
Added a statement that electronic case report forms (eCRFs) will be closed after study 
data collection ends.
Rationale: Minor errors were noted
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes were made.
Amendment 3 (25 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 closes enrollment to the talacotuzumab arm as a 
precautionary measure due to benefit / risk considerations in patients with low-risk MDS and based on the 
occurrence of a Grade 4 infusion-related reaction in the first subject to receive talacotuzumab.
Applicable Section(s)
Description of Change(s)
Rationale: To close enrollment in the talacotuzumab arm following a Grade 4 infusion-related reaction that 
occurred in the first subject to receive talacotuzumab.
Synopsis: Overview of Study Design; Section 3.1
Overview of Study Design; Section 3.2 Study Design 
Rationale; Section 5.1 Treatment Allocation; Section 16.1 
Study-Specific Design Considerations
Added language to close enrollment to the 
talacotuzumab arm based on the occurrence of a 
Grade 4 infusion-related reaction in the first subject to 
receive talacotuzumab. 
Amendment 2 (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 6.2.1 Talacotuzumab: 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: Provide time window for talacotuzumab dosing 
NCT03011034


JNJ-56022473 (talacotuzumab) and JNJ-54767414 (daratumumab)
Clinical Protocol 56022473MDS2002 – Amendment 4
8
Status: Approved, Date: 13 December 2018
Applicable Section(s)
Description of Change(s)
Time and Events Schedule – Talacotuzumab; Section 6.1 
Dosing Schedule
Provided details for the talacotuzumab dosing schedule 
and a time window of +/- 24 hours for talacotuzumab 
dosing 
Rationale: Added premedication section to talacotuzumab Time and Events Schedule
Time and Events Schedule – Talacotuzumab
Added preinfusion medication to Time and Events 
Schedule for talacotuzumab
Rationale: Clarified daratumumab dosing 
Time and Events Schedule – Daratumumab; Section 6.3.1 
Dosing Schedule
Clarified daratumumab dosing schedule; Provided a 
time window of +/- 24 hours for daratumumab dosing
Rationale: Clarified daratumumab pre- and post-infusion medications
Time and Events Schedule – Daratumumab Study Drug 
Administration
Added pre and postinfusion medication 
Rationale: Added requirement for blood type assessment and indirect antiglobulin results
Time and Events Schedule – Daratumumab Study Drug 
Administration
Added requirement for blood type assessment and 
indirect antiglobulin results on Day 1 of Cycle 1 only
Rationale: Clarified daratumumab dosing
Section 6.3.2 Preparation and Administration of
Daratumumab
Clarified daratumumab dosing and premedications
Rationale: Clarified daratumumab premedication of methylprednisolone 
Section 6.3.3 Daratumumab Premedications
Expanded footnote “a” to Table 4 to allow the 
reduction of corticosteroid (IV methylprednisolone 
60mg or equivalent in Cycle 2 + subsequent cycles)
Rationale: update inclusion criterion number
Section 4.1 Inclusion Criteria
Updated the number of inclusion criterion 9 to 9.1
Rationale: Bone marrow assessments for disease evaluation are not done by a central laboratory
Section 9.2.3 Bone Marrow Assessment
Title of section changed to Clinical Bone Marrow 
Assessment; removed language stipulating central 
laboratory assessment
Rationale: Added Section for recommendations for Herpes Zoster reactivation prophylaxis
Section 9.5.2 Prophylaxis for Herpes Zoster Reactivation
Added recommendations for herpes zoster reactivation 
prophylaxis
Rationale: To clarify daratumumab storage conditions
Section 14.4 Preparation, Handling, and Storage
Modified language regarding daratumumab storage 
NCT03011034


JNJ-56022473 (talacotuzumab) and JNJ-54767414 (daratumumab)
Clinical Protocol 56022473MDS2002 – Amendment 4
9
Status: Approved, Date: 13 December 2018
Amendment 1 (6 October 2016)
The overall reason for the amendment: To correct an error in the Time and Events table under the collection of 
vital signs during the infusion of daratumumab and to revise the bilirubin inclusion criterion.
Applicable Section(s)
Description of Change(s)
Rationale: Corrected the collection of vital signs collected during the study.
Time and Events Table
Corrected the collection of vital signs in the daratumumab arm 
Rationale: Expanded inclusion limit for total bilirubin due to disease characteristics of MDS.
Section 4.1, criterion #9
The inclusion limit for total bilirubin was increased from ≤1.5 x ULN to ≤3.0 x ULN.
Rationale: Minor errors were noted.
Throughout the protocol
Minor changes were made for consistency
NCT03011034


JNJ-56022473 (talacotuzumab) and JNJ-54767414 (daratumumab)
Clinical Protocol 56022473MDS2002 – Amendment 4
10
Status: Approved, Date: 13 December 2018
SYNOPSIS
A Phase 2 Proof-of-Concept Study to Separately Evaluate the Activity of Talacotuzumab (JNJ-56022473) 
or Daratumumab in Transfusion-Dependent Subjects with Low or Intermediate-1 Risk Myelodysplastic 
Syndromes (MDS) who are Relapsed or Refractory to Erythropoiesis-Stimulating Agent (ESA) Treatment
Talacotuzumab (JNJ-56022473) is a humanized monoclonal antibody (mAb) that specifically targets the
human interleukin-3 receptor alpha chain (IL-3Ror CD123), and inhibits the signaling through this 
receptor.
Daratumumab is a human immunoglobulin G1 kappa (IgG1ĸ) mAb that binds with high affinity to a 
unique epitope on CD38, a transmembrane glycoprotein. 
Preclinical
and clinical
data indicate that
talacotuzumab and daratumumab may
eliminate
immunosuppressive cell types in the bone marrow microenvironment of patients with MDS. Elimination 
of MDSCs (by both compounds) and Tregs (daratumumab only) may alter the immunosuppressive 
microenvironment and allow normal hematopoietic progenitor cells to differentiate, and ultimately 
improve clinical outcomes. Elimination of CD123+ MDS blasts by talacotuzumab may further alter 
disease progression.
The purpose of this study is to separately evaluate 2 agents with different mechanisms of action that may 
be effective in subjects with low-risker MDS. The design of this study will allow an unbiased assessment 
of which agent, if either, will provide benefit to this patient population and further evaluate in clinical 
development. The generally accepted primary endpoint of transfusion independence (TI) has a subjective 
component based on transfusion practices that can be different across institutions, and randomizing 
subjects for talacotuzumab or daratumumab treatment with standardized inclusion and exclusion criteria 
and evaluation procedures will allow a more objective assessment of these 2 different agents.
OBJECTIVES, ENDPOINTS, AND HYPOTHESISES
Primary Objective
The primary objective of the study is to evaluate the efficacy (transfusion independence) of 
talacotuzumab (JNJ-56022473) or daratumumab in transfusion-dependent subjects with low or 
intermediate-1 risk MDS whose disease has relapsed during treatment with or is refractory to ESAs.
Primary Endpoint
The primary endpoint of this study is 8-week red blood cell (RBC) TI, defined as absence of RBC 
transfusion during any consecutive 56 days (8 weeks) post randomization.
Hypothesis
The primary hypothesis of this study is that the treatment with talacotuzumab or daratumumab separately 
will produce a TI rate 30% or greater against a minimal acceptable value of 15%. The statistical 
evaluation of the hypothesis will use a Bayesian approach to assess the likelihood of whether a true TI 
rate ≤15% can be ruled out.
OVERVIEW OF STUDY DESIGN
This is a multicenter, randomized, Phase 2, open-label study to evaluate the safety and efficacy of single-
agent talacotuzumab or single-agent daratumumab in subjects with low or intermediate-1 risk MDS who 
are transfusion-dependent and whose disease has relapsed during or is refractory to ESA treatment. 
Approximately 60 subjects (30 to receive talacotuzumab and 30 to receive daratumumab) will be enrolled 
in this study.
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JNJ-56022473 (talacotuzumab) and JNJ-54767414 (daratumumab)
Clinical Protocol 56022473MDS2002 – Amendment 4
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Status: Approved, Date: 13 December 2018
Randomization will be stratified based on transfusion burden (4 or >4 units) prior to randomization, and 
then assigned randomly on a 1:1 basis to receive either talacotuzumab or daratumumab. Enrollment to the 
talacotuzumab arm was closed (refer to Section 3.1 Overview of Study Design for details). Transfusion 
burden is defined as the maximum number of RBC units transfused over any 8 consecutive weeks during 
the 16 weeks prior to randomization. The study consists of: a Screening Phase of up to 28 days during 
which subject eligibility will be reviewed and approved by the sponsor prior to randomization, a 
Treatment Phase that will extend from the first dose on Cycle 1 Day 1 until study drug discontinuation, 
and a Posttreatment Follow-up Phase beginning once the subject discontinues talacotuzumab or 
daratumumab. 
Talacotuzumab will be administered at 9 mg/kg intravenously (IV) every 2 weeks. Daratumumab will be 
administered at 16 mg/kg IV weekly on Weeks 1 to 8, every 2 weeks for Weeks 9 to 24, and every 
4 weeks thereafter. Cycle length is a 28 days for both agents. Study drugs will continue to be administered 
until disease progression, lack of response, unacceptable toxicity, withdrawal of consent, or study end. 
The clinical cutoff for the purpose of the primary endpoint analysis will be 6 months after randomization 
of the last subject. The end of the study data collection is defined as either 1 year after the last subject has 
been randomized or anytime the sponsor terminates the study. At that time, study follow-up of subjects 
and study data collection will end. Subjects who are continuing to derive benefit from daratumumab 
treatment as assessed by their investigator may continue to receive daratumumab according to the 
protocol. During this period after study data collection has ended, only serious adverse events will be 
monitored and only entered into the company safety repository as described under Amendment 4 and in 
the Time and Events Schedule.
EVALUATIONS
Efficacy evaluations will include transfusion data, blood count assessments, and bone marrow biopsy and 
aspirate for disease assessment.
For all subjects in the talacotuzumab or daratumumab treatment groups, PK samples will be evaluated to 
determine serum concentration of talacotuzumab or daratumumab.
Serum concentrations of talacotuzumab or daratumumab and detection and characterization of anti-
talacotuzumab or anti-daratumumab antibodies will be performed.
Biomarker evaluations will include immunophenotyping of immune cell populations, enumeration of 
CD123 and CD38 expression on suppressor cells, reduction of blasts, mutation analysis, and proteomic 
analysis.Safety will be assessed by adverse events, physical examinations, clinical laboratory parameters, 
electrocardiograms, vital sign measurements, ECOG performance status, and concomitant medication 
usage. A sponsor safety review committee will review all the safety data on a quarterly basis, or ad hoc, 
as needed.
The follow-up of subjects in the study and study data collection will end either 1 year after the last subject 
is randomized or anytime the sponsor terminates the study. Subjects who are continuing to derive benefit 
from daratumumab treatment as assessed by their investigator may continue to receive daratumumab
according to the protocol. During this period after study data collection has ended, only serious adverse 
events will be monitored and only entered into the company safety repository as described under 
Amendment 4 and in the Time and Events Schedule.
STATISTICAL METHODS
There will be no formal statistical comparison between the 2 arms. Each treatment regimen will be 
analyzed separately to determine the likelihood that the true TI rate is 30% or greater against a minimum 
acceptable value of 15%. The planned sample size is approximately 30 subjects per treatment arm, which 
ensures at least 90% probability that the true TI rate is ≥15% if at least 8 subjects reach TI.
NCT03011034


JNJ-56022473 (talacotuzumab) and JNJ-54767414 (daratumumab)
Clinical Protocol 56022473MDS2002 – Amendment 4
12
Status: Approved, Date: 13 December 2018
TIME AND EVENTS SCHEDULE - TALACOTUZUMAB
PHASE
Screening 
Phase
Treatment Phase
(4-week cycles +/-3 days)
Posttreatment
Follow-up Phase
Study Procedures
Notes
Up to 28 
days 
before 
first dose
Cycle 1
Day 1
Cycle 1
Day 15
Cycle 2
until EOT
Day 1, 15
EOT Visit
Within 30 
days after 
last dose
Survival Follow-up
Every 16 weeks
(+/- 7 days)
Screening/Administrative
Informed consent
Subjects must sign before any study-
specific procedures are performed.
X
Inclusion/exclusion criteria
X
Medical history, blood typing, and 
demographics
X
Study Drug Administration
Dispense/administer study drug
(+/- 24 hours)
Screening weight is baseline for dose 
calculation. Recalculate if weight changes 
>10% from screening.
X
X
X 
Preinfusion medications
All subjects receiving talacotuzumab must 
receive premedication during the first 4 
cycles, as outlined in Section 6.2.2. If no 
infusion-related reactions are seen during 
the first 4 cycles of talacotuzumab 
treatment, then premedication is optional 
for subsequent talacotuzumab treatments. If 
an infusion-related reaction of any severity 
occurs in subsequent talacotuzumab 
treatments, premedication must be 
reintroduced.
X
X
X
Safety Assessments
Physical exam (including weight)
At post-screening visits, only a limited 
symptom-directed physical examination.
X
Xa
Only Day 1a
X
Vital signs
Vital signs should be measured and 
recorded (prior to study medication 
administration) and include heart rate and 
systolic/diastolic blood pressure, preferably 
while the subject is in a seated position.
X
Xa
Only Day 1a
X
12-lead ECG 
X
Xa
Efficacy Assessments
Transfusion history and status;
myeloid growth factor treatment
Assessment of RBC transfusion 
requirements and myeloid growth factor use
16 weeks prior to randomization, at each 4-
week cycle visit, disease evaluation visit, 
X
Xa
Only Day 1a
X
X
(first visit and every 
4-6 weeks if 
feasible)
NCT03011034


JNJ-56022473 (talacotuzumab) and JNJ-54767414 (daratumumab)
Clinical Protocol 56022473MDS2002 – Amendment 4
13
Status: Approved, Date: 13 December 2018
PHASE
Screening 
Phase
Treatment Phase
(4-week cycles +/-3 days)
Posttreatment
Follow-up Phase
Study Procedures
Notes
Up to 28 
days 
before 
first dose
Cycle 1
Day 1
Cycle 1
Day 15
Cycle 2
until EOT
Day 1, 15
EOT Visit
Within 30 
days after 
last dose
Survival Follow-up
Every 16 weeks
(+/- 7 days)
and all unscheduled visits during treatment.
Complete transfusion information must be 
collected, including both in-patient and out-
patient transfusions.
TIME AND EVENTS SCHEDULE – TALACOTUZUMAB
PHASE
Screening 
Phase
Treatment Phase
(4-week cycles +/-3 days)
Posttreatment
Follow-up Phase
Study Procedures
Notes
Up to 28 
days 
before 
first dose
Cycle 1
Day 1
Cycle 1
Day 15
Cycle 2
until EOT
Day 1, 15
EOT Visit
Within 30 
days after 
last dose
Survival Follow-up
Every 16 weeks
(+/- 7 days)
Bone marrow aspirate/biopsy with 
cytogenetics 
Bone marrow aspirate and biopsy with iron 
stain must be performed during screening or 
up to 12 weeks prior to first dose. Following 
the bone marrow at PR and CR, bone 
marrow should be repeated 4 to 8 weeks 
later for confirmatory purposes. The EOT 
bone marrow does not have to be performed 
if the prior assessment occurred within 
8 weeks. Bone marrow assessments can be 
performed within a window of ± 7 days.
X
Every 24 weeks after C1D1, and at time of 
suspected PR, CR, or PD
If PR/CR occurs, a bone marrow is collected 
every 24 weeks thereafter
X
Response assessment
Per IWG 2006 (see Attachment 6)
Week 12, 24, 36, 48, 60, 72 and then every 24 
weeks until PD
X
ECOG performance status
X
Xa
Only Day 1a
X
Survival status
X
Biomarker Assessments
Bone marrow biopsy
See Efficacy Assessments Section
X
Bone marrow aspirate 
See Efficacy Assessments Section
X
At time of suspected PR/CR and every 24 weeks 
thereafter until PD
X
(or PD)
Peripheral blood
Peripheral blood will be collected at 
specified visits and at the time of PR/CR 
and every 24 weeks thereafter. 
Immunophenotyping will be performed by 
flow cytometry and CyTOF. 
Xa
Xa
Only Day 1 of 
Cycles 2, 4 and 
6a
X
(or PD)
NCT03011034


JNJ-56022473 (talacotuzumab) and JNJ-54767414 (daratumumab)
Clinical Protocol 56022473MDS2002 – Amendment 4
14
Status: Approved, Date: 13 December 2018
TIME AND EVENTS SCHEDULE – TALACOTUZUMAB
PHASE
Screening 
Phase
Treatment Phase
(4-week cycles +/-3 days)
Posttreatment
Follow-up Phase
Study Procedures
Notes
Up to 28 
days 
before 
first dose
Cycle 1
Day 1
Cycle 1
Day 15
Cycle 2
until EOT
Day 1, 15
EOT Visit
Within 30 
days after 
last dose
Survival Follow-up
Every 16 weeks
(+/- 7 days)
Plasma
Plasma will also be collected at specified 
visits and at the time of PR/CR and every 
24 weeks thereafter.
Xa
Only Day 1 of 
Cycle 4a
X
(or PD)
Clinical Laboratory 
Assessments
Hematology
Hematology laboratory assessments to 
determine subject eligibility must be 
performed within 14 days prior to first dose. 
For Cycle 1 Day 1, clinical laboratory 
assessments do not need to be repeated if 
the Screening tests were performed within 
5 days of the first dose of study treatment. 
X
Xa
Xa
Xa
X
Chemistry
Chemistry laboratory assessments to 
determine subject eligibility must be 
performed within 14 days prior to first dose. 
For Cycle 1 Day 1, clinical laboratory 
assessments do not need to be repeated if 
the Screening tests were performed within 
5 days of the first dose of study treatment
X
Xa
Only Day 1a
X
Serum EPO level
X
Serum ferritin, transferrin 
saturation 
X
Serology
HIV antibody, hepatitis B surface antigen,
and hepatitis C virus antibody
X
Serum β-hCG or urine pregnancy 
test
For women of childbearing potential only;
must be performed within 14 days prior to 
first dose
X
Only if clinically indicated
Ongoing Subject Review
Concomitant therapy
Continuous from the time of signing ICF 
until 30 days after the end of dosing or until 
the start of subsequent anticancer treatment, 
if earlier
X
Continuous
X
Adverse events
Continuous from the time of signing ICF 
until 30 days after the end of dosing or until 
the start of subsequent anticancer treatment, 
if earlier
X
Continuous
X
NCT03011034


JNJ-56022473 (talacotuzumab) and JNJ-54767414 (daratumumab)
Clinical Protocol 56022473MDS2002 – Amendment 4
15
Status: Approved, Date: 13 December 2018
TIME AND EVENTS SCHEDULE – TALACOTUZUMAB
PHASE
Screening 
Phase
Treatment Phase
(4-week cycles +/-3 days)
Posttreatment
Follow-up Phase
Study Procedures
Notes
Up to 28 
days 
before 
first dose
Cycle 1
Day 1
Cycle 1
Day 15
Cycle 2
until EOT
Day 1, 15
EOT Visit
Within 30 
days after 
last dose
Survival Follow-up
Every 16 weeks
(+/- 7 days)
Subsequent therapy
Subsequent therapy to be collected 
throughout survival follow-up period
X
X
Abbreviations: C1D1=Cycle 1, Day 1; CR=complete remission; CyTOF=cytometry by time of flight; EOT=end-of-treatment; EPO=erythropoietin; PD=disease progression; PR=partial 
remission
a.
To be performed before the start of the infusion.
NCT03011034


JNJ-56022473 (talacotuzumab) and JNJ-54767414 (daratumumab)
Clinical Protocol 56022473MDS2002 – Amendment 4
16
Status: Approved, Date: 13 December 2018
TIME AND EVENTS SCHEDULE - TALACOTUZUMAB PHARMACOKINETICS AND IMMUNOGENICITY ASSESSMENTS
Visit/Timepoint
Talacotuzumab
PK
Samplea,b
ADA
(taken from PK sample)a,c,d
Cycle 1
Day 1
predose
X
X
end of infusion
X
Cycle 1
Day 15
predose
X
X
Cycle 2
Day 1
predose
X
X
Cycle 3
Day 1
predose
X
X
Cycle 4
Day 1
predose
X
X
end of infusion
X
Cycle 4
Day 15
predose
X
Cycle 5
Day 1
predose
X
X
Cycle 6
Day 1
predose
X
(Cycle 6 or Cycle 7)
X
(Cycle 6 or Cycle 7)
Cycle 7
Day 1
predose
EOT
X
X
Follow-up
4 and 8 weeks after last dose of talacotuzumab
X
X
ADA=anti-drug antibody, EOT=end-of-treatment, PK=pharmacokinetics
a.
Sent to central laboratory.
b.
Sample to be taken before the start of the infusion (-2 hours) and end of infusion sample to be taken 0.5 to 2 hours after the end of the infusion. Venous blood samples (5 mL per 
sample) will be collected for PK/ADA analysis and the serum will be divided into 3 aliquots (1 aliquot for PK analysis, 1 aliquot for antibodies to talacotuzumab analysis [when 
appropriate], and 1 aliquot as a backup).
c.
An aliquot from the PK sample will be used to assess immunogenicity. A separate blood draw is not needed. 
d.
Sample to be taken at time of infusion-related reaction.
TIME AND EVENTS SCHEDULE – DARATUMUMAB
PHASE
Screening 
Phase
Treatment Phase
(4-week cycles +/-3 days)
Posttreatment
Follow-up Phase
Study Procedures
Notes
Up to 28 
days 
before 
first dose
Cycle 1
Day 1
Cycle 1
Day 8,
15, 22
Cycle 2
Day 1, 8, 
15, 22
Cycle 3, 4, 
5, 6
Day 1, 15
Cycle 7
until EOT 
Day 1
EOT Visit
Within 30 
days after 
last dose
Survival Follow-up
Every 16 weeks
(+/- 7 days)
Screening/Administrative
Informed consent
Subjects must sign before any study-
specific procedures are performed.
X
Inclusion/exclusion criteria
X
Medical history, blood 
X
NCT03011034


JNJ-56022473 (talacotuzumab) and JNJ-54767414 (daratumumab)
Clinical Protocol 56022473MDS2002 – Amendment 4
17
Status: Approved, Date: 13 December 2018
PHASE
Screening 
Phase
Treatment Phase
(4-week cycles +/-3 days)
Posttreatment
Follow-up Phase
Study Procedures
Notes
Up to 28 
days 
before 
first dose
Cycle 1
Day 1
Cycle 1
Day 8,
15, 22
Cycle 2
Day 1, 8, 
15, 22
Cycle 3, 4, 
5, 6
Day 1, 15
Cycle 7
until EOT 
Day 1
EOT Visit
Within 30 
days after 
last dose
Survival Follow-up
Every 16 weeks
(+/- 7 days)
typing, and demographics
Study Drug 
Administration
Dispense/administer study 
drug (+/- 24 hours)
Screening weight is baseline for dose 
calculation. Recalculate if weight 
changes >10% from screening.
X
X
X 
X
X
Pre and postinfusion 
medications
Subjects will receive preinfusion
medications before all daratumumab 
infusions, and postinfusion medications 
on the 2 days following all daratumumab 
infusions (beginning the day after the 
infusion). Refer to Sections 6.3.3 and 
6.3.3.1 for additional information.
X
X
X
X
X
Safety Assessments
Physical exam (including 
weight)
At post-screening visits, only a limited 
symptom-directed physical examination.
X
Xa
Only 
Day 1a
Only 
Day 1a
Xa
X
Vital signs
Vital signs should be measured and 
recorded (prior to study medication 
administration) and include heart rate and 
systolic/diastolic blood pressure, 
preferably while the subject is in a seated 
position.
X
Xa
Only 
Day 1a
Only 
Day 1a
Xa
X
12-lead ECG
X
Xa
Efficacy Assessments
Transfusion history and 
status; myeloid growth factor 
treatment
Assessment of RBC transfusion 
requirements and myeloid growth factor 
use 16 weeks prior to randomization, at
each 4-week cycle visit, disease 
evaluation visit, and all unscheduled 
visits during treatment. Complete 
transfusion information must be 
collected, including both in-patient and 
out-patient transfusions
X
Xa
Only 
Day 1a
Only 
Day 1a
Only 
Day 1a
X
X
(first visit and every 
4-6 weeks if feasible)
NCT03011034


JNJ-56022473 (talacotuzumab) and JNJ-54767414 (daratumumab)
Clinical Protocol 56022473MDS2002 – Amendment 4
18
Status: Approved, Date: 13 December 2018
TIME AND EVENTS SCHEDULE - DARATUMUMAB
PHASE
Screening 
Phase
Treatment Phase
(4-week cycles +/-3 days)
Posttreatment
Follow-up Phase
Study Procedures
Notes
Up to 28 
days 
before 
first dose
Cycle 1
Day 1
Cycle 1
Day 8,
15, 22
Cycle 2
Day 1, 8, 
15, 22
Cycle 3, 4, 
5, 6
Day 1, 15
Cycle 7
until EOT 
Day 1
EOT Visit
Within 30 
days after 
last dose
Survival Follow-up
Every 16 weeks
(+/- 7 days)
Bone marrow aspirate with 
cytogenetics and bone 
marrow biopsy
Bone marrow aspirate and biopsy with 
iron stain must be performed during 
screening or up to 12 weeks prior to first 
dose. Following the bone marrow at PR 
and CR, bone marrow should be repeated 
4 to 8 weeks later for confirmatory 
purposes. The EOT bone marrow does 
not have to be performed if the prior 
assessment occurred within 8 weeks.
Bone marrow assessments can be 
performed within a window of ± 7 days.
X
Every 24 weeks, at time of PR, CR, and at PD
If PR/CR occurs, a bone marrow is collected every 24 weeks 
thereafter
X 
Response assessment 
Per IWG 2006
Week 12, 24, 36, 48, 60, 72 and then every 24 weeks until PD
X
ECOG performance status
X
Xa
Only 
Day 1a
Only 
Day 1a
Xa
X
Survival status
X
Biomarker Assessments
Bone marrow biopsy
See Efficacy Assessments Section
X
Bone marrow aspirate 
See Efficacy Assessments Section
X
At time of suspected PR/CR and every 24 weeks thereafter 
until PD
X
(or PD)
Peripheral blood
Peripheral blood will be collected at 
specified visits and at the time of PR/CR 
and every 24 weeks thereafter. 
Immunophenotyping will be performed 
by flow cytometry and CyTOF. 
Xa
Only 
Day 15a
Only 
Day 1a
Only Day 1 
of Cycles 4 
and 6a
X 
(or PD)
Plasma
Plasma will also be collected at specified 
visits and at the time of PR/CR and every 
24 weeks thereafter.
Xa
Only Day 1 
of Cycle 4a
X
(or PD)
NCT03011034


JNJ-56022473 (talacotuzumab) and JNJ-54767414 (daratumumab)
Clinical Protocol 56022473MDS2002 – Amendment 4
19
Status: Approved, Date: 13 December 2018
TIME AND EVENTS SCHEDULE - DARATUMUMAB
PHASE
Screening 
Phase
Treatment Phase
(4-week cycles +/-3 days)
Posttreatment
Follow-up Phase
Study Procedures
Notes
Up to 28 
days 
before 
first dose
Cycle 1
Day 1
Cycle 1
Day 8,
15, 22
Cycle 2
Day 1, 8, 
15, 22
Cycle 3, 4, 
5, 6
Day 1, 15
Cycle 7
until EOT 
Day 1
EOT Visit
Within 30 
days after 
last dose
Survival Follow-up
Every 16 weeks
(+/- 7 days)
Clinical Laboratory 
Assessments
Hematology
Hematology laboratory assessments to 
determine subject eligibility must be 
performed within 14 days prior to first 
dose. For Cycle 1 Day 1, clinical 
laboratory assessments do not need to be 
repeated if the Screening tests were 
performed within 5 days of the first dose 
of study treatment. 
X
Xa
X
Only 
Day 1a
Only 
Day 1a
X
X
Chemistry
Chemistry laboratory assessments to 
determine subject eligibility must be 
performed within 14 days prior to first 
dose. For Cycle 1 Day 1, clinical 
laboratory assessments do not need to be 
repeated if the Screening tests were 
performed within 5 days of the first dose 
of study treatment. 
X
Xa
Only 
Day 1a
Only 
Day 1a
Xa
X
Blood type assessment and 
indirect antiglobulin results
Prior to dosing on Day 1 of Cycle 1 only
Serum EPO level
X
Serum ferritin, transferrin 
saturation 
X
Serology
HIV antibody, hepatitis B surface 
antigen, and hepatitis C virus antibody
X
Serum β-hCG or urine 
pregnancy test
For women of childbearing potential 
only; must be performed within 14 days 
prior to first dose
X
Only if clinically indicated
Ongoing Subject Review
Concomitant therapy
Continuous from the time of signing ICF 
until 30 days after the end of dosing or 
until the start of subsequent anticancer 
treatment, if earlier
X
Continuous
X
NCT03011034


JNJ-56022473 (talacotuzumab) and JNJ-54767414 (daratumumab)
Clinical Protocol 56022473MDS2002 – Amendment 4
20
Status: Approved, Date: 13 December 2018
TIME AND EVENTS SCHEDULE - DARATUMUMAB
PHASE
Screening 
Phase
Treatment Phase
(4-week cycles +/-3 days)
Posttreatment
Follow-up Phase
Study Procedures
Notes
Up to 28 
days 
before 
first dose
Cycle 1
Day 1
Cycle 1
Day 8,
15, 22
Cycle 2
Day 1, 8, 
15, 22
Cycle 3, 4, 
5, 6
Day 1, 15
Cycle 7
until EOT 
Day 1
EOT Visit
Within 30 
days after 
last dose
Survival Follow-up
Every 16 weeks
(+/- 7 days)
Adverse events
Continuous from the time of signing ICF 
until 30 days after the end of dosing or 
until the start of subsequent anticancer 
treatment, if earlier
X
Continuous
X
Subsequent therapy
Subsequent therapy to be collected 
throughout survival follow-up period
X
X
Abbreviations: C1D1=Cycle 1, Day 1; CR=complete remission; CyTOF=cytometry by time of flight; EOT=end-of-treatment; EPO=erythropoietin; PD=disease progression; PR=partial 
remission
a.
To be performed before the start of the infusion.
NCT03011034


JNJ-56022473 (talacotuzumab) and JNJ-54767414 (daratumumab)
Clinical Protocol 56022473MDS2002 – Amendment 4
21
Status: Approved, Date: 13 December 2018
TIME AND EVENTS SCHEDULE - DARATUMUMAB PHARMACOKINETICS AND IMMUNOGENICITY ASSESSMENTS
Visit/Timepoint
Daratumumab
PK
Samplea,b
ADA
(taken from PK sample)a,c
Cycle 1
Day 1
predose
X
X
end of infusion
X
Cycle 2
Day 1
predose
X
X
end of infusion
X
Cycle 3
Day 1
predose
X
X
end of infusion
X
Cycle 7
Day 1
predose
X
X
end of infusion
X
Cycle 12
Day 1
predose
X
X
end of infusion
X
Follow-up
4 and 8 weeks after last dose of daratumumab
X
X
ADA=anti-drug antibody, EOT=end-of-treatment, PK=pharmacokinetics
a.
Sent to central laboratory.
b.
Predose sample to be taken before the start of the infusion (-2 hours) and end of infusion sample to be taken within 2 hours after the end of the infusion. Venous blood samples (5 mL 
per sample) will be collected for PK/ADA analysis and the serum will be divided into 3 aliquots (1 aliquot for PK analysis, 1 aliquot for antibodies to daratumumab analysis [when 
appropriate], and 1 aliquot as a backup).
c.
An aliquot from the PK sample will be used to assess immunogenicity. A separate blood draw is not needed.
TIME AND EVENTS SCHEDULE – DARATUMUMAB - TABLE FOLLOWING AMENDMENT 4
PHASE
NOTE: After the end of study data collection, subjects who are deriving benefit may continue receiving daratumumab treatment, and will be monitored for serious 
adverse events that occur during treatment through resolution and entered only into the company safety repository as described under Amendment 4. These subjects will 
continue to be followed by the study physician according to local standard of care practices and in accordance with daratumumab dosing guidelines.
NCT03011034


JNJ-56022473 (talacotuzumab) and JNJ-54767414 (daratumumab)
Clinical Protocol 56022473MDS2002 – Amendment 4
22
Status: Approved, Date: 13 December 2018
ABBREVIATIONS
ADA
anti-drug antibody
ADCC
antibody-dependent cell-mediated cytotoxicity
AE
adverse event
AML
acute myeloid leukemia
ANC
absolute neutrophil count 
ALT
alanine aminotransferase
ARC
Anticipated Event Review Committee
AST
aspartate aminotransferase
ALP
alkaline phosphatase
Breg
regulatory B cell
Cmax
maximum observed serum concentration
Cmin
minimum observed serum concentration
CMML
chronic myelomonocytic leukemia
COPD
chronic obstructive pulmonary disease
CR
complete response
CyTOF
cytometry by time of flight
eCRF
electronic case report form
eDC
electronic data capture
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EMA
European Medicines Agency
EOT
end-of-treatment
EPO
erythropoietin
ESA
Erythropoiesis-Stimulating Agent
FDA
Food and Drug Administration
FEV1
forced expiratory volume in 1 second
HI
hematologic improvement
HI-E
hematologic improvement-erythroid
HI-P
hematologic improvement-platelet
HI-N
hematologic improvement-neutrophil
HIV
human immunodeficiency virus
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IgG1ĸ
immunoglobulin G1 kappa
IHC
immunohistochemistry
IMiD
immunomodulatory drug
IPSS
International Prognostic Scoring System
IRB
Institutional Review Board
IRR
infusion-related reactions
IV
intravenous
IWRS
interactive web response system
IWG
International Working Group
mAb
monoclonal antibody
MDS
Myelodysplastic Syndrome
MDSCs
Myeloid-derived suppressor cells
MedDRA
Medical Dictionary for Regulatory Activities
NCI-CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NK
natural killer
OS
overall survival
pDCs
plasmacytoid dendritic cells
PD
disease progression / progressive disease
PD
pharmacodynamics
PK
pharmacokinetic
PQC
poor quality complaint
NCT03011034


JNJ-56022473 (talacotuzumab) and JNJ-54767414 (daratumumab)
Clinical Protocol 56022473MDS2002 – Amendment 4
23
Status: Approved, Date: 13 December 2018
PR
partial response
pRBC
packed red blood cell
RBC
red blood cell
SC
subcutaneous
SAE
serious adverse event
SUSAR
suspected unexpected serious adverse reactions
TI
transfusion independence
Treg
regulatory T cell
ULN
upper limit of normal
US
United States
WHO
World Health Organization
WPSS
WHO classification-based Prognostic Scoring System
NCT03011034


JNJ-56022473 (talacotuzumab) and JNJ-54767414 (daratumumab)
Clinical Protocol 56022473MDS2002 – Amendment 4
24
Status: Approved, Date: 13 December 2018
1.
INTRODUCTION
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.
Myelodysplastic Syndromes
Myelodysplastic syndromes (MDS) are a heterogeneous group of malignant hematopoietic stem 
cell disorders that are characterized by cytopenias, myeloid dysplasia and a risk of 
transformation to acute myeloid leukemia.3 In MDS, an increase of inflammatory cells is 
observed in the bone marrow microenvironment, which may lead to suppression of normal 
differentiation of hematopoietic cells via recruitment of various immunosuppressor cell types. 
The immunosuppressive environment is also thought to induce tolerance of MDS blasts and 
allows further accumulation of genetic aberrations leading to disease progression.
The primary immunosuppressive cell types found in MDS are myeloid-derived suppressor cells 
(MDSCs), which are a key component in suppressing normal immune cell function. Upon 
stimulation, they cause a reduction in T-cell proliferation and IFNγ secretion2 and can inhibit NK 
cell function as well.11 When analyzing the secretome of MDSCs, high levels of suppressive 
cytokines IL-10 and TGF-β were expressed in vitro.2 Specifically in MDS, it has been shown by 
several groups that the frequency of MDSCs is increased in both the bone marrow and peripheral 
blood of patients with MDS compared to healthy controls.6 Interestingly, MDSCs were also 
shown to alter normal hematopoiesis through direct contact with hematopoietic stem and 
progenitor cells in vitro, which may contribute to anemia.2 Targeting these cells may improve 
anemias and lead to transfusion independence (TI) in MDS patients.
The standard prognostic tool in MDS is the International Prognostic Scoring System (IPSS),
which classifies patients into low, intermediate-1, intermediate-2, and high risk categories on the 
basis of the percentage of bone marrow blasts, the karyotype, and the number of cytopenias. The 
median survival rates for the low, intermediate-1, intermediate-2, and high risk categories are 
estimated at 5.7, 3.5, 1.2, and 0.4 years, respectively.3,7 Other prognostic systems have also been 
described, namely the WHO classification-based Prognostic Scoring System (WPSS)25 and 
IPSS-Revised (IPSS-R).8 The IPSS is more frequently referenced in clinical trials. Patients with 
low and intermediate-1 risk MDS are also often referred to as having “lower risk” disease, 
whereas those with intermediate-2 and high risk MDS are referred to as patients with “higher 
risk” disease.
Treatment Options for MDS 
For patients with IPSS low and intermediate-1 risk MDS, the initial approach to treatment 
typically involves supportive care measures, ie, red blood cell (RBC) transfusions or 
erythropoiesis-stimulating agents (ESAs) or other hematopoietic growth factors, aimed at 
alleviating cytopenias. Approximately 40% of the patients will achieve an International Working 
Group (IWG)-defined hematologic improvement to ESAs for a median duration of 2 years. The 
Nordic MDS group has developed a model that identifies patients more likely to respond to 
ESAs. Those with low or no transfusion requirements (<2 packed red blood cell [pRBC] 
units/month) and a low serum erythropoietin (EPO) level (<500 units/L) have a higher response 
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rate than those with high transfusion needs (≥2 units/month) and serum EPO
level
(≥500 units/L); 74% versus 7%, respectively.10
A marker of disease severity appears to be associated with early ESA failure (no response to 
ESA or relapse within 6 months). Patients whose disease fails ESA early compared to later 
failure have a higher rate of transformation to acute myeloid leukemia (AML) (5-year 
cumulative incidence of 22% versus 9%, respectively; p=0.02) with a much shorter median 
overall survival (OS) (37 months versus 54 months, respectively; p=0.02).15 This median 
survival is considerably shorter than predicted at the time of diagnosis.
For a small subset of patients with lower risk MDS that carry the del(5q) chromosomal 
abnormality, lenalidomide is approved by both the US Food and Drug Administration (FDA) and
European Medicines Agency (EMA) based on the data that shows approximately 60% of 
subjects achieving durable (>24 weeks) RBC TI. The median duration of response was 
approximately 2 years.
For the larger subset of patients, comprising about 90% of all lower risk MDS that does not have 
the del(5q) chromosomal abnormality, there is currently no universally accepted therapeutic 
option. Phase 2 and Phase 3 studies with lenalidomide have been conducted. Rates and durability 
of TI were lower than those observed in the cohorts with the del(5q) abnormality. Approximately 
one-quarter of patients (27%) who received lenalidomide achieved RBC TI, with median 
duration of response ranging from 33 to 41 weeks.20,21
Hypomethylating agents, approved for patients with higher-risk MDS, have been evaluated for
patients with lower risk MDS with multiple cytopenias after failure of other agents. In one study 
of decitabine given to 65 subjects with lower risk MDS, 23% achieved an overall improvement 
rate as assessed by modified IWG response of PR or better.5 In another study of 25 subjects, 44% 
achieved a CR or hematologic improvement (HI, IWG response).22 In this MDS patient 
population, a study with subcutaneous azacitidine resulted in a 23% response rate; and 17% of 
subjects who were RBC transfusion dependent at baseline became transfusion independent.24
Despite their efficacy, the hypomethylating agents are generally reserved for patients with higher 
risk MDS because of their myelosuppressive toxicity.
Most patients with IPSS low and intermediate-1 risk MDS who have failed to respond to ESAs
eventually require long-term RBC transfusions. Patients with low-risk MDS who are transfusion-
dependent, have limited treatment options and generally have poorer outcomes. Findings from a 
recent systematic literature review and meta-analysis reported a reduction in mortality in patients 
who were transfusion independent compared to those who were transfusion dependent.9 In 
addition, iron toxicity is an inevitable consequent of frequent red-blood-cell transfusions.19
Although data are preliminary regarding the role of MDSCs in MDS, experimental treatments 
with proposed mechanisms to treat the underlying pathophysiology of MDS and decrease 
dependence on transfusions and their resulting complications may be of benefit of patients in this 
population with a high unmet need for effective therapies.
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1.1.
Study Drugs
Talacotuzumab (JNJ-56022473) is a humanized monoclonal antibody (mAb) that specifically 
targets the human interleukin-3 receptor alpha chain (IL-3Rα or CD123), and inhibits the 
signaling through this receptor. Talacotuzumab has been engineered to have increased affinity to 
human FcγRIIIa (CD16) expressed on NK cells and, as a consequence, has an enhanced ability 
to induce NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC) against target cells
expressing CD123. In lower risk MDS, these cell types are primarily MDSCs and may include 
blasts. To date, one Phase 1 study (Study CSLCT-AML-11-73) has been completed for patients 
with AML in CR at high risk for relapse. This study established the dose and showed promising 
efficacy in small subset of patients with the primary mechanism of action being targeting CD123 
on AML blasts. In addition, an ongoing Phase 2/3 study (Study 56022473AML2002) is being 
conducted for patients older than 65 years with AML who are not candidates for intensive 
chemotherapy. In these studies, approximately 78 subjects have been treated with talacotuzumab 
as of 15 June 2016. Infusion-related reactions have been observed. These are generally mild to 
moderate, although Grade 3 events have been reported. Other potential risks include 
hypersensitivity (as part of an infusion-related reactions or alone), increased risk of infection, 
impaired response to live virus vaccinations, and immunogenicity to talacotuzumab.
Daratumumab (JNJ-54767414) is a human immunoglobulin G1 kappa (IgG1ĸ) mAb that binds 
with high affinity to a unique epitope on CD38, a transmembrane glycoprotein. It is a targeted 
immunotherapy directed towards tumor cells that express high levels of CD38, such as plasma 
cells from patients with multiple myeloma. Daratumumab was approved as monotherapy by the 
FDA and the EMA for the treatment of patients with relapsed and refractory multiple myeloma. 
Daratumumab is thought to mediate these responses, in part, through the elimination of CD38+
immunosuppressive cells (MDSCs, regulatory T cells [Tregs] and regulatory B cells [Bregs]) 
that synergizes with direct elimination of the myeloma cells.17 The identified risks associated 
with daratumumab include infusion-related reaction and interference with blood typing. 
Increased risk for infection is a potential risk, with upper respiratory tract infection (17%) the 
most frequent infection.
For the most comprehensive nonclinical and clinical information regarding talacotuzumab and 
daratumumab, refer to the latest version of the respective Investigator’s Brochures and 
Addenda.12,13
1.2.
Overall Rationale for the Study
CD123 has been shown to be expressed on Lin- HLA-DRlow CD11b+ CD33+ MDSCs. Preliminary 
data demonstrated an increase in frequency of MDSCs in MDS patient samples compared to 
healthy controls (sponsor data on file).2 More importantly, the MDSCs in patients with MDS 
exhibit high levels of expression of CD123 (sponsor data on file). It is hypothesized that 
talacotuzumab will eliminate CD123+ MDSCs in patients with MDS through NK cell-mediated 
cytotoxicity, and promote effective hematological differentiation.
CD123 has also been regarded as a marker of leukemic stem cells (LSC), and overexpression of 
CD123 on LSCs has been shown to correlate to blast proliferation and poor prognosis in AML.23
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Myelodysplastic syndromes, as a pre-leukemia status, are clonal disorders with enhanced risk of 
evolution towards AML,26 and it has been shown that CD123+ LSCs were increased in patients 
with MDS compared to healthy controls.27 Although the overall frequency of blasts in lower risk 
MDS is determined by having less than 5% blasts in the bone marrow, the CD123+ LSCs in 
MDS patients display similar malignant features observed in CD123+ LSCs in AML.18
Therefore, talacotuzumab may also eliminate CD123+ blasts in lower risk MDS patients and 
augment progression of disease.
Preliminary data on MDS patient samples has also shown high levels of expression of CD38 on 
MDSCs (sponsor data on file). In patients with multiple myeloma, MDSCs have been shown to 
express CD38, and are depleted after the first daratumumab infusion. More importantly, the 
MDSCs are sensitive and remain sensitive throughout daratumumab treatment.17 Therefore, it is 
also hypothesized that daratumumab will target CD38+ MDSCs in patients with MDS.
Lastly, Tregs have also been shown to be involved in the immunosuppressive microenvironment 
of low to intermediate 1-risk MDS patients.16 Univariate analysis of overall and progression-free 
survival of 38 low to intermediate 1-risk MDS patients showed that patients with increased 
numbers of Tregs (above the median) had a lower progression-free and OS than patients with 
less than median number of Tregs.14 In patients with multiple myeloma, CD38 has been shown 
to be expressed on a subset of Tregs, and the CD38+ subset of Tregs has been shown to be highly 
immunosuppressive of T cell activity compared to CD38- Tregs. Importantly, this highly 
immunosuppressive fraction of Tregs is targetable by daratumumab17 and therefore may also be 
a therapeutic target in patients with low-risk MDS. Reducing highly immunosuppressive CD38+
Tregs may alter the progression of disease.
These data indicate that talacotuzumab and daratumumab may eliminate immunosuppressive cell 
types in the bone marrow microenvironment of patients with MDS. Elimination of MDSCs (both 
compounds) and Tregs (daratumumab only) may alter the immunosuppressive microenvironment 
and allow normal hematopoietic progenitor cells to differentiate, and ultimately improve clinical 
outcomes. Lastly, elimination of CD123+ MDS blasts by talacotuzumab may further alter disease 
progression.
2.
OBJECTIVES, ENDPOINTS, AND HYPOTHESISES
2.1.
Objectives and Endpoints
2.1.1.
Objectives
Primary Objectives
The primary objective of the study is to evaluate the efficacy (transfusion independence) of 
talacotuzumab (JNJ-56022473) or daratumumab in transfusion-dependent subjects with low or 
intermediate-1 risk MDS whose disease has relapsed during treatment with or is refractory to 
ESAs. 
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Secondary Objectives

To evaluate the safety of talacotuzumab or daratumumab in the study population

To evaluate the clinical benefit of talacotuzumab and daratumumab in this study population 
through:

Time to TI and duration of TI

Rate of HI, CR, and PR

Overall survival (OS)

Progression to AML

Rate and amount of supportive care, including transfusions and myeloid growth factors

To characterize the PK of talacotuzumab and daratumumab in the study population

To evaluate the immunogenicity of talacotuzumab and daratumumab in subjects with MDS
Exploratory Objectives
The tertiary/exploratory objectives of this study are: 

To evaluate pharmacodynamic biomarkers for talacotuzumab activity

To determine CD123 and CD38 expression and to explore the association with clinical 
outcomes
2.1.2.
Endpoints
Primary Endpoint
The primary endpoint is 8-week RBC TI, defined as absence of RBC transfusion during any 
consecutive 56 days (8 weeks) post randomization.
Secondary Endpoints
The secondary endpoints of this study are: 

Transfusion independence lasting 168 days (24 weeks)

Time to TI

Duration of TI

Transfusions and myeloid growth factors usage

HI (including HI-E, HI-P, HI-N), CR, PR and cytogenetic response per IWG 2006

Overall survival

Progression to AML
Exploratory Endpoint

Immunophenotyping of the bone marrow and peripheral blood by flow cytometry (MDSC, 
blasts, basophils, pDC, T and B cells, NK cells, and immunogenicity).
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Refer to Section 9, Study Evaluations for evaluations related to endpoints.
2.2.
Hypothesis
The primary hypothesis of this study is that the treatment with talacotuzumab or daratumumab
separately will produce a TI rate 30% or greater against a minimal acceptable value of 15%. The 
statistical evaluation of the hypothesis will use a Bayesian approach to assess the likelihood of 
whether a true TI rate ≤15% can be ruled out.
3.
STUDY DESIGN AND RATIONALE
3.1.
Overview of Study Design
This is a multicenter, randomized, Phase 2, open-label study to evaluate the safety and efficacy 
of single-agent talacotuzumab or single-agent daratumumab in subjects with low or 
intermediate-1 risk MDS who are transfusion-dependent and whose disease has relapsed during 
or is refractory to ESA treatment. Approximately 60 subjects (30 to receive talacotuzumab and 
30 to receive daratumumab) will be enrolled in this study. There will be no statistical hypothesis 
testing, and each arm will be assessed separately without formal comparison between the 2 arms. 
Statistical methods focus on the evaluation of the likelihood that either treatment regimen will 
result in a true TI rate of 30% or greater against a minimum acceptable value of 15%. The 
planned sample size is approximately 30 subjects per treatment arm, which will ensure at least 
90% probability that the true TI rate is greater than the minimum acceptable value 15% if at least 
8 subjects reach TI. A diagram of the study design is provided below in Figure 1.
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Figure 1:
Schematic Overview of the Study
Note: As a precautionary measure, due to benefit / risk considerations for patients with low-risk 
MDS, enrollment to the talacotuzumab arm is closed based upon the occurrence of a Grade 4
infusion-related reaction in the first subject to receive talacotuzumab. The IWRS was modified to 
only permit enrollment to the daratumumab arm of the study.
The end of study data collection is defined as either 1 year after the last subject is randomized or 
anytime the sponsor terminates the study. At that time, study follow-up of subjects and study 
data collection will end. Subjects who are continuing to derive benefit from daratumumab
treatment as assessed by their investigator may continue to receive daratumumab according to 
the protocol. During this period after study data collection has ended, only serious adverse events 
will be monitored and only entered into the company safety repository as described under 
Amendment 4 and in the Time and Events Schedule.
Treatment Phase
Talacotuzumab
28-day treatment cycle
N=30
Talacotuzumab 9 mg/kg IV every 2 weeks
Treatment Phase
Daratumumab
28-day treatment cycle
N=30
Daratumumab 16 mg/kg IV weekly on Weeks 1 to 8, 
every 2 weeks for Weeks 9 to 24, and every 4 weeks 
thereafter
Screening Phase
≤28 days before Cycle 1, Day 1
Random allocation to talacotuzumab or daratumumab
(1:1)
Posttreatment Follow-up Phase
Every 16 weeks
End-of-Treatment Visit
Within 30 days after last dose
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3.2.
Study Design Rationale
Inflammatory changes are a prominent feature in MDS with increased populations of
inflammatory cells in the bone marrow microenvironment. Inflammation in the bone marrow 
microenvironment leads to suppression of normal differentiation of hematopoietic cells via 
recruitment of suppressor cells. Myeloid-derived suppressor cells are thought to be a key 
component in suppressing normal immune cell function, and may have a profound role in the 
pathogenesis of MDS. The immunosuppressive environment is thought to promote tolerance to 
MDS blasts allowing accumulation of additional genetic aberrations. Targeting the inflammatory 
changes by eliminating either CD123- or CD38-expressing MDSCs may be a beneficial 
approach to the management of MDS.
Rationale for Randomization
Randomization will be used to allocate subjects to treatment groups. Although there is no formal 
statistical comparison between the 2 treatment groups, randomization can enhance the validity of 
statistical assessments to facilitate the decision making for further development of either or both 
treatment therapies if both treatment arms have met the primary objective. The primary endpoint 
of this study is defined by transfusion, and randomization can alleviate potential biases due to 
differences in transfusion practices across different sites and different countries. Enrollment to 
the talacotuzumab arm was closed (refer to Section 3.1 Overview of Study Design for details).
Rationale for Study Population 
Limited treatment options are available for patients who are RBC-transfusion dependent and who 
have IPSS low risk or intermediate-1 risk MDS that is relapsed/refractory to ESA treatment. An 
unmet need exists for agents that reduce the transfusion burden of these patients. The median 
survival for patients with low-risk MDS for whom ESA treatment has failed is about 3.5 years, 
which is considerably shorter than predicted at the time of diagnosis.4,15 Furthermore, emerging 
data describe the role of MDSCs as well as Tregs in the pathogenesis of MDS. Targeting CD123 
or CD38 on MDSCs with talacotuzumab or daratumumab, respectively, may show clinical 
benefit in patients with low-risk MDS.
Rationale for Endpoints
Transfusion independence for 8 weeks is a clinically meaningful and robust endpoint that is 
included in the IWG response criteria, and has been the basis for regulatory approvals.
The rate of HI-E will provide further explanation of the hematologic response (as per IWG 
criteria). Progression to AML and OS are important endpoints considering that the natural 
history of MDS progression includes transformation to AML in a proportion of patients. 
The depth of the response will be captured by assessment of CR and PR. Duration of responses 
will be assessed. Subjects will be followed for OS.
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3.3.
Dose Rationales for Talacotuzumab and Daratumumab
Dose Rationale for Talacotuzumab
The proposed 9 mg/kg every 2 weeks (q2w) dose was selected based on analysis of the PK, 
CD123 receptor occupancy (RO), pharmacodynamic (PD), and safety data generated in the 
Phase 1 study for patients with AML in CR at high risk for relapse (CSLCT-AML-11-73).
The 9 mg/kg q2w dose level has been selected as the talacotuzumab recommended Phase 2 dose
for patients with AML. It is the only dose level being tested in the ongoing Phase 2/3 study for 
talacotuzumab in patients older than 65 years with AML who are not candidates for intensive 
chemotherapy (Study 56022473AML2002).
Dose Rationale for Daratumumab
The dose and schedule used in this study (16 mg/kg weekly for 8 weeks, every 2 weeks for 
16 weeks, and every 4 weeks thereafter) is the approved dosing regimen of daratumumab for the 
treatment of subjects with relapsed and refractory multiple myeloma. This dose was selected
based on an acceptable safety profile, maximal clinical activity, and pharmacokinetics consistent 
with saturation of the target. This dose and similar schedules have been shown to be tolerable in 
several combination studies.
4.
SUBJECT POPULATION
Subject eligibility will be reviewed and approved by the sponsor during the Screening Phase. 
Screening will be performed within 28 days prior to randomization.
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 subject selection, refer to Section 11.2, 
Sample Size Determination.
4.1.
Inclusion Criteria
Each potential subject must satisfy all of the following criteria to be enrolled in the study: 
1.
18 years of age
2.
MDS according to World Health Organization (WHO, Attachment 1) criteria confirmed 
by bone marrow aspirate and biopsy within 12 weeks prior to first dose. A local 
laboratory report from this diagnostic bone marrow aspirate and biopsy must be 
approved by the sponsor. 
3.
IPSS low risk or intermediate-1 risk MDS (Attachment 2)
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4.
RBC transfusion dependent

Received at least 4 units of RBCs over any 8 consecutive weeks during the 
16 weeks prior to randomization

Pretransfusion Hb must have been ≤9.0 g/dL
Source documentation for transfusions verified by the sponsor.
5.
Relapsed/refractory to ESA treatment; the sponsor must verify this diagnosis as defined 
by meeting any of the criteria below:

Received at least 8 weeks of treatment with a minimum weekly dose of epoetin alfa 
40,000 U, epoetin beta 30,000 U or darbepoetin alfa 150 mcg (or equivalent 
agent/dose) without having achieved a Hb rise ≥1.5 g/dL or decreased RBC 
transfusion requirement by at least 4 units over 8 weeks

Transfusion dependence or reduction in Hb by ≥1.5 g/dL after hematologic
improvement, in the absence of another explanation

Endogenous serum EPO level >500 mU/mL 
Source documentation for failure of ESA treatment verified by the sponsor
6. 
Adequate iron stores, defined as transferrin saturation greater than 20% and serum 
ferritin greater than 400 ng/mL, measured within the screening period, or adequate iron 
stores as demonstrated by recent (within 12 weeks prior to first dose) bone marrow 
examination with iron stain.
7.
ECOG performance status 0, 1 or 2 (Attachment 3)
8.
Hematology laboratory test values within the following limits:

ANC ≥1.0 x 109/L (ie, ≥1,000/mm3) independent of growth factor support. For the 
screening ANC to be considered growth factor independent, a 7-day period after 
stopping the growth factor should be observed, or 7 half-lives of growth factor 
used, whichever is longer.

Platelets ≥50 x 109/L independent of platelet transfusion support. For the screening 
platelets to be considered independent of platelet transfusion support, platelet count 
must be stable for 3-4 days after the transfusion. 
9.
9.1
Criterion numbering modified per Amendment 2
Biochemical laboratory test values must be within the following limits:

Aspartate aminotransferase (AST), alanine aminotransferase (ALT) ≤2.5 times 
the upper limit of normal (x ULN)

Creatinine clearance >40 mL/min
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
Total bilirubin ≤3.0 x ULN, except for subjects with Gilbert syndrome
10.
Women of childbearing potential and men who are sexually active must be practicing
highly effective method of contraception (failure rate of <1% per year when used 
consistently and correctly) during and after the study. Contraceptive use by men or 
women should be consistent with local regulations regarding the use of contraceptive 
methods for subject participating in clinical studies. Men must agree to not father a child 
or donate sperm during and after the study. Women must agree not to donate eggs (ova, 
oocytes) for the purpose of assisted reproduction. For females and males, these 
restrictions apply for at least 3 months after the last dose of study drug.
11.
A woman of childbearing potential must have a negative highly sensitive serum 
(-human chorionic gonadotropin [-hCG]) or urine pregnancy test at Screening.
12.
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. Subject must be willing and able 
to adhere to the prohibitions and restrictions specified in this protocol.
4.2.
Exclusion Criteria
Any potential subject who meets any of the following criteria will be excluded from participating 
in the study: 
1.
Known allergies, hypersensitivity, or intolerance to talacotuzumab and daratumumab or 
their excipients (refer to Investigator’s Brochure)
2.
Received any chemotherapy, immunomodulatory or immunosuppressive therapy, 
corticosteroids (>30 mg/day prednisone or equivalent) within 28 days prior to 
randomization
3.
Received other treatments for MDS within 28 days prior to first dose (eg, azacitidine, 
decitabine, lenalidomide, ESA (8 weeks for long-acting ESAs)
4.
History of hematopoietic stem cell transplant
5.
Del(5q) karyotype unless treatment with lenalidomide has failed. Failure is defined as 
either: 1) having received at least 3 months of lenalidomide treatment without RBC 
transfusion benefit (IWG 2006); 2) progression or relapse after hematologic 
improvement with lenalidomide (IWG 2006); 3) discontinuation of lenalidomide due to 
toxicity; or 4) unable to receive lenalidomide due to a contraindication. Source 
documentation for lenalidomide treatment failure must be verified by the sponsor.
6.
Anemia attributed to factors other than MDS (including hemolysis, chronic renal failure, 
hepatitis, gastrointestinal bleeding)
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7.
Major surgery within 4 weeks prior to first dose (excludes the placement of a vascular 
access device and other minor surgical procedures)
8.
Active malignancy other than MDS ≤3 years before first dose, except

Adequately treated non-melanoma skin cancer or lentigo maligna without current 
evidence of disease

Adequately treated cervical carcinoma in situ without current evidence of disease
9.
Clinically significant cardiovascular disease including:

myocardial infarction within 6 months of screening

unstable or uncontrolled disease/condition related to or affecting cardiac function 
(eg, unstable angina, cardiac disease meeting New York Heart Association 
Class 3-4 definition, Attachment 4)

uncontrolled or symptomatic cardiac arrhythmias 

screening 12-lead ECG showing a baseline corrected QT interval (QTc) >470 msec
10.
Known chronic obstructive pulmonary disease (COPD) with a forced expiratory volume 
in 1 second (FEV1) <50% of predicted normal
11.
Known moderate or severe persistent asthma within the past 2 years (see Attachment 5), 
or uncontrolled asthma of any classification. Note that subjects who currently have 
controlled intermittent asthma or controlled mild persistent asthma are allowed to 
participate in the study.
12.
Uncontrolled active systemic infection requiring IV antibiotics
13.
Known history of human immunodeficiency virus (HIV) infection
14.
Active systemic hepatitis infection requiring treatment or other clinically active liver 
disease
15.
Females who are pregnant or are breastfeeding
16.
Any life-threatening illness, medical condition, or organ system dysfunction that, in the 
investigator’s opinion, could compromise the subject’s safety, or put the study outcomes 
at undue risk. 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 that 
could prevent, limit, or confound the protocol-specified assessments
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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.
A woman of childbearing potential must remain on a highly effective method of birth
control (see inclusion criteria) during the study. These restrictions apply for 3 months
after the end of dosing.
2.
A man who is sexually active with a woman of childbearing potential must use a highly 
effective adequate method of birth control and all men must also not donate sperm 
during the study. These restrictions apply for 3 months after the end of dosing.
3.
Section 8 details prestudy and concomitant therapies used in this study.
5.
TREATMENT ALLOCATION AND BLINDING
5.1.
Treatment Allocation
Central randomization will be implemented in this study using an IWRS. Randomization will be 
stratified based on transfusion burden (4 or >4 units) prior to randomization, and then assigned 
randomly on a 1:1 basis to receive either talacotuzumab or daratumumab. Transfusion burden is 
defined as the maximum number of RBC units transfused over any 8 consecutive weeks during 
the 16 weeks prior to randomization. Enrollment to the talacotuzumab arm was closed (refer to 
Section 3.1 Overview of Study Design for details) and the IWRS was modified to only permit 
enrollment to the daratumumab arm of the study.
6.
DOSAGE AND ADMINISTRATION
Talacotuzumab and daratumumab are the investigational medicinal products in this study and 
will be provided by the sponsor.
Subjects may receive treatment until disease progression, lack of response, unacceptable toxicity, 
withdrawal of consent, or study end. Continuation of treatment for subjects who are not deriving 
benefit, ie, after 6 months of treatment a subject has not achieved HI-E or RBC TI for ≥8 weeks, 
should be discussed with the sponsor.
Supportive Care
All subjects will receive supportive care (including transfusions if Hb ≤11 g/dL or myeloid 
growth factors) as needed per investigator discretion and according to local standard practices. 
Should an exceptional situation arise where it is deemed clinically necessary to give a transfusion 
for an Hb >11 g/dL, the sponsor should be notified.
6.1.
Dosing Schedule
Details of the procedures performed during the Treatment Phase are outlined in the Time and 
Events Schedule. Subjects should start study treatment within 72 hours after randomization. A 
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Clinical Protocol 56022473MDS2002 – Amendment 4
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Status: Approved, Date: 13 December 2018
window of ±3 days is allowed for Day 1 of each cycle visits to the clinic. Each cycle is 28 days. 
The first visit of a cycle should be 4 weeks after the start of the previous cycle. The start of each 
cycle may occur ±3 days of the scheduled day in order to accommodate the schedule of the site 
or subject. Day 1 of subsequent cycles should be adjusted accordingly to maintain the 28-day 
cycle duration
Study drug is to be administered as described in the Time and Events Schedules. 
Talacotuzumab 9
mg/kg will be administered on Days 1 and 15 for all cycles.
Daratumumab 16 mg/kg will be administered on Days 1, 8, 15, and 22 (+/- 24 hours) for Cycles 
1 and 2; on Days 1 and 15 (+/- 24 hours) for Cycles 3 to 6; and on Day 1 (+/- 24 hours) for all 
subsequent cycles. Cycles may be delayed due to drug-related toxicities (See Sections 6.2.3 and 
6.3.5). 
The follow-up of subjects in the study and study data collection will end either 1 year after the 
last subject is randomized or anytime the sponsor terminates the study. Subjects who are 
continuing to derive benefit from daratumumab treatment as assessed by their investigator may 
continue to receive daratumumab according to the protocol. During this period after study data 
collection has ended, only serious adverse events will be monitored and only entered into the 
company safety repository as described under Amendment 4 and in the Time and Events 
Schedule.
6.2.
Talacotuzumab
6.2.1.
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 180 minutes using an infusion pump. The talacotuzumab treatment will be 
administered per the dosing schedule described in Section 6.1. If an infusion-related reaction is 
observed during the administration of talacotuzumab, then follow the procedures described in 
Section 6.2.4. The sponsor may modify the infusion rates or the preinfusion medications 
prospectively based upon the information collected to date from this and other studies. 
Additional details for administration times and rates, as well as preinfusion medications, will be 
provided in the administration guidelines (study site investigational product and procedures 
manual).
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, 
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JNJ-56022473 (talacotuzumab) and JNJ-54767414 (daratumumab)
Clinical Protocol 56022473MDS2002 – Amendment 4
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Status: Approved, Date: 13 December 2018
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 Three Cycles: Initiate the IV infusion at a rate of 20 mL/hr. In the absence of any infusion-
related reaction during the first 30 minutes, increase the infusion rate to 40 mL/hr for 30 minutes.
If no infusion reaction is observed during this 30 minute period, increase the infusion rate by 40 
mL/hr increments 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.
Subsequent Cycles (after the first 3 cycles): If no infusion reaction observed in the first 3 
cycles, initiate the IV infusion at a rate of 40 mL/hr for 30 minutes. 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.
6.2.2.
Talacotuzumab: Premedication 
All subjects receiving talacotuzumab must receive premedication during the first 4 cycles, as 
outlined in Table 1. If no infusion-related reactions are seen during the first 4 cycles of 
talacotuzumab treatment, then premedication is optional for subsequent talacotuzumab
treatments. If an infusion-related reaction of any severity occurs in subsequent talacotuzumab
treatments, premedication must be reintroduced. 
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JNJ-56022473 (talacotuzumab) and JNJ-54767414 (daratumumab)
Clinical Protocol 56022473MDS2002 – Amendment 4
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Status: Approved, Date: 13 December 2018
Table 1:
Premedication for Subjects Receiving Talacotuzumab
Treatment Cycle
Infusion-
related 
Reaction
Mandatory Premedication
Optional Premedication
Cycle 1 - Cycle 4
Methylprednisolone (100 mg IV)a
1-2 hours prior to infusion
Dexamethasone (8 mg IV or PO)
approx. 12 and 3 hours prior to 
infusion
Leukotriene inhibitor 
(montelukast 10 mg PO, or 
equivalent) within 
1-2 hours prior to infusion
Acetaminophen (paracetamol) 
650 – 1000 mg IV or PO 
approx.1 hour prior to infusion
Antihistamine (diphenhydramine 
25 – 50 mg IV or PO)b
approx. 1 hour prior to infusion
Additional doses of corticosteroids 
prior to treatment with talacotuzumab 
may be given at the discretion of the 
investigator
Cycle 5 +
Subsequent 
cycles
If Prior Event:
Methylprednisolone (100 mg IV)a
1-2 hours predose
Dexamethasone (8 mg IV or PO)
approx. 12 and 3 hours prior to 
infusion
Leukotriene inhibitor 
(montelukast 10 mg PO, or 
equivalent) within 
1-2 hours prior to infusion
Acetaminophen (paracetamol)
650 – 1000 mg IV or PO
approx.1 hour prior to infusion
Antihistamine (diphenhydramine 
25 – 50 mg IV or PO)b
approx. 1 hour prior to infusion
Additional doses of corticosteroids 
prior to treatment with talacotuzumab 
may be given at the discretion of the 
investigator
No Prior Event 
for 2 
consecutive 
cycles:
Premedication may be modified 
per investigator discretion and 
after discussion with the sponsor
a.
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.
b.
Or similar sedating antihistamine per institutional standards; avoid the use of promethazine
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JNJ-56022473 (talacotuzumab) and JNJ-54767414 (daratumumab)
Clinical Protocol 56022473MDS2002 – Amendment 4
40
Status: Approved, Date: 13 December 2018
6.2.3.
Talacotuzumab Dosing Modifications
Refer to Section 6.2.4 for details on management of infusion-related reactions. 
Dose delay is the primary method for managing talacotuzumab-related toxicities. 
A dose delay should occur if any of the following criteria are met:

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 only be allowed to 
continue treatment if the investigator and sponsor believe it is in the best interest of the subject. 
However, this must be approved by the sponsor.
6.2.4.
Management of Talacotuzumab Hypersensitivity/Infusion-related
Reactions
Subjects should be carefully observed during infusions. It is recommended that subjects are 
monitored for at least 1 hour after the infusion has been completed.
Subjects who experience treatment-emergent adverse events during the IV infusion of 
talacotuzumab will be treated according to the investigator’s judgment and best clinical practice. 
It is suggested that standing orders are readily available so that timely treatment can be provided 
to patients who experience infusion-related reactions. The following guidelines are suggestions 
for how reactions may be managed:

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.

In the event of a life-threatening infusion-related reaction (which may include pulmonary or
cardiac events), or anaphylactic reaction, talacotuzumab should be permanently discontinued 
and no additional talacotuzumab should be administered to the subject. 
6.2.4.1.
Guidelines for the Interruption of Talacotuzumab Infusion due to 
Infusion-related Reaction
If an infusion-related reaction develops, then the infusion should be temporarily interrupted and 
the actions in Table 2 should be taken.
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JNJ-56022473 (talacotuzumab) and JNJ-54767414 (daratumumab)
Clinical Protocol 56022473MDS2002 – Amendment 4
41
Status: Approved, Date: 13 December 2018
Table 2:
Management of Talacotuzumab Infusion-related Reactions
Severity [per CTCAE 4.03]
Recommended action
Grade 1 or Grade 2

If the investigator assesses a TEAE to be related to the talacotuzumab, 
pause infusion

When the subject’s condition is stable, the infusion may be restarted at 
the investigator’s discretion. The infusion rate should be at half the 
previous rate

Subsequently, the infusion rate may be increased at the 
investigator’s discretion but should not exceed 150 mL/hr 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
Grade 3

For infusion-related TEAEs that are Grade 3, stop infusion

Observe subject carefully until resolution of the TEAE or until the 
severity 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 150 mL/hr at any time.

If the severity 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. 
Grade 4

For infusion-related TEAEs that are Grade 4, stop infusion

Discontinue study drug
6.3.
Daratumumab
6.3.1.
Dosing Schedule
Details of the procedures performed during the Treatment Phase are outlined in the Time and 
Events Schedules. Subjects should start study treatment within 72 hours after randomization. A 
window of ±3 days is allowed for Day 1 of each cycle visits to the clinic. Each cycle is 28 days. 
The first visit of a cycle should be 4 weeks after the start of the previous cycle. The start of each 
cycle may occur ±3 days of the scheduled day in order to accommodate the schedule of the site 
or subject. Day 1 of subsequent cycles should be adjusted accordingly to maintain the 28-day 
cycle duration. In Cycles 1 through 6, weekly or bi-weekly daratumumab infusions may be given 
within ±1 day of the scheduled day in order to accommodate the schedule of the site or subject.
6.3.2.
Preparation and Administration of Daratumumab
The infusion solution will be prepared as a 1,000-mL (first dose) or 500-mL (second and 
subsequent doses) dilution of daratumumab in sterile, pyrogen-free 0.9% NaCl. Preparation of 
infusion bags should be done on the day of the planned infusion. Daratumumab must be 
administered as an IV infusion given through a well-functioning IV catheter by using an infusion 
pump. The study drug must be filtered by using an inline filter (0.2 μM) during the infusion. 
Manuals with detailed descriptions for preparation and administration of daratumumab will be 
supplied to each pharmacy and site.
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JNJ-56022473 (talacotuzumab) and JNJ-54767414 (daratumumab)
Clinical Protocol 56022473MDS2002 – Amendment 4
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Status: Approved, Date: 13 December 2018
The daratumumab dose administered will be calculated based on the subject’s weight at Cycle 1 
Day 1 rounded to the nearest kilogram. The dose of daratumumab will remain constant 
throughout the study, unless the subject’s weight changes more than 10% from Cycle 1 Day 1. 
All infusions will be planned as outpatient visits. The daratumumab treatment will be 
administered per the dosing schedule described in Section 6.1.
The dilution volumes, initial infusion rates, and increment of infusion rates for the first, second, 
and subsequent doses in the absence of an infusion-related reaction >Grade 1 are provided 
in Table 3. The first infusion, with a volume of 1,000 mL, takes approximately 8 hours; the 
second and subsequent infusions, with volumes of 500 mL, take approximately 4 hours. The 
maximum infusion rate for all infusions is 200 mL/hour. The sponsor may modify the infusion 
rates or the preinfusion medications prospectively based upon the information collected to date 
from this and other studies. Additional details for administration times and rates, as well as
preinfusion medications, will be provided in the administration guidelines (study site 
investigational product and procedures manual).
Table 3:
Daratumumab Infusion Rates
Dilution 
Volume
Initial Infusion 
Rate (first hour)
Incremental Increases 
in Infusion Rate
Maximum 
Infusion Rate
First infusion
1,000 mL
50 mL/hour
50 mL/hour 
every hour
200 mL/hour
Second infusiona
500 mL
50 mL/hour
50 mL/hour 
every hour
200 mL/hour
Subsequent infusionsb
500 mL
100 mL/hour
50 mL/hour 
every hour
200 mL/hour
a.
Modified rates should only be used if the first infusion of daratumumab was well tolerated as defined by an absence of 
>Grade 1 infusion-related reactions during the first 3 hours.
b.
Modified rates should only be used if the first 2 infusions of daratumumab were well tolerated as defined by an absence of 
>Grade 1 infusion-related reactions during a final infusion rate of ≥100 mL/hr.
As noted in the Time and Events Schedule, vital signs should be monitored extensively on 
Cycle 1 Day 1 before, during, and after the first infusion of daratumumab. For all other infusions, 
vital signs should be measured before the start of the infusion and at the end of the infusion. If a 
subject experiences any significant medical event, then the investigator should assess whether 
the subject should stay overnight for observation. If the subject has not experienced a significant 
medical event but is hospitalized overnight only for observation, then the hospitalization should 
not be reported as a serious adverse event.
6.3.3.
Daratumumab: Premedication
All subjects receiving daratumumab must receive premedication as outlined in Table 4. On 
daratumumab infusion days, subjects will receive the following medications up to 3 hours before 
the dose of daratumumab.
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JNJ-56022473 (talacotuzumab) and JNJ-54767414 (daratumumab)
Clinical Protocol 56022473MDS2002 – Amendment 4
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Status: Approved, Date: 13 December 2018
Table 4:
Premedication for Subjects Receiving Daratumumab
Treatment Cycle
Mandatory Premedication
Optional Premedication
Strongly recommended by Sponsor
Cycle 1
Methylprednisolone (100 mg IV
or PO) a
within 3 hours prior to infusion
Acetaminophen (paracetamol)
650 – 1000 mg IV or PO
within 3 hours prior to infusion
Antihistamine (diphenhydramine 
25 – 50 mg IV or PO)b
within 3 hours prior to infusion
Leukotriene inhibitor (montelukast 
10 mg PO, or equivalent)
within 3 hours prior to infusion
Additional doses of steroids prior to 
treatment with daratumumab may be 
given at the discretion of the 
investigator.
Cycle 2 +
Subsequent 
cycles
Methylprednisolone (60-100 mg 
IV or PO)a
within 3 hours prior to infusion
Acetaminophen (paracetamol)
650 – 1000 mg IV or PO
within 3 hours prior to infusion
Antihistamine (diphenhydramine 
25 – 50 mg IV or PO)b
within 3 hours prior to infusion
Leukotriene inhibitor (montelukast 
10 mg PO, or equivalent)
within 3 hours prior to infusion
Additional doses of steroids prior to 
treatment with daratumumab may be 
given at the discretion of the 
investigator.
a. Substitutions for methylprednisolone are allowed, please refer to Attachment 7 for conversion table. Following 
the second infusion, the dose of methylprednisolone or equivalent can be reduced to 60 mg
b. Or similar sedating antihistamine per institutional standards; avoid the use of promethazine (see Attachment 8
for list of antihistamines that may be used)
If necessary, all PO preinfusion medications may be administered outside of the clinic on the day 
of the infusion, provided they are taken within 3 hours before the infusion.
6.3.3.1.
Daratumumab: Postinfusion Medication
Postinfusion medication should be administered to reduce the risk of delayed infusion reactions 
in all subjects who receive daratumumab:

Oral corticosteroid (20 mg methylprednisolone or equivalent) on the first and second day 
after all infusions (if no infusion-related reaction is observed after the first 3 infusions, then 
postinfusion corticosteroids should be administered per investigator discretion)
For subjects with a higher risk of respiratory complications (eg, subjects with mild asthma or 
subjects with COPD) the following postinfusion medications should be considered:

Antihistamine (diphenhydramine or equivalent) 

Leukotriene inhibitor (montelukast or equivalent)

Short-acting β2 adrenergic receptor agonist such as salbutamol aerosol 

Control medications for lung disease (eg, inhaled corticosteroids ± long-acting β2 adrenergic 
receptor agonists for subjects with asthma; long-acting bronchodilators such as tiotropium or 
salmeterol ± inhaled corticosteroids for subjects with COPD)
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JNJ-56022473 (talacotuzumab) and JNJ-54767414 (daratumumab)
Clinical Protocol 56022473MDS2002 – Amendment 4
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Status: Approved, Date: 13 December 2018
In addition, these at-risk subjects may be hospitalized for monitoring for up to 2 nights after an 
infusion. If subjects are hospitalized, then their spirometry test (FEV1) should be performed 
before discharge. If these subjects are not hospitalized, then a follow-up telephone call should be 
made to monitor their condition within 48 hours after all infusions. If no infusion-related reaction 
has occurred, the follow-up telephone call 48 hours after the infusion is not required. If the 
subject has not experienced a significant medical event but is hospitalized overnight only for 
observation, then the hospitalization should not be reported as a serious adverse event.
Investigators may prescribe bronchodilators, H1-antihistamines, and corticosteroids that are 
deemed necessary to provide adequate supportive care in the event a bronchospasm occurs after 
subjects are released from the hospital/clinic. If an at-risk subject experiences no major infusion-
related reactions, then these postinfusion medications may be waived after 4 doses at the 
investigator’s discretion. 
Any postinfusion medication will be administered after the infusion has completed.
Refer to Section 6.3.6 for additional details on the management of infusion reactions. 
6.3.4.
Daratumumab Dosing Delay and Modification
Dose modification of daratumumab is not permitted. Dose delay is the primary method for 
managing daratumumab-related toxicities.
6.3.5.
Daratumumab Toxicity Management
Cycle Delays
On the first day of each new treatment cycle and before each daratumumab dose, the subject will 
be evaluated by the treating physician for possible toxicities that may have occurred after the 
previous dose(s). Toxicities are to be assessed according to NCI-CTCAE, Version 4.03. Dose 
delays will be based on the toxicity experienced during the previous infusion or newly 
encountered on Day 1 of a new cycle. 
To allow for recovery from toxicity, the study treatment must be held if any of the following 
criteria are met, regardless of relationship to daratumumab.

Grade 4 hematologic toxicity, except for Grade 4 lymphopenia

Grade 3 or thrombocytopenia with (any grade) bleeding 

Febrile neutropenia

Neutropenia with infection, of any grade

Grade 3 or higher non-hematologic toxicities with the following exceptions: 

Grade 3 nausea that responds to antiemetic treatment within 7 days

Grade 3 vomiting that responds to antiemetic treatment within 7 days

Grade 3 diarrhea that responds to antidiarrheal treatment within 7 days
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JNJ-56022473 (talacotuzumab) and JNJ-54767414 (daratumumab)
Clinical Protocol 56022473MDS2002 – Amendment 4
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Status: Approved, Date: 13 December 2018

Grade 3 fatigue that was present at baseline or that lasts for <7 days after the last 
administration of daratumumab

Grade 3 asthenia that was present at baseline or that lasts for <7 days after the last 
administration of daratumumab
Administration of daratumumab may be restarted upon recovery from toxicity to Grade 2 or 
baseline, with the exception of Grade 2 laryngeal edema or Grade 2 bronchospasm, which must 
be fully recovered. If daratumumab administration does not commence within the prespecified 
window (Table 5) of the scheduled administration date, then the dose will be considered a missed 
dose. Administration may resume at the next planned dosing date. A missed dose will not be 
made up.
Table 5:
Daratumumab-Related Toxicity Management
Cycles 
Frequency 
Dose Held 
Dosing Re-start 
1 and 2 
Weekly (q1wk) 
>3 days 
next planned weekly dosing date 
3 to 6 
Biweekly (q2wks)` 
>1 week 
next planned biweekly dosing date 
7+ 
Every 4 weeks (q4wks) 
>2 weeks 
next planned every 4 weeks dosing date 
Doses of daratumumab may be delayed up to 4 weeks (Cycle 1 to Cycle 6) or up to 6 weeks 
(Cycle 7 and beyond). If Day 1 of a cycle is delayed, Day 1 of subsequent cycles should be 
adjusted accordingly to maintain the 28-day cycle duration. However, if a within-cycle dose is 
delayed, then the dates of the subsequent within-cycle doses should not be adjusted. Any adverse 
event deemed to be related to daratumumab that requires a dose hold of more than 4 weeks 
(Cycle 1 to Cycle 6) or more than 6 weeks (Cycle 7 and beyond) will result in permanent 
discontinuation of daratumumab. If a dose delay occurs, then pharmacokinetic and 
pharmacodynamic assessments should be performed on the actual administration day of 
daratumumab, not on the original scheduled administration day.
A daratumumab dose that is held for more than the permitted time (Table 5) from the per-
protocol administration date for any reason other than toxicities suspected to be related to 
daratumumab should be brought to the attention of the sponsor at the earliest possible time. 
Subjects whose dose was delayed for more than 4 weeks (Cycle 1 to Cycle 6) or more than 
6 weeks (Cycle 7 and beyond) should have study treatment discontinued, unless, upon 
consultation with the sponsor and the review of safety and efficacy, continuation is agreed upon.
6.3.6.
Guidelines for Daratumumab Infusion-Related Reactions
Subjects should be carefully observed during infusions.
Trained study staff at the clinic should be prepared to intervene in case of any infusion reactions,
and resources necessary for resuscitation must be available. Attention to staffing should be 
considered when multiple subjects will be dosed at the same time.
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Clinical Protocol 56022473MDS2002 – Amendment 4
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Status: Approved, Date: 13 December 2018
For infusion reactions of any grade/severity, immediately interrupt the daratumumab infusion 
and manage symptoms. Management of infusion reactions may further require reduction in the 
rate of infusion, or treatment discontinuation of daratumumab (see Table 6).
Table 6:
Management of Daratumumab Infusion-related Reactions
Severity [per CTCAE 4.03]
Recommended action
Grade 1 or Grade 2

Interrupt infusion and manage symptoms

Once reaction symptoms resolve, resume the infusion at no more than 
half the rate at which the reaction occurred.

If patient does not experience any further reaction symptoms, infusion 
rate escalation may resume at increments and intervals as appropriate as 
outlined in Table 3.
Grade 3

Interrupt infusion and manage symptoms

Once reaction symptoms resolve, consider restarting the infusion at no 
more than half the rate at which the reaction occurred.

If the subject does not experience additional symptoms, resume infusion 
rate escalation at increments and intervals as outlined in Table 3.

Repeat the procedure above in the event of recurrence of Grade 3 
symptoms.

Permanently discontinue daratumumab upon the third occurrence of a 
Grade 3 or greater infusion-related reaction.
Grade 4

Permanently discontinue daratumumab treatment and manage 
symptoms
7.
TREATMENT COMPLIANCE
Talacotuzumab and daratumumab will be administered by qualified site staff, and each 
administration will be recorded in the eCRF. Following Amendment 4 and either 1 year after the 
last subject is randomized or anytime the sponsor terminates the study (whichever occurs first), 
the eCRFs will be closed.
8.
PRESTUDY AND CONCOMITANT THERAPY
8.1.
Prestudy Therapy
Prestudy MDS therapies administered up to 30 days before first dose of study drug must be 
recorded at screening. Transfusions up to 16 weeks prior to randomization also must be recorded 
at screening.
8.2.
Concomitant Medications
Subjects should receive supportive care as clinically indicated. This includes blood product 
support (blood transfusions and use of granulocyte colony stimulating growth factors), anti-
diarrheals, anti-emetics, analgesics, anti-infective treatment, and treatment of other medical 
conditions.
The following medications are prohibited during the study: ESA therapy, chemotherapy 
(anticancer), immunomodulatory drugs, immunotherapy, experimental therapy, and radiotherapy. 
Systemic use of corticosteroids in excess of prednisone 20 mg/day or its equivalent for more than 
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JNJ-56022473 (talacotuzumab) and JNJ-54767414 (daratumumab)
Clinical Protocol 56022473MDS2002 – Amendment 4
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Status: Approved, Date: 13 December 2018
10 days is prohibited unless reviewed and approved by the sponsor. Long-term, chronic use of 
corticosteroids at any dose should also be reviewed and approved by the sponsor. Corticosteroids 
used as premedication are permitted. The sponsor must be notified in advance (or as soon as 
possible thereafter) of any instances in which prohibited therapies are administered.
All concomitant therapies (prescription or over-the-counter medications, including vaccines, 
vitamins, herbal supplements), including growth factors, transfusions, anti-infectives 
(antibacterials, antivirals, and antimycotics), corticosteroids, anti-arrhythmics and other cardiac 
supportive therapy, anti-histamines, anti-emetics, anti-diarrheals, and anti-coagulants must be 
recorded throughout the study beginning with signing of the ICF to 30 days after the end of 
dosing or until the start of subsequent anticancer treatment, if earlier. Modification of an 
effective preexisting therapy should not be made for the explicit purpose of entering a subject 
into the study. Concomitant therapies should be recorded beyond 30 days after the last dose of 
study treatment only in conjunction with new or worsening adverse events or serious adverse 
events that meet the criteria outlined in Section 12.3.2, Serious Adverse Events. The follow-up of 
subjects in the study and study data collection will end either 1 year after the last subject is 
randomized or anytime the sponsor terminates the study. Subjects who are continuing to derive 
benefit from daratumumab treatment as assessed by their investigator may continue to receive 
daratumumab according to the protocol. During this period after study data collection has ended, 
only serious adverse events will be monitored and only entered into the company safety 
repository as described under Amendment 4 and in the Time and Events Schedule.
9.
STUDY EVALUATIONS
The follow-up of subjects in the study and study data collection will end either 1 year after the 
last subject is randomized or anytime the sponsor terminates the study. Subjects who are 
continuing to derive benefit from daratumumab treatment as assessed by their investigator may 
continue to receive daratumumab according to the protocol. During this period after study data 
collection has ended, only serious adverse events will be monitored and only entered into the 
company safety repository as described under Amendment 4 and in the Time and Events 
Schedule.
9.1.
Study Procedures
9.1.1.
Overview
The Time and Events Schedule summarize the frequency and timing of efficacy, PK, 
immunogenicity, biomarker, and safety measurements applicable to this study.
If multiple assessments are scheduled for the same timepoint, it is recommended that procedures 
be performed in the following sequence: ECG, vital signs/physical exam, bone marrow 
assessments/clinical laboratory assessments/peripheral blood sampling for central lab 
submission, response assessment and other subject review data collection, study drug 
administration. Blood collections for PK assessments should be kept as close to the specified 
time as possible. Other measurements may be done earlier than specified timepoints if needed. 
Actual dates and times of assessments will be recorded in the source documentation and eCRF.
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JNJ-56022473 (talacotuzumab) and JNJ-54767414 (daratumumab)
Clinical Protocol 56022473MDS2002 – Amendment 4
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The total blood volume to be collected from each subject will be approximately 330 mL for 
subjects completing 8 cycles. Repeat or unscheduled samples may be taken for safety reasons or 
for technical issues with the samples.
An indwelling intravenous cannula may be used for blood sample collection. If a mandarin 
(obturator) is used, blood loss due to discard is not expected.
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. Repeat or unscheduled samples may be taken for 
safety reasons or technical issues with the samples.
9.1.2.
Screening Phase
Screening procedures will be performed within 28 days before randomization, as described in the 
Time and Events Schedules.
9.1.3.
Open-Label Treatment Phase
The Treatment Phase will begin on Day 1 of Cycle 1 and will continue until discontinuation of 
study drug.
Treatment Phase
A treatment cycle is defined as 28 days. Details of the procedures performed during the 
Treatment Phase are outlined in the Time and Events Schedules. Subjects will be monitored for 
adverse events, laboratory abnormalities, hematologic improvement, reduction in transfusion 
requirement, and clinical response. All Treatment Phase visit procedures are to be performed
predose, unless otherwise specified, and laboratory test results must be reviewed prior to 
administering study drug. Adverse events and changes to concomitant medications will be 
recorded. The investigator will assess subject response to therapy using the efficacy 
measurements and disease response criteria according to the IWG 2006 (Attachment 6). If a 
subject develops features of response (eg, recovery from all cytopenias) and CR or PR are 
clinically suspected at a time not specified on the Time and Events Schedules, then all required 
disease assessments should be performed. In order to confirm a CR or PR per IWG 2006 criteria, 
all disease assessments including bone marrow aspirate should be repeated 4-8 weeks from time 
of CR or PR. If progressive disease is diagnosed, or the subject discontinues study drug for other 
reasons, then the subject will complete the End-of-Treatment Visit within 30 days after the last 
dose of study drug, and enter the Posttreatment Follow-up Phase. 
End of Treatment/Early Withdrawal
An End-of-Treatment Visit will be scheduled within 30 days after the last dose of study drug for 
all subjects, including those who discontinued study drug for any reason, except for those lost to 
follow-up, death, or withdrawal of consent for study participation. Subjects who discontinued 
study drug due to disease progression, adverse event, lack of response, or other reasons and enter 
the Posttreatment Follow-up Phase should have the End-of-Treatment Visit completed before 
starting any subsequent MDS treatment. If a subject is unable to return to the site for the End-of-
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Treatment Visit, then the subject should be contacted to collect adverse events that occur within 
30 days after the last dose of the last study drug. Additional information on reporting adverse 
events may be found in Section 12.3.1. 
9.1.4.
Posttreatment Phase (Follow-Up)
The Posttreatment Follow-up Phase is the time between the End-of-Treatment Visit and the end 
of study participation or end of study. Subjects who are continuing to derive benefit from 
treatment as assessed by their investigator will continue to receive treatment and be monitored 
for safety by the sponsor.
During this phase, contact will be made as detailed in the Time and Events Schedules every 
16 weeks. 
If the information on survival status and subsequent therapy is obtained via telephone contact, 
then written documentation of the communication must be available for 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. Where allowed by local law, public records may be used to document 
death for the purpose of obtaining survival status.
9.1.5.
Clinical Cutoff and End of Study
The clinical cutoff for the purpose of primary endpoint analysis is 6 months after randomization 
of the last subject. 
The end of study data collection is defined as either 1 year after the last subject is randomized or 
anytime the sponsor terminates the study. At that time, study follow-up of subjects and study 
data collection will end. Subjects who are continuing to derive benefit from daratumumab 
treatment as assessed by their investigator may continue to receive daratumumab according to 
the protocol. During this period after study data collection has ended, only serious adverse events 
will be monitored and only entered into the company safety repository as described under 
Amendment 4 and in the Time and Events Schedule.
9.2.
Efficacy Evaluations
Efficacy evaluations will include transfusion data, blood count assessments, and bone marrow 
biopsy and aspirate for disease assessment.
9.2.1.
Transfusions
Data to be collected at each visit include the number of units and type of blood products 
transfused and the pre-transfusion hemoglobin and platelet count. Transfusion data will be 
collected during the treatment and posttreatment periods as specified in the Time and Event 
Schedules. Transfusion is monitored at each visit for infusion (every 4-week cycle), at each 
disease evaluation visit, and at all unscheduled visits during treatment. During the posttreatment 
phase, transfusion data will be collected every 4 to 6 weeks. Specific operational monitoring will 
be implemented to seek transfusion information from other documented sources. Specific and 
continuous medical review will be implemented to identify any sudden but unsustained increase 
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of Hb values and to query whether transfusion has occurred. Red blood cell transfusions may be 
administered based on hemoglobin level (sponsor should be notified for Hb >11 g/dL), 
investigator’s assessment of the subject’s clinical signs and symptoms, and local clinical 
practice.
As the volume of 1 unit of RBC transfusion may vary regionally, 1 unit is defined as the amount 
that is intended to raise Hb by approximately 1 g/dL in an adult patient (ie, 1 standard pRBC unit 
or equivalent). The total number of RBC units required over consecutive 8-week time periods 
will be calculated to identify subjects who achieve RBC TI or transfusion reduction.
9.2.2.
Hemoglobin Assessment
Hemoglobin levels will be measured weekly during the first 8 weeks, at the start of each cycle, 
and as clinically needed.
For a given subject, the same local laboratory should be used for each hematology assessment 
throughout the study, to the extent possible. Hematologic improvement-erythroid response 
(HI-E) is defined as a Hb rise of at least 1.5 g/dL above baseline, measured 28 days or more 
following the last RBC transfusion or reduction of at least 4 units of RBC transfusions/8 weeks 
compared with the 8 weeks prior to start of treatment (criterion adapted from IWG 2006).
9.2.3.
Clinical Bone Marrow Assesment 
Bone marrow aspirate and biopsy must be performed during screening or up to 12 weeks before 
randomization. Follow-up bone marrow exams will be performed every 24 weeks, at the time of 
PR and CR (as indicated by peripheral blood counts), at disease progression, and at end-of-
treatment. Following the bone marrow exams at PR and CR, bone marrow sampling should be 
repeated 4 to 8 weeks later. Bone marrow sampling does not have to be repeated at the End-of-
Treatment visit if the prior assessment occurred within 8 weeks. 
9.3.
Pharmacokinetics and Immunogenicity
9.3.1.
Sample Collection and Handling
For all subjects in the talacotuzumab or daratumumab treatment groups, PK samples to 
determine serum concentration of talacotuzumab or daratumumab will be obtained according to 
the Time and Events Schedules. 
Venous blood samples (5 mL per sample) will be collected to determine serum concentration of 
talacotuzumab or daratumumab. The serum will be divided into 3 aliquots: 1 aliquot for PK 
analyses for talacotuzumab or daratumumab, 1 aliquot for anti-talacotuzumab or anti-
daratumumab antibodies assessment (when appropriate), and 1 aliquot as a backup. Samples 
collected for determining serum concentrations of talacotuzumab or daratumumab in this study 
may be used to 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. In addition, samples will be collected at the time of an infusion-related reaction. Genetic 
analyses will not be performed on these samples. 
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The exact dates and times of blood sampling must be recorded. Refer to the laboratory manual or 
equivalent document for sample collection 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
Pharmacokinetics/Immunogenicity
Serum concentrations of talacotuzumab or daratumumab and detection and characterization of 
anti-talacotuzumab or anti-daratumumab antibodies will be performed using validated 
immunoassay methods by or under the supervision of the sponsor. 
9.3.3.
Pharmacokinetic Parameters 
Serum concentrations of talacotuzumab or daratumumab will be measured and resulting 
concentration over time data will be summarized by treatment. Population PK models may be 
explored and developed if data are sufficient from this study and may include data from other 
studies. 
The PK parameters are defined as:
If sufficient data are available, then pharmacokinetic/pharmacodynamics (PK/PD) modeling may 
be performed, including exploring the relationship between serum concentrations of 
talacotuzumab or daratumumab and biomarkers, PD markers, and endpoints of clinical efficacy,
and may include data from other studies. If these analyses are performed, the details and results 
will be presented in a separate report. 
9.3.4.
Immunogenicity Assessments (Antibodies to Talacotuzumab and 
Daratumumab)
Serum from venous blood samples collected from all subjects will be assessed for the generation 
of antibodies to talacotuzumab or daratumumab (immunogenicity) according to Time and Events 
Schedules. Talacotuzumab
or daratumumab concentration will be evaluated at all 
immunogenicity time points to ensure appropriate interpretation of immunogenicity data. When 
both serum concentration and immunogenicity analyses are specified for a particular timepoint, 
they are 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.
Additionally, blood samples to assess immunogenicity of either talacotuzumab or daratumumab 
should be collected at the final visit for subjects who discontinue treatment. Subjects who 
discontinue treatment will also be asked to return for immunogenicity evaluation during the 
Follow-up Phase.
Cmax
Maximum observed serum concentration
Cmin
Minimum observed serum concentration
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Serum samples will be screened for antibodies binding to talacotuzumab or daratumumab 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. 
A blood sample should be drawn, if possible, for determination of antibodies to talacotuzumab 
any time an infusion-related reaction is observed or reported during the study. 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 or daratumumab 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.
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 Schedules and will be analyzed at a central laboratory.
Assessment of Pharmacodynamic Markers (Basophils and pDC)
Previous clinical studies with talacotuzumab in patients with AML demonstrated that pDCs and 
basophils are reliable cellular PD markers for talacotuzumab activity, and that NK cells and 
monocytes are relatively stable in number from baseline during the treatment. Changes of cell 
numbers of cellular biomarkers (basophils, pDC, monocytes, eosinophils and NK cells) will be 
enumerated in the peripheral blood by flow cytometry.
Determination of CD123 and CD38 Expression 
CD123 expression in various cell populations at baseline (bone marrow aspirate) will be 
determined by flow cytometry of MDSCs and MDS blasts, and CD38 expression will be 
analyzed in MDSCs and Tregs. CD123 expression of various cell populations listed above will 
also be analyzed in the peripheral blood and bone marrow throughout the study (see Time and 
Events Schedules). The diagnostic block for each patient will be requested to evaluate CD123 
expression by immunohistochemistry (IHC) at a central laboratory. Upon disease progression, 
MDSCs (CD123 and CD38), blasts (CD123), and Tregs (CD38) will be evaluated.
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Mutation Analysis
Some somatic mutations are known to confer a poor prognosis and resistance to certain forms of 
therapy. Therefore, baseline mutation status will be evaluated in the baseline bone marrow 
biopsy to explore potential inter-individual variability in clinical outcomes or identification of 
population subgroups that respond differently to either treatment.
Immunophenotyping and Calculating Baseline Frequencies
Whole blood will be utilized for immunophenotyping (performed by flow cytometry or mass 
cytometry/CyTOF), which includes analyses of NK cells, MDSCs, MDS blasts, and T cells as 
well as other potential immune cell subpopulations and their absolute numbers. The NK cells 
(CD45+CD56+CD3-) and their activation markers (CD16, CD314, and CD335) will be assessed 
by flow cytometry because the primary mechanism of action of talacotuzumab is antibody-
dependent cellular cytotoxicity (ADCC) through NK cells.
Proteomic Analysis
Peripheral blood plasma will be analyzed for protein expression associated with disease 
progression or response to talacotuzumab or daratumumab.
9.5.
Safety Evaluations
All subjects who receive at least one dose of talacotuzumab or daratumumab will be considered 
evaluable for safety. Any clinically relevant changes occurring during the study must be recorded 
in the Adverse Event section of the eCRF. Any serious adverse events 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. A sponsor safety review committee will review all the safety data on 
a quarterly basis, or ad hoc, as needed (see Section 11.9).
The study will include the following evaluations of safety and tolerability according to the time 
points provided in the Time and Events Schedules:
Adverse Events
Adverse events (AEs) will be reported by the subject (or, when appropriate, by a caregiver, 
surrogate, or the subject's legally acceptable representative) for the duration of the study (ie, from 
the time of signing ICF until 30 days after the end of dosing or until the start of subsequent 
anticancer treatment, if earlier). Adverse events will be reported and graded according to the 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), 
Version 4.03. Adverse events will be followed by the investigator as specified in Section 12, 
Adverse Event Reporting.
The follow-up of subjects in the study and study data collection will end either 1 year after the 
last subject is randomized or anytime the sponsor terminates the study. Subjects who are 
continuing to derive benefit from daratumumab treatment after study data collection ends as 
assessed by their investigator may continue to receive daratumumab according to the protocol. 
During this period after study data collection has ended, only serious adverse events will be 
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monitored and only entered into the company safety repository as described under Amendment 4 
and in the Time and Events Schedules.
Clinical Laboratory Tests 
Required laboratory tests must be performed within 48 hours of the scheduled visit. For Cycle 1 
Day 1 only, clinical laboratory tests do not need to be repeated if the Screening tests were 
performed within 5 days of the first dose of study treatment.
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. 
For example, laboratory abnormalities leading to an action regarding any study treatment (dose 
reduction, temporary stop, delay of the start of a cycle or permanent stop) or the start of 
concomitant therapy should be reported. For each laboratory abnormality reported as an adverse 
event, the following laboratory values should be reported in the laboratory section of the eCRF: 
the value indicative of the onset of each toxicity grade; the most abnormal value observed during 
the adverse event, and the value supporting recovery to Grade ≤1 or to baseline values.
The following tests will be performed by the local laboratory at the timepoints shown in the 
Time and Events Schedules:

Hematology: hemoglobin, platelet count, white blood cell count, manual absolute peripheral 
blast count, absolute neutrophil count (ANC)

Serum Chemistry: Creatinine, total bilirubin (with fractionation if abnormal), ALT, AST, 
alkaline phosphatase (ALP), lactate dehydrogenase, albumin, serum EPO, serum ferritin,
and transferrin saturation

Serum -hCG or urine pregnancy testing for women of childbearing potential only 
(screening only) or if clinically indicated or required by local regulations

Serology (HIV antibody, hepatitis B surface antigen [HBsAg], and hepatitis C virus 
antibody)
Electrocardiogram (ECG) 
A 12-lead electrocardiogram will be performed in all subjects during Screening and on Day 1 of 
Cycle 1. 
During the collection of ECG, 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 timepoint as ECG recording, the procedures 
should be performed in the following order: ECG(s), vital signs, blood draw.
ECOG Performance Status
The ECOG performance status scale will be used to grade changes in the subject’s activities of 
daily living.
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Vital Signs 
Pulse and blood pressure will be recorded, preferably while the subject is seated, at the time 
points specified in the Time and Events Schedules. Vital signs that are considered to be clinically 
relevant by the investigator are to be documented as adverse events.
Physical Examination 
Screening physical examination should include body weight, height, and the evaluation of head, 
eye, ear, nose, and throat; cardiovascular, dermatological, musculoskeletal, respiratory, 
gastrointestinal, and neurological systems. Only a limited symptom-directed physical 
examination and weight assessment is required on Day 1 of all cycles after baseline. New or
worsened abnormalities should be recorded as adverse events if appropriate.
9.5.1.
Indirect Antiglobulin Test (IAT)
Blood Type, Rh, and IAT should be done before the first dose of daratumumab. Subject RBC 
phenotyping (standard or extended) is an alternative option to the IAT test, if locally required. 
Either method must be completed prior to first daratumumab infusion.
Daratumumab interferes with the Indirect Antiglobulin Test (IAT), which is a routine pre-
transfusion test performed to identify a patient’s antibodies to minor antigens so that suitable 
donor blood can be given for transfusion. Daratumumab does not interfere with ABO/RhD 
typing. CD38 is expressed at very low levels on erythrocytes. Daratumumab binds to the CD38 
on erythrocytes, which results in a positive IAT (Indirect Coombs Test). This positive result 
masks the detection of antibodies to minor antigens and may prevent or delay blood banks from 
issuing donor blood for transfusion. This effect occurs during daratumumab treatment and for up 
to 6 months after treatment ends. Subjects will receive a patient identification wallet card for the 
study that includes the blood profile (ABO, Rh, and IAT or phenotyping) determined before the 
first infusion of daratumumab along with information on the IAT interference for healthcare 
providers/blood banks. Subjects are to carry this card throughout the treatment period and for at 
least 6 months after treatment ends. Blood banks can eliminate the daratumumab interference 
with IAT by treating reagent RBCs with dithiothreitol (DTT).1
Possible methods for blood banks to provide safe RBCs for transfusion to subjects receiving 
daratumumab include:
a) Providing ABO/RhD compatible, phenotypically (standard or extended phenotyping) or 
genotypically matched units
b) Providing ABO/RhD compatible, K-negative units after ruling out or identifying 
alloantibodies using DTT-treated reagent RBCs
Uncrossmatched, ABO/RhD compatible RBC units should be administered if transfusion is 
needed emergently as per local blood bank practice.
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Despite daratumumab binding to CD38 on erythrocytes, no indication of clinically significant 
hemolysis has been observed in daratumumab studies. For additional details, refer to the 
daratumumab Investigator’s Brochure.12
9.5.2.
Prophylaxis for Herpes Zoster Reactivation
Prophylaxis for herpes zoster reactivation is recommended during the Treatment Phase for 
subjects enrolled in the daratumumab arm, as per institutional guidelines.
9.6.
Sample Collection and Handling
The actual dates and times of sample collection must be recorded in the eCRF or laboratory 
requisition form. Refer to the Time and Events Schedules for the timing and frequency of all 
sample collections. Instructions for the collection, handling, storage, and shipment of samples are 
found in the laboratory manual that will be provided. 
10.
SUBJECT COMPLETION/DISCONTINUATION OF STUDY TREATMENT/ 
WITHDRAWAL FROM THE STUDY
10.1.
Completion
A subject will be considered to have completed the study if he or she has died or has been lost to 
follow-up. All other subjects will be followed until the end of the study. The end of study data 
collection is defined as either 1 year after the last subject is randomized or anytime the sponsor 
terminates the study. At that time, study follow-up of subjects and study data collection will end. 
Subjects who are continuing to derive benefit from daratumumab treatment as assessed by their 
investigator may continue to receive daratumumab according to the protocol. During this period 
after study data collection has ended, only serious adverse events will be monitored and only 
entered into the company safety repository as described under Amendment 4 and in the Time and 
Events Schedule.
10.2.
Discontinuation of Study Treatment/Withdrawal from the Study
If a subject’s study drug must be discontinued, this will not result in automatic withdrawal of the 
subject from the study.
Discontinuation of Study Treatment
A subject's study treatment must be discontinued if:

The investigator believes that for safety reasons (eg, adverse event) it is in the best interest 
of the subject to discontinue study treatment

The subject becomes pregnant 

The subject experiences disease progression or relapse

The subject refuses further treatment

A serious protocol violation has occurred, as determined by the principal investigator or the 
sponsor
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End-of-treatment and posttreatment follow-up assessments should be obtained. The reason(s) a 
subject discontinues treatment will be recorded on the eCRF.
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 sponsor discontinues 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.
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 before the end of the Treatment Phase, end-of-treatment and 
posttreatment follow-up assessments should be obtained, unless the subject withdraws consent.
10.3.
Withdrawal From the Use of Research Samples
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 (SAP). 
11.1.
Subject Information
Efficacy and safety analyses will be performed using the Treated Population, which will include 
all subjects who received at least 1 dose of study drug.
The PK/PD evaluable population will consist of all subjects who received at least 1 dose of study 
drug and had at least 1 sample collected during treatment to determine the drug concentration or 
PD biomarker response. Continuous variables will be summarized using descriptive statistics 
such as mean, median, standard deviation, 25th and 75th percentiles, and range. Categorical 
variables will be summarized using frequency tables. For time-to-event variables, the Kaplan-
Meier method will be used for descriptive summaries.
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11.2.
Sample Size Determination
On the basis of historical data, the TI rate with treatment of best supportive care is expected to be 
approximately 2.5% in subjects with low or intermediate-1 risk MDS.17 The primary objective is 
to evaluate the likelihood that treatment with talacotuzumab or daratumumab can result in a true 
TI rate ≥30%. A true TI rate ≤15% (6 times of the TI rate of best supportive care) will be 
considered as of no clinical interest in the context of this Phase 2 study. The number of subjects 
to be randomized into each arm will be 30, with which the lower boundary of the 2-sided 80% 
credible interval will exceed 15% if ≥8 (26.7%) subjects achieve TI. This sample size 
determination utilizes a Bayesian approach with Beta(0.5, 0.5) as the prior distribution and 
Beta(0.5+m, 0.5+30-m) as the posterior distribution for the true TI rate, where m is the observed 
number of subjects who achieve TI.
11.3.
Efficacy Analyses 
Primary Endpoint
The primary efficacy endpoint is RBC TI, lasting for at least 8 weeks.
There is no statistical hypothesis testing and no formal statistical comparison between the 
2 arms.
Based on the observed number of subjects achieving TI (number of TIs), a Bayesian approach 
will be used to determine if the outcome of each treatment arm is “meeting” or “not meeting” the 
primary objective, or statistically “inconclusive.” This statistical assessment will be used to guide 
decision making for further development of either or both compounds. The evaluation will be 
performed against the target value (TV) of 30% and the minimum acceptable value (MAV) 15% 
for the TI rate. The TV of 30% is defined according to study primary objective and is deemed 
clinically meaningful. A TI rate below 15%, the MAV, will be of no clinical interest. TI rates 
between MAV and TV will be considered modest, which will define a statistically inconclusive 
outcome. Operating characteristics (false positive and false negative error rates) of the statistical 
criteria are calculated using a Bayesian approach with Beta(0.5, 0.5) as the prior distribution and 
Beta(0.5+m, 0.5+30-m) as the posterior distribution of the true TI rate, where m is the observed 
number of TIs. 
The TI rate point-estimate and corresponding 2-sided 80% credible interval (CI) will also be 
summarized for each treatment arm.
The above statistical inferences are summarized in the Table 7.
The lower boundary of the 2-sided 80% credible interval will exceed 15% (the MAV) if the 
observed number of TI is ≥8. If number of TIs is ≥13, then the outcome will be considered 
highly desirable as the lower boundary of the credible interval will exceed 30% (the TV). If the 
number of TIs is ≤5, then this will be an undesirable outcome as the upper bound of the credible 
interval is below 30%. When outcomes are statistically inconclusive (number of TI=6 or 7), 
results of additional sensitivity analyses and other endpoints (secondary, safety, PK, 
PD/biomarker) will play a more important role in decision making.
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Table 7:
Observed TI, 2-Sided Credible Interval, and Statistical Decision Criteria
Number (%) of Observed TI
80% CI1
“Meeting” Primary Objective
  4 (13.3)
(7.1, 22.9)
No2
  5 (16.7)
(9.6, 26.8)
  6 (20.0)
(12.2, 30.6)
Inconclusive
  7 (23.3)
(14.8, 34.3)
  8 (26.7)
(17.6, 37.9)
Yes3
  9 (30.0)
(20.4, 41.4)
10 (33.3)
(23.3, 44.9)
11 (36.7)
(26.2, 48.3)
12 (40.0)
(29.2, 51.7)
13 (43.3)
(32.3, 55.0)
14 (46.7)
(35.4, 58.2)
1 Using B(0.5, 0.5) as the prior distribution for true IT rate
2 With false negative error rate <10%; ie, when observing number of TI ≤5, there is a <10% chance that the true
   TI rate is ≥30%
3 With false positive error rate <10%; ie, when observing number of TI ≥8, there is a <10% chance that the true
  TI rate is ≤15%
In addition to the aforementioned statistical assessments, sensitivity analyses will also be 
performed for the primary endpoint. In these analyses, additional subjects will also be considered 
transfusion independent if they are transfusion-free for less than 8 weeks but have maintained 
such a status for at least 6 consecutive weeks (42 days) by the time of the clinical cutoff 
(6 months after last randomization).
Secondary Endpoints
The proportion of subjects with TI lasting at least 168 days (24 weeks), CR, PR, and HI will be
summarized descriptively.
The distributions of time to TI, and duration of TI will be estimated for each treatment arm using
Kaplan-Meier method. These analyses will be based on subjects who achieve TI.
Other time-to-event endpoints including OS and time to progression to AML will be analyzed 
using Kaplan-Meier methods.
11.4.
Pharmacokinetic Analyses 
Data for all subjects who have sufficient and interpretable data for treatment with talacotuzumab 
or daratumumab will be included in both the PK and the PD analysis. Descriptive statistics 
(geometric and arithmetic means, standard deviation, and coefficient of variation [%]) will be 
provided to summarize serum concentrations of talacotuzumab or daratumumab at each sampling 
time point and PK parameters such as: Cmax and Cmin as appropriate.
Pharmacokinetic analyses will be performed on the PK-evaluable population, defined as subjects 
who have received at least 1 dose of talacotuzumab or daratumumab and have at least 1 
postinfusion sample.
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All concentrations below the lowest quantifiable concentration or missing data will be labeled as 
such in the concentration database. Concentrations below the lowest quantifiable concentration 
will be treated as zero in the summary statistics. The number of subjects and samples excluded 
from the analysis will be clearly documented in the Clinical Study Report.
Descriptive statistics will be used to summarize talacotuzumab or daratumumab serum 
concentrations at each sampling time point. Cmin is defined as the minimal concentration 
observed immediately before infusion and Cmax is defined as the maximum concentration 
observed at the end of infusion, as presented in the summary of serum concentration by sampling 
timepoint. Other PK parameters, if available, may also be summarized. 
If sufficient data are available, population-PK analysis of serum concentration-time data of 
talacotuzumab or daratumumab may be performed and may be combined with data from other 
studies. If the population-PK analysis is conducted, details will be given in a population-PK 
analysis plan and the results of the analysis will be presented in a separate report.
11.5.
Immunogenicity Analyses 
The incidence of anti-talacotuzumab and anti-daratumumab antibodies will be summarized for 
all subjects who receive at least 1 dose of talacotuzumab and daratumumab and have appropriate 
samples for detection of antibodies to talacotuzumab and daratumumab (ie, subjects with at least 
1 sample obtained after their first dose of talacotuzumab and daratumumab). A listing of subjects 
positive for anti-talacotuzumab or anti-daratumumab antibodies will also be presented.
11.6.
Biomarker Analyses
Biomarker measures and the change from baseline will be listed, tabulated, and plotted where 
appropriate. Subjects may be grouped by treatment, biomarker subgroups, or clinical response. 
Correlation of baseline or changes of biomarkers with clinical parameters will be analyzed by 
appropriate statistical methods (eg, parametric or non-parametric, univariate or multivariate).
Results of biomarker analyses may be presented in a separate report. Planned biomarker analyses 
may be deferred if emerging study data show no likelihood of providing useful scientific 
information. 
11.7.
Pharmacokinetic/Pharmacodynamic Analyses
If sufficient data are available, pharmacokinetic/pharmacodynamic modeling may be performed, 
including exploring the relationship between serum concentrations of talacotuzumab or 
daratumumab and biomarkers, PD markers, and endpoints of clinical efficacy and safety, and 
may include data from other studies. If these analyses are performed, the details and results will 
be presented in a separate report.
11.8.
Safety Analyses
Safety analyses will be performed using the Treated Population. Safety will be evaluated using 
the NCI-CTCAE (Version 4.03). The safety parameters to be evaluated are the incidence, 
intensity, and type of adverse events, clinically significant changes in the subject’s physical 
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examination findings, vital signs measurements, clinical laboratory results (hematology and 
chemistry), and deaths. Exposure to study treatment and reasons for discontinuation will be 
tabulated. 
Adverse Events
Treatment-emergent adverse events are adverse events that occur after the first dose of study 
drug through 30 days following the last dose of study drug; any adverse event considered study 
drug-related regardless of the start date of the event; or any event that is present at baseline but 
worsens in severity or is subsequently considered drug-related by the investigator. Treatment-
emergent adverse events will be summarized by System Organ Class and preferred term, by 
intensity (NCI-CTCAE, Version 4.03), and by drug relationship.
The verbatim terms used in the eCRF by investigators to identify adverse events will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA).
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 included in the summary of 
laboratory data. Descriptive statistics will be calculated for each laboratory analyte at baseline.
Parameters with predefined NCI-CTCAE toxicity grades will be summarized. A summary of the 
shifts in selected laboratory hematology and serum chemistry parameters from baseline to the 
worst toxicity grade during the study will be provided. The worst toxicity grade during the study 
will be tabulated.
Electrocardiogram 
Electrocardiogram data will be listed.
Vital Signs
Descriptive statistics of temperature, heart rate, and blood pressure (systolic and diastolic) values 
and changes from baseline will be summarized at each scheduled time point. The percentage of 
subjects with values beyond clinically important limits will be summarized.
11.9.
Safety Review
A sponsor safety review committee will review all the safety data on a quarterly basis, or ad hoc, 
as needed. Committee members include study team clinicians and company safety officer. 
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 
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.
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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.
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

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
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
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 daratumumab, 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, Attribution Definitions.
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.
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).
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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/SAE should be completed using the NCI-CTCAE 
Version 4.03. Any adverse event/SAE not listed in the NCI-CTCAE will be graded by the 
investigator 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 or safety 
evaluation include, but are not limited to:

Overdose of a sponsor study drug

Suspected abuse/misuse of a sponsor study drug

Accidental or occupational 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)

Exposure to a sponsor study drug from breastfeeding
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.
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12.3.
Procedures
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 completion of the subject's last 
study-related procedure, which may include contact for follow-up of safety. Serious adverse 
events, including those spontaneously reported to the investigator within 30 days after the last 
dose of study drug, and those that are considered related to study treatment occurring within the 
Follow-up Phase, 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.
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. Anticipated events will be 
recorded and reported as described in Attachment 9. 
The follow-up of subjects in the study and study data collection will end either 1 year after the 
last subject is randomized or anytime the sponsor terminates the study. Subjects who are 
continuing to derive benefit from daratumumab treatment as assessed by their investigator may 
continue to receive daratumumab according to the protocol. During this period after study data 
collection has ended, only serious adverse events will be monitored and only entered into the 
company safety repository as described under Amendment 4 and in the Time and Events 
Schedule.
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). The investigator (or sponsor where 
required) must report SUSARs to the appropriate Independent Ethics Committee/Institutional 
Review Board (IEC/IRB) that approved the protocol unless otherwise required and documented 
by the IEC/IRB.
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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
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:

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 course 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 
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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.

For convenience the investigator may choose to hospitalize the subject for the duration of 
the treatment period.
Disease progression should not be recorded as an adverse event or serious adverse event term; 
instead, signs and symptoms of clinical sequelae resulting from disease progression/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).
12.3.3.
Pregnancy
All initial reports of pregnancy in female subjects or partners of male subjects 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, 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. 
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.
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the 
infant will be required.
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 in the Contact Information 
page(s), which will be provided as a separate document.
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.
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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 in 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 (JNJ-56022473) is supplied for this study 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 daratumumab supplied for this study is a colorless to yellow liquid and 
sterile concentrate of 20 mg/mL as a liquid vial. Both will be manufactured and provided under 
the responsibility of the sponsor. Refer to the Investigator’s Brochure for a list of excipients.
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.
14.4.
Preparation, Handling, and Storage
All study drug must be stored at controlled temperatures ranging from 36°F to 46°F (2°C to 8°C)
and protected from exposure to light. 
Daratumumab product must be stored in the original carton in a refrigerator at controlled 
temperatures ranging from 2°C to 8°C. Study drug must not be utilized after the expiry date 
printed on the label. The daratumumab product must be protected from light and must not be 
frozen. Daratumumab does not contain preservatives; therefore, any unused portion remaining in 
the vial must be discarded.
Refer to the study site investigational product and procedures manual for additional guidance on 
study drug preparation, handling, and storage.
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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, and study drug returned by the subject, 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, or used returned study drug for destruction, 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. 
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. Returned study drug must not be dispensed again, even to 
the same subject. 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.
The end of study data collection is defined as either 1 year after the last subject is randomized or 
anytime the sponsor terminates the study. At that time, study follow-up of subjects and study 
data collection will end. Subjects who are continuing to derive benefit from daratumumab 
treatment as assessed by their investigator may continue to receive daratumumab according to 
the protocol. During this period after study data collection has ended, only serious adverse events 
will be monitored and only entered into the company safety repository as described under 
Amendment 4 and in the Time and Events Schedule.
15.
STUDY-SPECIFIC MATERIALS
The investigator will be provided with the following supplies:

Study Protocol

Investigator's Brochures Package Insert for Daratumumab

Pharmacy manual/study site investigational product manual

Laboratory manual

NCI-CTCAE Version 4.03

IVRS/IWRS Manual
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
Electronic data capture (eDC) Manual

Sample ICF
16.
ETHICAL ASPECTS
16.1.
Study-Specific Design Considerations
This is a proof-of-concept study that evaluates talacotuzumab and daratumumab as separate 
agents in subjects with low risk MDS. There is an unmet need for agents that relieve the 
transfusion requirements, mostly RBC, for subjects with low-risk MDS. Preclinical evidence 
suggests that these agents may promote normal hematopoiesis in the bone marrow by elimination 
of immune suppressor cells and potentially improve TI. Talacotuzumab is currently being 
evaluated in a Phase 2 study in patients with AML, a myeloid disease closely related to MDS and 
is considered safe and tolerable at the dose specified in this protocol. Daratumumab has been 
approved in the US and EU for the treatment of patients with relapsed and refractory multiple 
myeloma under the regimen specified in this protocol. In the AML and MM indications, the 
health of patients is likely to be more compromised than for patients with low-risk MDS. The 
sponsor considers the potential clinical benefits to outweigh the known risks of talacotuzumab or 
daratumumab treatment for patients with low-risk MDS.
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.
Treatment allocation is randomized therefore patients have equal chances of receiving either of 
the 2 experimental treatments. Patients will undergo the same procedures and testing regardless 
of which treatment that they receive. As a precautionary measure, due to benefit / risk 
considerations for patients with low-risk MDS, enrollment to the talacotuzumab arm has been 
closed based upon the occurrence of a Grade 4 infusion-related reaction in the first subject to 
receive talacotuzumab. The IWRS was modified to only permit enrollment to the daratumumab 
arm of the study.
Infusion-related reactions are associated with both agents. Several safeguards, including 
premedication regimens for both agents as well as postmedications for daratumumab, are 
mandated to reduce the occurrence or the severity of infusion-related reactions. 
Because of the cytopenias associated with MDS, routine hematology values will be monitored. 
The follow-up of subjects in the study and study data collection will end either 1 year after the 
last subject is randomized or anytime the sponsor terminates the study. Subjects who are 
continuing to derive benefit from daratumumab treatment as assessed by their investigator may 
continue to receive daratumumab according to the protocol. During this period after study data 
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collection has ended, only serious adverse events will be monitored and only entered into the 
company safety repository as described under Amendment 4 and in the Time and Events 
Schedule.
The total blood volume to be collected is considered to be an acceptable amount of blood for 
subjects participating in an MDS clinical study and is deemed reasonable over this time period in 
this study.
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 
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)

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 
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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
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. 
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 
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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, which includes permission to obtain information about 
his or her survival status. It also denotes that the subject agrees to allow his or her study 
physician to recontact the subject for the purpose of obtaining consent for additional safety 
evaluations, and subsequent disease-related treatments, if needed.
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.
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 
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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 PD, biomarker, PK 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 talacotuzumab and 
daratumumab, to understand MDS, to understand differential drug responders, and to develop 
tests/assays related to talacotuzumab and daratumumab and MDS. The research may begin at any 
time during the study or the post-study storage period. 
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 10.3, Withdrawal From the Use of Research Samples.
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 16.1, 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 
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sponsor. When the change(s) involves only logistic or administrative aspects of the study, the 
IEC/IRB (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 listed in the Contact Information page(s), which will be provided as a separate 
document. 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.
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
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
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
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. 
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).
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:
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
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.
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. If the electronic source 
system is utilized, references made to the eCRF 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 eCRF. 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 eCRF 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 eCRF 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 eCRF. Any 
such worksheets will become part of the subject's source documents. Data must be entered into 
eCRF 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.
If necessary, queries will be generated in the eDC tool. If corrections to an eCRF are needed 
after the initial entry into the eCRF, 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.
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, and periodic monitoring visits by the sponsor[, and direct 
transmission of biomarker, immunogenicity and PK data from central laboratories into the 
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sponsor's data base. 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 eCRFs 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 CRF 
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.
17.8.
Monitoring
The sponsor will use a combination of monitoring techniques (central, remote, or on-site 
monitoring) to monitor this study.
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 CRF with the source documents 
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(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 
CRF 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 documents (medical records) must be allowed for the purpose of 
verifying that the recorded data are consistent with the original source data. Findings from this 
review 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 documents 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.
In addition to on-site monitoring visits, remote contacts can occur. It is expected that during 
these remote contacts, study-site personnel will be available to provide an update on the progress 
of the study at the site. 
Central monitoring will take place for data identified by the sponsor as requiring central review.
17.9.
Study Completion/Termination
17.9.1.
Study Completion/End of Study
The end of study data collection is defined as 1 year after last subject has been randomized or 
anytime the sponsor terminates the study (see Section 17.9.2). At that time, study follow-up of 
subjects and study data collection will end. Subjects who are continuing to derive benefit from 
daratumumab treatment as assessed by their investigator may continue to receive daratumumab
according to the protocol. During this period after study data collection has ended, only serious 
adverse events will be monitored and only entered into the company safety repository as 
described under Amendment 4 and in the Time and Events Schedule.
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
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
Inadequate recruitment of subjects by the investigator

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 
daratumumab 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 exploratory or 
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 daratumumab, 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 exploratory or 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 disclose the existence of and the results of clinical studies as 
required by law.
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malignant features similar to those in AML. Int J Hematol (2014) 100:60-69.
19.
Porter JB New insights into transfusion-related iron toxicity: implications for the oncologist Critical reviews in 
oncology/hematology 2016:99:261-271.
20.
Raza A, Reeves JA, Feldman EJ, et al. Phase 2 study of lenalidomide in transfusion-dependent, low-risk, and 
intermediate-1 risk myelodysplastic syndromes with karyotypes other than deletion 5q. Blood. 2008; 
111(1):86-93.
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21.
Santini V, Almeida A, Giagounidis A, et al. Randomized phase III study of lenalidomide versus placebo in 
RBC-transfusion dependent patients with lower-risk non-del(5q) myelodysplastic syndromes ineligible for or 
refractory to erythropoiesis-stimulating agents. J Clin Oncol. 2016;34:2988-2996.
22.
Saunthararajah Y, Skeres M, Advani A, et al. Evaluation of cytotoxic DNMT1-depleting therapy in patients 
with myelodysplastic syndromes. J Clin Invest. 2015;125(3):1043–55.
23.
Testa U, Riccioni R, Militi S, Coccia E, Stellacci E, Samoggia P,et al. Elevated expression of IL-3Ra in acute 
myelogenous leukemiais associated with enhanced blast proliferation, increasedcellularity, and poor prognosis. 
Blood. 2002;100:2980–8.
24.
Tobiasson M, Dybedahl I, Holm MS, et al. Limited clinical efficacy of azacitidine in transfusion-dependent, 
growth factor-resistant, low- and Int-1-risk MDS: Results from the nordic NMDSG08A phase II trial. Blood 
Cancer J 2014;4,e189;doi:10,1038/bcj.2014.8.
25.
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 (5) 
937-51.
26.
Yue L, Shao Z. Multi-parameter diagnosis of myelodysplasticsyndrome. Chin J Pract Intern Med. 
2010;30(5):389–92.
27.
Yue LZ, Fu R, Wang HQ, Li LJ, Shao ZH. Expression of CD123and CD114 on the bone marrow cells of 
patients with myelodysplastic syndrome. Chin Med J (Engl). 2010;123(15):2034–7.
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Attachment 1: World Health Organization (WHO) Classification
Once a diagnosis of myelodysplastic syndrome (MDS) is established, 8 subtypes of MDS are recognized 
in the WHO classification that are distinguished by the percentage of myeloblasts, the presence of ringed 
sideroblasts, the number of dysplastic lineages, and karyotype as summarized in the following table:
MDS Subtype 
Findings: Peripheral Blood 
Findings: Bone Marrow
Refractory anemia (RA) 
Anemia
No or rare blasts
Erythroid dysplasia only
<5% blasts
<15% ringed sideroblasts
Refractory anemia with ringed
sideroblasts (RARS)
Anemia
No blasts
Erythroid dysplasia only
>15% ringed sideroblasts
<5% blasts
Refractory cytopenia with multi-
lineage dysplasia (RCMD)
Cytopenias (bi- or pancytopenia)
No or rare blasts
No Auer rods
<1 x 109/L monocytes
Dysplasia in ≥10% of cells in 2 or 
more myeloid cell lines
<5% blasts in marrow
No Auer rods
<15% ringed sideroblasts
Refractory cytopenia with multi-
lineage dysplasia and ringed 
sideroblasts (RCMD-RS)
Cytopenias (bi- or pancytopenia)
No or rare blasts
No Auer rods
<1 x 109/L monocytes
Dysplasia in ≥10% of cells in 2 or 
more myeloid cell lines
≥15% ringed sideroblasts
<5% blasts
No Auer rods
Refractory anemia with excess 
blasts-1 (RAEB-1)
Cytopenias
<5% blasts
No Auer rods
<1 x 109/L monocytes
Uni-lineage or multi-lineage 
dysplasia
5% to 9% blasts
No Auer rods
Refractory anemia with excess 
blasts-2 (RAEB-2)
Cytopenias
<5% to 19% blasts
Auer rods ± <1 x 109/L monocytes
Uni-lineage or multi-lineage 
dysplasia
10% to 19% blasts
Auer rods ± 
Myelodysplastic syndromes, 
unclassified (MDS-U)
Cytopenias
No or rare blasts
No Auer rods
Uni-lineage dysplasia in 
granulocytes or megakaryocytes
<5% blasts
No Auer rods
Myelodysplastic syndromes 
associated with isolated del(5q)
Anemia
<5% blasts
Platelets normal or increased
Normal to increased 
megakaryocytes with hypolobated 
nuclei
<5% blasts
No Auer rods
Isolated del(5q)
SOURCE: Brunning RD, Bennet JM, Flandrin G, et al. Myelodysplastic Syndromes. In: Jaffe ES, Harris NL, Stein H, Vardiman JW, eds. 
Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2001:61-73.
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Attachment 2: International Prognostic Scoring System (IPSS) for Myelodysplastic Syndrome
SOURCE: Greenberg P, Cox C, LeBeau MM, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 
1997;89:2079-2088.
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Attachment 3: Eastern Cooperative Oncology Group (ECOG) Performance Status Scale
Grade
Score 
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, eg, light house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more 
than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair.
SOURCE: Eastern Cooperative Oncology Group (ECOG). http://ecog.dfci.harvard.edu/general/perf_stat.html
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Attachment 4: NYHA Classification
The Stages of Heart Failure – New York Heart Association (NYHA) Classification
Class
Subject Symptoms
Class I (Mild)
No limitation of physical activity. Ordinary 
physical activity does not cause undue fatigue, 
palpitation, or dyspnea (shortness of breath)
.
Class II (Mild)
Slight limitation of physical activity. 
Comfortable at rest, but ordinary physical 
activity results in fatigue, palpitation, or 
dyspnea.
Class III 
(Moderate)
Marked limitation of physical activity. 
Comfortable at rest, but less than ordinary 
activity causes fatigue, palpitation, or dyspnea.
Class IV 
(Severe)
Unable to carry out any physical activity 
without discomfort. Symptoms of cardiac 
insufficiency at rest. If any physical activity is 
undertaken, discomfort is increased.
Heart Failure Society of America The Stages of Heart Failure – NYHA Classification. Available at 
http://www.hfsa.org/hfsa-wp/wp/stages-of-heart-failure/
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Attachment 5: Asthma Guidelines
Components of
Severity
Classification of Asthma Severity
Intermittent
Persistent
Mild
Moderate
Severe
0-4
yrs
5-11 yrs
12 + yrs
0-4 yrs
5-11 yrs
12 + yrs
0-4 yrs
5-11 yrs 12 + yrs
0-4 yrs
5-11 yrs 12 + yrs
Impairment
Normal FEV1/FVC :
8-19 yr 85%
20-39 yr 80%
40-59 yr 75%
60-80 yr 70%
Symptoms
≤2 days/week
≥ 2 d a y s / w e e k  b u t  n o t  d a i l y
Daily
Throughout the day
Nighttime awakenings
0
≤2x/month
1-2x/
month
3-4x/month
3-4x/
month
> 1x/week but not 
nightly
> 1x/
month
Often 7x/week
SABA use for 
symptom control (not 
prevention
of EIB)
≤2 days/week
≤2 days/week but not daily
>2 days/ 
week but
not daily,
and
not more 
than 1x on
d
Daily
Several time per day
Interference with 
normal activity
None
Minor limitation
Some limitation
Extremely limited
Lung function
FEV1
FEV1/FVC
N/A
Normal FEV1 
between 
exacerbations
> 80%
> 85%
Normal FEV1 
between 
exacerbations
> 80%
Normal
N/A
> 80%
> 80%
> 80% 
Normal
N/A
60-80%
75-80%
60-80% 
Reduced
N/A
< 60%
< 75%
< 60% 
Reduced
Risk
Exacerbations 
requiring oral 
systemic 
corticosteroids
0-1/year
≥2 exacerbations in 6
months requiring oral 
steroids or >4 wheezing 
episodes/1 year lasting
>1 day and risk factors
for persistent asthma
≥ 2/year
Relative 
annual risk 
may be 
related to 
FEV1.
≥ 2/year
Relative 
annual risk 
may be 
related to 
FEV1.
≥ 2 exacerbations 
in 6 months 
requiring oral 
steroids or >4 
wheezing 
episodes/1 year 
lasting >1 day and
risk factors for 
persistent asthma
≥ 2/year
Relative 
annual risk 
may be 
related to 
FEV1.
≥ 2/year
Relative 
annual risk 
may be 
related to 
FEV1.
≥ 2 exacerbations
in
6 months requiring 
oral steroids or >4 
wheezing 
episodes/1 year 
lasting >1 day and 
risk factors for 
persistent asthma
≥ 2/year
Relative 
annual risk 
may be 
related to 
FEV1.
≥ 2/year
Relative 
annual risk
may be
related
to FEV1.
Consider severity and interval since last exacerbation. Frequency and severity may fluctuate over time for patients in any severity category.
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Recommended Step for
Initiating Treatment
Step 1
Step 2
Step 3 and 
consider short 
course of oral 
steroids
Step 3: 
medium
dose ICS
and 
consider
short 
course of
oral 
steroids
Step 3 and 
consider 
short 
course of
oral steroids
Step 3 and 
consider short 
course of oral 
steroids
Step 3: 
medium
dose ICS
OR Step 4 
and
consider 
short
course of 
oral
steroids
Step 4 or 5 
and
consider 
short 
course
of oral
steroids
In 2-6 weeks, evaluate level of asthma control that is achieved.
0-4 years: If no clear benefit is observed in 4-6 weeks, stop treatment and consider alternate diagnosis or adjusting therapy. 5-11 and 12+ years: adjust therapy accordingly.
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JNJ-56022473 (talacotuzumab) and JNJ-54767414 (daratumumab)
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Attachment 6: International Working Group (IWG) Response Criteria 2006
PROPOSED MODIFIED INTERNATIONAL WORKING GROUP RESPONSE CRITERIA FOR 
ALTERING NATURAL HISTORY OF MDS
Category
Response Criteria (responses must last ≥4 weeks)
Complete remission (CR)
Bone marrow: ≤5% myeloblasts with normal maturation of all cell lines*
Persistent dysplasia will be noted*†
Peripheral blood‡: Hb ≥11 g/dL; platelets ≥100 x 109/L; neutrophils
≥1.0 x 109/L†; blasts, 0%
Partial remission (PR)
All CR criteria if abnormal before treatment except:
Bone marrow blasts decreased by ≥50% over pretreatment but still >5%
Cellularity and morphology not relevant
Marrow CR†
Bone marrow: ≤5% myeloblasts and decrease by ≥50% over pretreatment†
Peripheral blood: if HI responses, they will be noted in addition to marrow CR†
Stable disease
Failure to achieve at least PR but no evidence of progression for >8 weeks
Failure
Death during treatment or disease progression characterized by worsening of 
cytopenias, increase in percentage of bone marrow blasts, or progression to a more 
advanced MDS FAB subtype than pretreatment
Relapse after CR or PR
At least 1 of the following:
Return to pretreatment bone marrow blast percentage
Decrement of ≥50% from maximum remission/response levels in granulocytes 
or platelets
Reduction in Hb concentration by ≥1.5 g/dL or transfusion dependence
Cytogenetic response
Complete: Disappearance of the chromosomal abnormality without appearance of 
new ones
Partial: At least 50% reduction of the chromosomal abnormality
Disease progression
For patients with:
<5% blasts: ≥50% increase in blasts to >5% blasts
5%–10% blasts: ≥50% increase to >10% blasts
10%–20% blasts: ≥50% increase to >20% blasts
20%–30% blasts: ≥50% increase to >30% blasts
Any of the following:
≥50% decrement from maximum remission/response in granulocytes or platelets
Reduction in Hb by ≥2 g/dL
Transfusion dependence
Survival
Endpoints:
Overall: death from any cause
Event free: failure or death from any cause
PFS: disease progression or death from MDS
DFS: time to relapse
Cause-specific death: death related to MDS
∗
Dysplastic changes should consider the normal range of dysplastic changes (modification).
† Modification to IWG response criteria.
‡ In some circumstances, protocol therapy may require the initiation of further treatment (eg, consolidation, 
maintenance) before the 4-week period. Such patients can be included in the response category into which they 
fit at the time the therapy is started. Transient cytopenias during repeated chemotherapy courses should not be
considered as interrupting durability of response, as long as they recover to the improved counts of the previous 
course.
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Proposed modified International Working Group response criteria for hematologic improvement
Hematologic Improvement*
Response criteria (responses must last ≥8 weeks)†
Erythroid response 
(pretreatment, <11 g/dL)
Hb increase by ≥1.5 g/dL
Relevant reduction of units of RBC transfusions by an absolute number of at 
least 4 RBC transfusions/8 weeks compared with the pretreatment transfusion 
number in the previous 8 weeks. Only RBC transfusions given for a Hb of 
≤9 g/dL pretreatment will count in the RBC transfusion response evaluation†
Platelet response 
(pretreatment, <100 x 109/L)
Absolute increase of ≥30 x 109/L for patients starting with >20 x 109/L platelets
Increase from <20 x 109/L to >20 x 109/L and by at least 100%†
Neutrophil response 
(pretreatment, <1 x 109/L)
At least 100% increase and an absolute increase >0.5 x 109/L†
Progression or relapse after 
HI‡
At least 1 of the following:
At least 50% decrement from maximum response levels in granulocytes or 
platelets
Reduction in Hb by ≥1.5 g/dL
Transfusion dependence
∗
Pretreatment counts averages of at least 2 measurements (not influenced by transfusions) ≥1 week apart (modification).
† 
Modification to IWG response criteria.
‡ 
In the absence of another explanation such as acute infection, repeated courses of chemotherapy (modification), gastrointestinal bleeding, 
hemolysis, and so forth. It is recommended that 2 kinds of erythroid and platelet responses be reported overall as well as by the individual 
response pattern.
Notes: Deletions to the IWG response criteria are not shown. To convert hemoglobin levels (concentrations) from grams per deciliter to grams 
per liter, multiply grams per deciliter by 10.
Abbreviations: CR: complete remission; DFS: disease-free survival; FAB: French-American-British; Hb: hemoglobin; HI: hematologic 
improvement; IWG: International Working Group; MDS: myelodysplastic syndromes; PFS: progression-free survival; PR: partial remission; 
RBC: red blood cell
SOURCE:
Cheson BD, Greenberg PL, Bennett JM, et al. Clinical application and proposal for modification of the International Working 
Group (IWG) response criteria in myelodysplasia. Blood 2006;108:419-425.
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Attachment 7: Conversion Table for Glucocorticosteroid Dose
Generic Name
Oral or Intravenous
Dose (mg)
Dexamethasone
0.75
Hydrocortisone
20
Methylprednisolone
4
Prednisolone
5
Prednisone
5
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Attachment 8: The Family of Antihistamine Medications
The following antihistamines may be used for daratumumab preinfusion medication (including, 
but not limited to):

Diphenhydramine

Cetirizine

Fexofenadine

Loratadine

Clemastine

Dexchlorpheniramine

Promethazine*
* The IV use of promethazine should be avoided. 
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Attachment 9: 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: 
Indication related

Dyspnea

Fatigue

Malaise

Asthenia

Hemorrhage (with thrombocytopenia)

Infection 

Cytopenias

Thrombocytopenia

Neutropenia
o
Febrile neutropenia

Leukopenia

Lymphopenia

Pancytopenia
Population Related

Arrhythmia, Atrial fibrillation

Cardiac failure congestive

Myocardial infarction; Cerebrovascular accident
Reporting of Anticipated Events
All adverse events will be recorded in the eCRF 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 
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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.
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INVESTIGATOR AGREEMENT
NCT03011034

SAP_001.pdf: 
1 
Approved, Date: 21 September 2018  
 
Janssen Research & Development * 
 
 
Statistical Analysis Plan 
 
A Phase 2 Proof-of-Concept Study to Separately Evaluate the Activity of Talacotuzumab 
(JNJ-56022473) or Daratumumab in Transfusion-Dependent Subjects with Low or 
Intermediate-1 Risk Myelodysplastic Syndromes (MDS) who are Relapsed or Refractory to 
Erythropoiesis-Stimulating Agent (ESA) Treatment 
 
Protocol 56022473MDS2002; Phase 2 
 
 JNJ-56022473 (Talacotuzumab)  
JNJ-54767414 (Daratumumab) 
 
 
 
Status: 
Approved 
Date: 
21 September 2018 
Prepared by: 
Janssen Research & Development, LLC 
Document No.: 
 
 
Compliance:  The study described in this report was performed according to the principles of Good Clinical Practice (GCP).  
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.
NCT03011034


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Approved, Date: 21 September 2018  
TABLE OF CONTENTS 
1. 
INTRODUCTION.................................................................................................................................. 3 
2. 
TRIAL OBJECTIVES ........................................................................................................................... 3 
2.1. 
PRIMARY OBJECTIVE .................................................................................................................... 3 
2.2. 
SECONDARY OBJECTIVES ........................................................................................................... 3 
2.3. 
EXPLORATORY OBJECTIVES ....................................................................................................... 3 
3. 
TRIAL DESIGN .................................................................................................................................... 3 
3.1. 
OVERVIEW OF STUDY DESIGN .................................................................................................... 3 
3.2. 
STATISTICAL HYPOTHESIS .......................................................................................................... 5 
3.3. 
SAMPLE SIZE JUSTIFICATION ...................................................................................................... 5 
3.4. 
STATISTICAL METHODS ............................................................................................................... 5 
3.5. 
RANDOMIZATION AND BLINDING ................................................................................................ 7 
3.6. 
CHANGE IN STUDY CONDUCT ..................................................................................................... 7 
4. 
GENERAL DESCRIPTIONS AND DEFINITIONS ............................................................................... 8 
4.1. 
BASELINE AND STUDY PHASES .................................................................................................. 8 
4.2. 
STUDY DAY AND CONVENTION OF TIME COMPUTATIONS ..................................................... 8 
4.3. 
ANALYSIS SETS ............................................................................................................................. 8 
5. 
SUBJECT INFORMATION .................................................................................................................. 8 
5.1. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS ............................................................. 8 
5.2. 
DISPOSITION INFORMATION ........................................................................................................ 9 
5.3. 
EXTENT OF EXPOSURE ................................................................................................................ 9 
5.4. 
PROTOCOL DEVIATIONS .............................................................................................................. 9 
5.5. 
PRIOR AND CONCOMITANT MEDICATIONS ............................................................................. 10 
6. 
EFFICACY ......................................................................................................................................... 10 
6.1. 
PRIMARY EFFICACY ENDPOINT ................................................................................................ 10 
6.1.1. 
DEFINITION ............................................................................................................................... 10 
6.1.2. 
HANDLING OF MISSING TRANSFUSION ASSESSMENTS .................................................... 10 
6.1.3. 
ANALYSIS METHODS ............................................................................................................... 10 
6.2. 
MAJOR SECONDARY ENDPOINTS ............................................................................................. 11 
6.2.1. 
DEFINITION ............................................................................................................................... 11 
6.2.2. 
ANALYSIS METHODS ............................................................................................................... 12 
7. 
SAFETY ............................................................................................................................................. 13 
7.1. 
ADVERSE EVENTS ....................................................................................................................... 13 
7.3. 
CLINICAL LABORATORY TESTS ................................................................................................. 13 
7.4. 
VITAL SIGNS AND PHYSICAL EXAMINATION FINDINGS ......................................................... 14 
 
 
 
 
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Approved, Date: 21 September 2018  
 
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-MDS-2002. 
2. TRIAL OBJECTIVES 
2.1. 
PRIMARY OBJECTIVE 
The primary objective of the study is to evaluate the efficacy (transfusion independence [TI]) of 
talacotuzumab (JNJ-56022473) or daratumumab in transfusion-dependent subjects with low or 
intermediate-1 risk MDS whose disease has relapsed during or is refractory to ESAs. 
2.2. 
SECONDARY OBJECTIVES 
The secondary objectives of this study are: 
• To evaluate the safety of talacotuzumab or daratumumab in the study population. 
• To evaluate the clinical benefit of talacotuzumab and daratumumab in this study population 
through: 
o Time to TI and duration of TI. 
o Rate of HI, CR, and PR. 
o Overall survival (OS). 
o Progression to AML. 
o Rate and amount of supportive care, including transfusions and myeloid growth factors. 
• To characterize the PK of talacotuzumab and daratumumab in the study population. 
• To evaluate the immunogenicity of talacotuzumab and daratumumab in subjects with MDS. 
2.3. 
EXPLORATORY OBJECTIVES 
The tertiary/exploratory objectives of this study are:  
• 
To evaluate pharmacodynamic biomarkers for talacotuzumab activity. 
• 
To determine CD123 and CD38 expression and to explore the association with clinical 
outcomes. 
3. TRIAL DESIGN 
3.1. 
OVERVIEW OF STUDY DESIGN 
This is a Phase 2, multicenter, open-label, randomized study to evaluate the safety and efficacy of 
single-agent talacotuzumab or single-agent daratumumab in subjects with low or intermediate-1 
risk MDS who are transfusion-dependent and whose disease has relapsed during or is refractory 
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Approved, Date: 21 September 2018  
to ESA treatment. Approximately 60 subjects (30 to receive talacotuzumab and 30 to receive 
daratumumab) will be enrolled in this study. 
The purpose of this study is to separately evaluate 2 agents with different mechanisms of action 
that may be effective in subjects with low-risk MDS. The design of this study will allow a 
preliminary assessment of efficacy and safety of both agents, to determine if either or both warrant 
further evaluation in phase 3 studies. Subjects will be randomized in a 1:1 ratio to receive 
talacotuzumab or daratumumab. Randomization will be stratified based on number of RBC units 
transfused burden (4 or >4) during the 8 weeks prior to randomization. 
Talacotuzumab will be administered at 9 mg/kg intravenously (IV) every 2 weeks. Daratumumab 
will be administered at 16 mg/kg IV weekly on Weeks 1 to 8, every 2 weeks for Weeks 9 to 24, 
and every 4 weeks thereafter. Cycle length is 28 days for both agents. Study drugs will continue 
to be administered until disease progression, lack of response, unacceptable toxicity, withdrawal 
of consent, or study end.  
The clinical cutoff for the purpose of the primary endpoint analysis will be 6 months after 
randomization of the last subject. The end of the study is defined as 1 year after the last subject 
has been randomized or anytime the sponsor terminates the study. 
There will be no statistical hypothesis testing, and each arm will be assessed separately. Statistical 
methods focus on the evaluation of the likelihood that either treatment regimen will result in a true 
TI rate of 30% or greater against a minimum acceptable value of 15%. A diagram of the study 
design is provided below in Figure 1. 
Figure 1: 
Schematic Overview of the Study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment Phase 
Talacotuzumnab 
28-day treatment cycle 
N=30 
 
Talacotuzumab 9 mg/kg IV every 2 weeks 
Screening Phase 
 ≤28 days before Cycle 1, Day 1  
Random allocation to talacotuzumab or daratumumab 
Treatment Phase 
Daratumumab 
28-day treatment cycle 
N=30 
 
Daratumumab 16 mg/kg IV weekly on Weeks 1 
Posttreatment Follow-up Phase 
Every 16 weeks  
End of Treatment Visit 
Within 30 days after last dose 
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3.2. 
STATISTICAL HYPOTHESIS  
The primary hypothesis of this study is that the treatment with talacotuzumab or daratumumab 
separately will produce a TI rate 30% or greater against a minimal acceptable value of 15%. The 
statistical evaluation of the hypothesis will use a Bayesian approach to assess the likelihood of 
whether a true TI rate ≤15% can be ruled out. 
3.3. 
SAMPLE SIZE JUSTIFICATION 
Approximately 60 (30 to receive talacotuzumab and 30 to receive daratumumab) subjects will be 
enrolled in the study to ensure at least 30 evaluable (see Section 4.3 for definition) subjects in each 
treatment arm.  
On the basis of historical data, the TI rate with treatment of best supportive care is expected to be 
approximately 7.5% in subjects with low or intermediate-1 risk MDS [17, 22, 23].  The primary 
objective is to evaluate the likelihood that treatment with talacotuzumab or daratumumab can result 
in a true TI rate ≥30%. A true TI rate ≤15% (twice the TI rate of best supportive care) will be 
considered as of no clinical interest in the context of this Phase 2 study. The number of subjects to 
be randomized into each arm will be 30, which will ensure at least 90% probability that the true 
TI rate is greater than the minimum acceptable value (MAV) 15% if at least 8 (26.7%) subjects 
reach transfusion independence. This sample size determination utilizes a Bayesian approach with 
Beta(0.5, 0.5) as the prior distribution and Beta(0.5+m, 0.5+30-m) as the posterior distribution for 
the true TI rate, where m is the observed number of subjects who achieve TI.  
3.4. 
STATISTICAL METHODS 
The objective of the study is to explore if treatment with talacotuzumab or daratumumab will result 
in an 8-week RBC TI rate ≥30%. 
There is no statistical hypothesis testing for the primary objective, and there is no formal statistical 
comparison between the 2 arms. Instead, statistical criteria, based on observed number of subjects 
achieving TI (number of TIs), are provided to determine if the outcome of each treatment arm is 
“meeting”, “not meeting” the primary objective, or statistically “inconclusive”. This statistical 
assessment will be used to guide the decision making for further development of either or both 
treatment therapies. The evaluation will be performed against the target value (TV) 30% and the 
minimum acceptable value (MAV) 15% for the TI rate. TV of 30% is defined according to study 
primary objective and is deemed clinically meaningful. A TI rate below 15%, the MAV, will be 
of no clinical interest. TI rates between MAV and TV will be considered modest, which will define 
a statistically inconclusive outcome. The statistical criteria is determined to control false positive 
and false negative error rates each at 10% level by evaluating its operating characteristics using a 
Bayesian approach with Beta(0.5, 0.5) as the prior distribution and Beta(0.5+m, 0.5+N-m) as the 
posterior distribution of the true TI rate, where N is the total number of subjects and m is the 
observed number of TIs. According to study design, N=30 for each treatment arm. 
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The TI rate point-estimate and the corresponding 2-sided 80% credible intervals (CI) will be 
calculated for each treatment arm. The 80% CI will be symmetric, i.e., 10% each tail. 
Given N=30 for each treatment arm, as shown in Figure 2 and Table 1 , the lower bound of the 2-
sided 80% CI will be >15% (the MAV) and the upper bound >30% (the TV) if the observed number 
of TI is ≥8, meaning statistically 15% TI rate has been ruled out and 30% ruled in, i.e., the study 
primary objective is “met”. If number of TIs is ≥13, then the outcome will be considered highly 
desirable as the lower bound of the CI will be >30% (the TV). Number of TIs ≤5 will be an 
undesirable outcome as the upper bound of the CI is <30% and the lower bound is <15%, implying 
the primary objective is “not met”. When number of TI=6 or 7, the outcomes are statistically 
inconclusive since the lower bound of the CI is <15% and the upper bound is >30%; and in such 
a case, results of additional sensitivity analyses and other endpoints (secondary, safety, PK, 
PD/biomarker) will play a more important role in the decision making.  
Table 1: Observed TI, 2-sided Credible Interval, and Statistical Decision Criteria (N=30) 
Number (%) of Observed TI 
80% C.I.1 
“Meeting” Primary Objective 
  4 (13.3) 
(  7.1, 22.9) 
No2 
  5 (16.7) 
(  9.6, 26.8) 
  6 (20.0) 
(12.2, 30.6) 
Inconclusive 
  7 (23.3) 
(14.8, 34.3) 
  8 (26.7) 
(17.6, 37.9) 
Yes3 
  9 (30.0) 
(20.4, 41.4) 
10 (33.3) 
(23.3, 44.9) 
11 (36.7) 
(26.2, 48.3) 
12 (40.0) 
(29.2, 51.7) 
13 (43.3) 
(32.3, 55.0) 
14 (46.7) 
(35.4, 58.2) 
1 Using B(0.5, 0.5) as the prior distribution for true IT rate 
2 With false negative error rate <10%; i.e., when observing # of TI ≤5, there is a <10% chance that the true 
   TI rate is ≥30% 
3 With false positive error rate <10%; i.e., when observing # of TI ≥8, there is a <10% chance that the true 
   TI rate is ≤15% 
 
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Figure 2: Plot Showing the Decision Rule for Each Treatment Arm 
 
 
The statistical method described in this section is also applicable if the number of subjects in each 
arm is not 30, in which case the posterior distribution corresponding to the actual sample size will 
be used. 
3.5. 
RANDOMIZATION AND BLINDING 
Central randomization will be implemented in this study using an IWRS. Randomization will be 
stratified based on transfusion burden (4 or >4 units) prior to randomization, and then assigned 
randomly on a 1:1 basis to receive either talacotuzumab or daratumumab. Transfusion burden is 
defined as the maximum number of RBC units transfused over any 8 consecutive weeks during 
the 16 weeks prior to randomization. However, due to safety concerns, enrollment to the 
talacotuzumab arm was closed (refer to Section 3.1 Overview of Study Design for details). 
3.6. 
CHANGE IN STUDY CONDUCT 
Enrollment to the talacotuzumab arm was closed based upon the occurrence of a Grade 4 infusion-
related reaction in the first subject who received talacotuzumab. All analyses and summaries 
described in this document will include data only in subjects who received daratumumab. Data 
listings will be provided separately for the single subject who received talacotuzumab. 
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4. GENERAL DESCRIPTIONS AND DEFINITIONS 
4.1. 
BASELINE AND STUDY PHASES 
Baseline Value: Unless specified otherwise, the baseline value is defined as the last non-missing 
value collected on or before the first dose.  
Screening Phase: Up to 28 days prior to the first dose of study drug, during which subject 
eligibility will be reviewed and approved by the sponsor. 
Treatment Phase: Between the date of first dose until study drug discontinuation. The Treatment 
Phase will be divided by cycles, based on the nominal treatment cycles as recorded on the CRF. 
Each cycle is planned to be 28 days.  
Post-treatment Follow-up Phase: After the End of Treatment Phase until the end of study 
participation or end of study, which is defined as 1 year after randomization of the last subject or 
anytime the Sponsor terminates the study, whichever comes first. 
4.2. 
STUDY DAY AND CONVENTION OF TIME COMPUTATIONS 
Study Day 1 is defined as the day of first dose. 
Study Day = assessment date – Study Day 1 + 1 for assessments performed on or after Study Day 1; Study 
Day = assessment date – Study Day 1 for assessments performed before Study Day 1. 
Cycle Day = assessment date – date of the first dose for the cycle + 1. 
By convention, one month equals to 30.4375 days and one year equals to 365.25 days. Duration 
in days between 2 timepoints will be calculated as (end date – start date + 1). 
4.3. 
ANALYSIS SETS 
Intent-to-Treat (ITT) analysis set: includes all subjects who are assigned to receive 
daratumumab. This analysis set will be used for all summaries of disposition, demographic, 
baseline disease characteristics, and efficacy analyses. 
Safety analysis set: includes all subjects who receive at least one dose of daratumumab. This 
analysis set will be used for all safety analyses and analyses of exposure. 
5. SUBJECT INFORMATION 
5.1. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
All demographic and baseline characteristic variables will be summarized for the ITT analysis set. 
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The stratification factors used during randomization (prior RBC transfusion burden) will be 
tabulated.  
Two panels of baseline clinical laboratory tests specified will be summarized: hematology and 
serum chemistry. Frequencies of National Cancer Institute (NCI) Common Terminology Criteria 
for Adverse Events (CTCAE) grade at baseline will be reported.  
Disease characteristics to be summarized will include WHO classification, IPSS risk category 
(low, intermediate-1), prior ESA treatment (Yes, No), serum EPO level (≤ 500 mU/mL, > 500 
mU/ml), and time since initial diagnosis (months). 
Hepatitis serology tests at baseline will be summarized by test type and results. 
Transfusion history summaries will include total transfusion units, and prior RBC transfusion 
burden (4, >4 units). Prior RBC transfusion burden is defined as the maximum number of RBC 
units transfused over an 8-week period during the 16 weeks prior to Study Entry. 
Medical history will be summarized including abnormality in physical examination.  
In addition, summaries of bone marrow findings at baseline will be provided. 
5.2. 
DISPOSITION INFORMATION 
Subject enrollment will be summarized by country and investigator.  
Disposition information will be summarized for the ITT analysis set at the end of treatment and at 
the end of study, respectively. 
5.3. 
EXTENT OF EXPOSURE 
All exposure summaries are to be presented for the Safety analysis set. 
The number of treatment cycles received will be summarized along with the duration of treatment 
exposure; dose intensity, which is equal to the sum of the total dose (mg/kg) received in all cycles 
divided by the number of cycles received; relative dose intensity, which is defined as intensity of 
total actual dose / intensity of total planned dose; and incidence of dose modifications (aborted 
infusion, infusion interruption, reduced dose, infusion delay within the cycle, and cycle delay), as 
well as reasons of dose modifications. Skipped doses are not captured in the database but will be 
derived and reviewed by study team physicians and provided in a data listing. 
5.4. 
PROTOCOL DEVIATIONS 
Subjects with major protocol deviations will be listed. Protocol deviations will be based on clinical 
review mainly on the following aspects (but not limited to): (1) eligibility criteria, (2) treatment 
compliance, and (3) prohibited concomitant medication. Protocol deviations will be closely 
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monitored during the execution of the study and the final set of protocol deviation criteria will be 
finalized before database lock. 
5.5. 
PRIOR AND CONCOMITANT MEDICATIONS 
Medications administered prior to the first dose of study drug will be considered prior medications. 
Concomitant therapies include those taken on or after first dose date through 30 days after last 
dose of study drug. Using this definition, a medication can be classified as both prior and 
concomitant. 
Use of prior and concomitant medications will be summarized by Anatomical Therapeutic 
Chemical (ATC) class and drug generic term. Prior anticancer therapy will be summarized by type 
(e.g., radiotherapy, surgery, chemotherapy). Best response to prior ESA therapy will also be 
summarized.  
Concomitant therapies of special interest will be summarized, including: myeloid growth factors 
[e.g., granulocyte-colony stimulating factor (G-CSF)], anticoagulants and antiplatelet agents. 
Other concomitant therapies, including anti-infectives (antibacterials, antivirals, and 
antimycotics), corticosteroids, anti-arrhythmics and other cardiac supportive therapy, anti-
histamines, anti-emetics, anti-diarrheals will be summarized. 
6. EFFICACY 
6.1. 
PRIMARY EFFICACY ENDPOINT 
6.1.1. DEFINITION 
The primary efficacy endpoint is the rate of RBC TI lasting for at least 8 weeks. The 8-week RBC 
TI rate is defined as the proportion of subjects without any RBC transfusion during any consecutive 
8 weeks (56 days) starting from Study Day 1 until the end of study. The starting date of 8-week 
RBC TI must be between Study Day 1 and End of treatment Phase ending date (date of last dose 
of study medication + 30 days).  
6.1.2. HANDLING OF MISSING TRANSFUSION ASSESSMENTS 
In order to be considered transfusion independent, a subject must have completed continuous 
transfusion assessments throughout the qualifying observation period where his/her transfusion 
independence is determined. An apparent transfusion free period with one or more missing 
transfusion assessments will not be considered a qualifying 8-week or 24-week TI period. Subjects 
with no qualifying observation periods will be considered non-responders. In addition, the number 
(%) of patients who have missed one or more visits will be tabulated.  
6.1.3. ANALYSIS METHODS 
Number and percent of subjects achieving TI and the corresponding 2-sided 80% confidence 
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interval (CI) will be summarized.  
6.2. 
MAJOR SECONDARY ENDPOINTS 
6.2.1. DEFINITION 
24-Week RBC TI Rate 
24-week RBC TI rate is defined as the proportion of subjects without any RBC transfusion during 
any consecutive 24 weeks (168 days) starting from Study Day 1 until the end of study. The starting 
date of 24-week RBC TI must be between Study Day 1 and End of treatment Phase ending date 
(date of last dose of study medication + 30 days). 
Time to 8-Week (24-Week) RBC TI  
Pertaining only to subjects who achieved TI, time to the 8-week (24-week) RBC TI is defined as 
the interval from Study Day 1 to the first day of the first 8-week (24-week) RBC TI period.    
Duration of RBC TI 
Pertaining only to subjects who achieved TI for at least 8 weeks, duration of RBC TI is defined as 
the maximal number of consecutive transfusion-free days that are ≥56 days (8 weeks). For subjects 
maintaining transfusion-free by the time of the cutoff date for the analysis or who withdraw from 
the study, duration will be censored at the date of the last transfusion evaluation. Duration of 24-
week TI is defined similarly. 
Rate of Hematologic Improvement per International Working Group Response Criteria 
2006 (IWG 2006) 
The IWG criteria for HI define specific responses of cytopenias in the three hematopoietic 
lineages: erythroid (HI-E), platelet (HI-P), and neutrophil (HI-N). Rate of hematologic 
improvement of erythroid lineage is the focus of this study , which is defined as the proportion of 
subjects who achieve HI-E. 
HI-E is defined as a hemoglobin (Hb) rise of at least 1.5 g/dL above pretreatment and lasting at least 8 
weeks or reduction of at least 4 units of RBC transfusions/8 weeks compared with the prior RBC transfusion 
burden. Pretreatment Hb level is defined as the average of all the Hb values in the 8 weeks prior to study 
entry, including the value on Cycle 1 Day 1 and excluding values that were within 14 days after transfusion 
(thus considered to be influenced by transfusion). If there were no Hb values that met this definition of not 
being influenced by transfusions, then the baseline value is used. 
Rate of Complete Remission (CR) or Partial Remission (PR)  
Defined as the proportion of subjects who achieve CR, or PR per IWG 2006 [4]. 
Overall Survival (OS)  
OS is defined as the interval from Study Day 1 to death from any cause. Survival time of living 
subjects will be censored on the last date a subject is known to be alive or lost to follow-up. 
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Time to Progression to AML 
Time to progression to AML is defined as the interval from Study Day 1 to the date of AML 
progression (bone marrow or peripheral blood blasts ≥20%). Subjects who have not progressed to 
AML at the cutoff date for the analysis or who withdraw from the study will be censored at the 
date of the last disease evaluation.  
Amount and Relative Change in RBC Transfusions 
Amount of RBC transfusions is defined as the total number of RBC transfusion units in a given 
post-baseline 8-week (any consecutive 56 days period) interval during study. The starting date of 
a post-baseline 8-week interval must be between Study Day 1 and End of treatment Phase ending 
date (date of last dose of study medication + 30 days). Relative change in RBC transfusions is 
defined as: 
Relative change in RBC Transfusion
= amount of RBC transfusions –  prior RBC transfusion burden
prior RBC transfusion burden
∗100 % 
Note that prior RBC transfusion burden is the maximum number of RBC units transfused over an 
8-week period during the 16 weeks prior to Study Entry. 
The best RBC transfusion reduction is defined as the “best” or the “minimum” number of RBC 
transfusions in any post-baseline 8-week interval. The time to the best transfusion reduction in an 
8-week interval (in weeks), the minimum number of RBC transfusions received during this 
interval, and the relative change from baseline will be summarized. 
Rate and Duration of Myeloid Growth Factor Usage 
Rate of myeloid growth factor usage is defined as the proportion of subjects receiving any myeloid 
growth factors starting from Study Day 1; duration of myeloid growth factor administered starting 
from Study Day 1. 
6.2.2. ANALYSIS METHODS 
Rate of 24-week TI, CR, PR, and hematologic improvement (HI), and other binary endpoints, will 
be summarized with percentage along with its 95% 2-sided exact Clopper-Pearson confidence 
interval.  
The time to 8-week RBC TI and time to 24-week RBC TI will be summarized descriptively.  
The Kaplan-Meier method will be used to estimate the distribution of duration of RBC TI for 8-
week and 24-week TI responders, respectively. The distribution of OS and time to progression to 
AML will be summarized using similar Kaplan-Meier methods.    
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Amount and relative change in RBC transfusions will be summarized descriptively by time point. 
7. SAFETY 
Safety analyses will be performed using the safety analysis set. The safety parameters to be 
evaluated are the incidence, intensity, and type of adverse events, clinically significant changes in 
the subject’s physical examination findings, vital signs measurements, clinical laboratory results 
(hematology and chemistry), and deaths. Exposure to study treatment and reasons for 
discontinuation will be tabulated. Descriptive statistics will be reported for all safety data. 
7.1. 
ADVERSE EVENTS 
Treatment-emergent adverse events are adverse events that (1) occur after the first dose of study 
drug through the 30 days following the last dose of study drug or until subsequent anti-cancer 
therapy if earlier; (2) any adverse event considered study drug-related regardless of the start date 
of the event; or (3) any event present at baseline but worsens in severity or is subsequently 
considered drug-related by the investigator. Treatment-emergent adverse events will be 
summarized by System Organ Class and preferred term, by intensity (National Cancer Institute 
(NCI) common terminology criteria for adverse events (CTCAE), Version 4.03), and by study drug 
relationship. 
For each treatment-emergent adverse event, the percentage of subjects who experience at least 1 
occurrence of the given event will be summarized. Tables will be sorted by frequency in incidence 
(the highest to lowest incidence). The same summary will be provided for serious treatment-
emergent AEs, and drug-related serious treatment-emergent AEs, as well as treatment-emergent 
AEs leading to treatment discontinuation, death, dose modifications or delays. 
The verbatim terms used in the electronic case report form (eCRF) by investigators to identify AEs 
will be coded using the Medical Dictionary for Regulatory Activities (MedDRA).  
7.3. 
CLINICAL LABORATORY TESTS 
Laboratory data of hematology and clinical chemistry from baseline up to 30 days after last dose 
will be reported in SI units.  
Summary statistics (N, mean, SD, median, and range) will be calculated for the raw data and for 
their changes from baseline by scheduled visits, as well as for last value and for the changes from 
baseline to the last value. Within a cycle, summary statistics from the worst values will be 
provided. Individual values outside the normal ranges will be identified (by “H” for high and “L” 
for low) in the data listings displaying the absolute values for each subject. 
Displays of over-time summaries will be presented for the following key laboratory parameters: 
hemoglobin, platelet count, white blood cell count, manual absolute peripheral blast count, 
absolute neutrophil count (ANC), creatinine, total bilirubin (with fractionation if abnormal), ALT, 
AST, ALP, lactate acid dehydrogenase, and albumin. 
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Shift tables for each cycle will be produced for selected laboratory parameters, including 
hemoglobin, platelet count, white blood cell count, peripheral blast count, ANC, total bilirubin, 
ALT, AST, and ALP. These tables will summarize by cycle the number of subjects with each 
baseline CTCAE grade and changes to the maximum CTCAE grade in the cycle. For laboratory 
parameters without CTCAE grade, shifts from baseline to highest per cycle (Low, Normal, High) 
categories will be used. 
Shift tables from baseline to worst value on treatment (from treatment start to 30 days after last 
dose or the end of treatment visit date, whichever is later) will also be provided. The worst toxicity 
grade during the treatment will be tabulated. 
In addition, incidence of persistent (≥2 or 4 weeks) and severe (≥3 or 4 grade) cytopenia 
(thrombocytopenia/neutropenia) will be evaluated. Maximum post-baseline CTCAE V 4.03 grade 
for anemia, leukopenia, neutropenia, and thrombocytopenia will be tabulated.          
7.4. 
VITAL SIGNS AND PHYSICAL EXAMINATION FINDINGS 
Descriptive statistics (N, mean, SD, median and range) of vital signs (temperature, blood pressure 
(systolic and diastolic)) values and changes from the baseline will be summarized at each 
scheduled time point. The percentage of subjects with values beyond the clinically important limits 
will be summarized. 
Screening physical examination should include body weight, height, and the evaluation of head, 
eye, ear, nose, and throat (HEENT), cardiovascular, dermatological, musculoskeletal, respiratory, 
gastrointestinal, and neurological systems. Only a limited symptom-directed physical examination 
and weight assessment is required on Day 1 of all cycles after baseline.  New or worsened 
abnormalities should be recorded as adverse events if appropriate. 
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