A Phase 3, Randomized, Controlled, Open-label, Clinical Study of Pevonedistat Plus Azacitidine Versus Single-Agent Azacitidine as First-Line Treatment for Patients With Higher-Risk Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, or Low-Blast Acute Myelogenous Leukemia
Phase: PHASE3
Conditions: Myelodysplastic Syndrome, Leukemia, Myelomonocytic, Chronic, Leukemia, Myeloid, Acute
Sponsor: Takeda

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PROTOCOL
A Phase 3, Randomized, Controlled, Open-label, Clinical Study of Pevonedistat Plus Azacitidine Versus 
Single-Agent Azacitidine as First-Line Treatment for Patients With Higher-Risk Myelodysplastic 
Syndromes, Chronic Myelomonocytic Leukemia, or Low-Blast Acute Myelogenous Leukemia
Pevonedistat Plus Azacitidine Versus Single-Agent Azacitidine as First-Line Treatment for Patients With 
Higher-Risk Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, or Low-Blast Acute 
Myelogenous Leukemia
Sponsor:
Takeda Development Center Americas, Inc. 
95 Hayden Avenue
Lexington, MA 02421
Study Number:
Pevonedistat-3001
IND Number:
78,427
EudraCT Number:
2017-000318-40
Compound:
Pevonedistat (TAK-924/MLN4924)
Date:
21 September 2021
Amendment Number:
14
Date
Amendment Number
Amendment Type 
Region
03 August 2017
Initial Protocol
Not applicable
Global
05 December 2017
01
Substantial
United Kingdom
03 January 2018
02
Substantial
France
17 January 2018
03
Substantial
Germany
20 March 2018
04
Substantial
United Kingdom
17 August 2018
05
Substantial
Global
09 October 2018
06
Substantial
United Kingdom
31 March 2020
07
Substantial
Global
13 April 2020
08
Substantial
United Kingdom
24 July 2020
09
Substantial
China
29 September 2020
10
Substantial
Global
29 September 2020
11
Substantial
United Kingdom
26 March 2021
12
Substantial
Global
26 May 2021
13
Substantial
Global
21 September 2021
14
Substantial
Global
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement by the recipient 
that no information contained herein will be published or disclosed without written authorization from Takeda except to the extent 
necessary to obtain informed consent from those persons to whom the drug may be administered. Furthermore, the information is
only meant for review and compliance by the recipient, his or her staff, and applicable institutional review committee and 
regulatory agencies to enable conduct of the study.
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1.0
ADMINISTRATIVE 
1.1
Contacts 
A separate contact information list will be provided to each site.
Serious adverse event and pregnancy reporting information is presented in Section 10.0, as is 
information on reporting product complaints. 
Takada Development Center sponsored investigators per individual country requirements will be 
provided with emergency medical contact information cards to be carried by each subject.
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site. Information on service providers is given in Section 3.1 and relevant guidelines 
provided to the site.
Contact Type/Role
North America
South America
Europe
Asia
Serious adverse 
event and 
pregnancy reporting
See Section 10.0
See Section 10.0
See Section 10.0
See Section 10.0
Medical Monitor
(medical advice on 
protocol and 
compound)
Refer to Study 
Manual
Refer to Study 
Manual
Refer to Study 
Manual
Refer to Study Manual
Responsible 
Medical Officer 
(carries overall 
responsibility for 
the conduct of the 
study)
Refer to Study 
Manual
Refer to Study 
Manual
Refer to Study 
Manual
Refer to Study Manual
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1.3
Protocol Amendment 14 Summary of Changes
Rationale for Amendment 14
This section describes the changes to the protocol incorporating Amendment 14. The primary 
reason for this amendment is to update the name of the legal entity to Takeda Development Center 
Americas, Inc. and to update its address. 
Minor grammatical, editorial, formatting, and administrative changes not affecting the conduct of 
the study are included for clarification and administrative purposes only.
For specific descriptions of text changes, the rationale for each change, and where the changes are 
located, see Appendix O. 
Changes in Amendment 14
1. Updated the name of the legal entity to Takeda Development Center Americas, Inc., 
95 Hayden Avenue, Lexington, MA 02421.
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INVESTIGATOR AGREEMENT 
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, and any 
other product information provided by the sponsor. I agree to conduct this study in accordance 
with the requirements of this protocol and also to protect the rights, safety, privacy, and well-being 
of study subjects in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Council for Harmonisation, E6 Good Clinical Practice: Consolidated Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting serious adverse events are defined in Section 10.0 of 
this protocol.

Terms outlined in the Clinical Study Site Agreement.

Responsibilities of the Investigator (Appendix D).
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix E of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Province)
Location of Facility (Country)
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TABLE OF CONTENTS
1.0
ADMINISTRATIVE.......................................................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
1.3
Protocol Amendment 14 Summary of Changes ..........................................................4
2.0
STUDY SUMMARY ....................................................................................................13
3.0
STUDY REFERENCE INFORMATION ......................................................................21
3.1
Study-Related Responsibilities.................................................................................21
3.2
Coordinating Investigator.........................................................................................21
3.3
List of Abbreviations ...............................................................................................22
3.4
Corporate Identification...........................................................................................25
4.0
INTRODUCTION.........................................................................................................26
4.1
Scientific Background..............................................................................................26
4.1.1
Diseases Under Treatment ...............................................................................26
4.1.2
Study Drug: Pevonedistat.................................................................................28
4.2
Nonclinical Experience............................................................................................29
4.2.1
Single-Agent Pevonedistat...............................................................................29
4.2.2
Pevonedistat With Azacitidine .........................................................................30
4.3
Clinical Experience..................................................................................................30
4.4
PK of Pevonedistat ..................................................................................................31
4.4.1
Nonclinical PK and Risk Assessment for Drug-Drug Interactions....................31
4.4.2
Clinical PK......................................................................................................33
4.5
Rationale for the Proposed Study.............................................................................33
4.5.1
Rationale for Study Population ........................................................................34
4.5.2
Rationale for the Combination of Pevonedistat Plus Azacitidine ......................34
4.5.3
Rationale for Dose and Schedule of Study Drugs.............................................34
4.5.4
Rationale for Molecular Analyses ....................................................................35
4.5.5
Rationale for Health-Related Quality of Life Assessments...............................38
4.6
Potential Risks and Benefits.....................................................................................38
4.6.1
Azacitidine ......................................................................................................38
4.6.1.1
Anemia, Neutropenia, and Thrombocytopenia .........................................39
4.6.1.2
Severe Pre-existing Hepatic Impairment ..................................................39
4.6.1.3
Renal Abnormalities ................................................................................39
4.6.2
Pevonedistat Plus Azacitidine ..........................................................................39
4.6.3
Potential for DDIs............................................................................................42
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4.6.4
Summary of Risks and Benefits .......................................................................42
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................43
5.1
Objectives................................................................................................................43
5.1.1
Primary Objectives ..........................................................................................43
5.1.2
Key Secondary Objective.................................................................................43
5.1.3
Other Secondary Objectives.............................................................................43
5.1.4
Safety Objective ..............................................................................................44
5.1.5
Exploratory Objectives ....................................................................................45
5.2
Endpoints.................................................................................................................45
5.2.1
Primary Endpoint.............................................................................................45
5.2.2
Key Secondary Endpoint .................................................................................45
5.2.3
Other Secondary Endpoints..............................................................................46
5.2.4
Safety Endpoints..............................................................................................47
5.2.5
Exploratory Endpoints .....................................................................................47
6.0
STUDY DESIGN..........................................................................................................48
6.1
Overview of Study Design.......................................................................................48
6.2
Number of Patients ..................................................................................................50
6.3
Duration of Study ....................................................................................................50
6.3.1
Duration of an Individual Patient’s Study Participation....................................50
6.3.2
End of Study/Study Completion Definition and Planned Reporting..................51
6.3.3
Timeframes for Primary and Secondary Endpoints to Support Disclosures ......51
6.3.4
Total Study Duration .......................................................................................53
7.0
STUDY POPULATION................................................................................................53
7.1
Inclusion Criteria .....................................................................................................53
7.2
Exclusion Criteria ....................................................................................................55
8.0
STUDY DRUG .............................................................................................................57
8.1
Study Drug Administration......................................................................................57
8.1.1
All Patients: Azacitidine Dosing ......................................................................58
8.1.2
Additional Instructions for the Combination Arm: Pevonedistat Plus 
Azacitidine Dosing ..........................................................................................58
8.2
Reference/Control Therapy: Azacitidine ..................................................................58
8.3
Dose Modification Guidelines..................................................................................59
8.3.1
Criteria for Retreatment and Dose Delays ........................................................59
8.3.2
Dose Modification for Hematologic Toxicities.................................................60
8.3.2.1
Azacitidine ..............................................................................................60
8.3.2.2
Pevonedistat ............................................................................................61
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8.3.3
Dose Modification for Nonhematologic Toxicities...........................................61
8.3.3.1
Azacitidine ..............................................................................................61
8.3.3.2
Pevonedistat ............................................................................................62
8.4
Excluded Concomitant Medications and Procedures ................................................62
8.5
Permitted Concomitant Medications and Procedures................................................63
8.6
Precautions and Restrictions ....................................................................................64
8.7
Management of Clinical Events ...............................................................................65
8.7.1
Azacitidine ......................................................................................................65
8.7.2
Combination Pevonedistat Plus Azacitidine .....................................................66
8.8
Blinding and Unblinding..........................................................................................67
8.9
Description of Investigational Agents ......................................................................67
8.9.1
Azacitidine ......................................................................................................67
8.9.2
Pevonedistat ....................................................................................................67
8.10
Preparation, Reconstitution, and Dispensation..........................................................67
8.11
Packaging and Labeling...........................................................................................68
8.12
Storage, Handling, and Accountability.....................................................................68
8.13
Other Protocol-Specified Materials ..........................................................................69
9.0
STUDY CONDUCT......................................................................................................69
9.1
Study Personnel and Organizations..........................................................................69
9.2
Arrangements for Recruitment of Patients................................................................69
9.3
Treatment Group Assignments.................................................................................69
9.4
Study Procedures.....................................................................................................69
9.4.1
Informed Consent ............................................................................................70
9.4.2
Inclusion/Exclusion Confirmation....................................................................70
9.4.3
Patient Demographics......................................................................................70
9.4.4
Medical History and IPSS-R Risk Categorization ............................................70
9.4.5
Modified Charlson Comorbidity Index Assessment .........................................72
9.4.6
Physical Examination ......................................................................................72
9.4.7
Patient Height..................................................................................................72
9.4.8
Patient Weight .................................................................................................72
9.4.9
ECOG PS ........................................................................................................72
9.4.10
Vital Signs.......................................................................................................73
9.4.11
Pregnancy Test ................................................................................................73
9.4.12
PROs ...............................................................................................................73
9.4.13
Hospitalization Assessment .............................................................................74
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9.4.14
Concomitant Medications and Procedures........................................................74
9.4.15
AEs .................................................................................................................74
9.4.16
Enrollment.......................................................................................................74
9.4.17
ECGs...............................................................................................................75
9.4.18
Chest X-ray .....................................................................................................75
9.4.19
Clinical Laboratory Evaluations.......................................................................75
9.4.19.1
Clinical Chemistry, Hematology, and Urinalysis......................................75
9.4.20
Disease Assessment.........................................................................................77
9.4.21
Biomarker, Pharmacodynamic, and PK Samples..............................................82
9.4.21.1
Primary Specimen Collection...................................................................82
9.4.22
PK Measurements............................................................................................83
9.4.23
Biomarker Measurements in Buccal Epithelial Cells........................................84
9.4.24
Bone Marrow Aspirate and Biopsy Collection and Analysis ............................84
9.5
Completion of Study Treatment (for Individual Patients) .........................................86
9.6
Completion of Study (for Individual Patients)..........................................................87
9.7
Discontinuation of Treatment With Study Drug and Patient Replacement................88
9.8
Withdrawal of Patients From Study .........................................................................88
9.9
Study Compliance....................................................................................................89
9.10
Posttreatment Follow-up Assessments (EFS Follow-up, Response Follow-up, and 
OS Follow-up).........................................................................................................89
9.11
Posttrial Access .......................................................................................................90
9.11.1
Posttrial Access ...............................................................................................90
9.11.2
Duration of PTA..............................................................................................90
10.0
ADVERSE EVENTS ....................................................................................................91
10.1
Definitions...............................................................................................................91
10.1.1
PTE Definition ................................................................................................91
10.1.2
AE Definition ..................................................................................................91
10.1.3
SAE Definition................................................................................................91
10.2
Procedures for Recording and Reporting AEs and SAEs..........................................92
10.3
Monitoring of AEs and Period of Observation .........................................................93
10.4
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events.........93
10.5
Procedures for Reporting Product Complaints or Medication Errors (Including 
Overdose) ................................................................................................................94
10.6
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities...........94
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................95
11.1
Takeda Safety Monitoring........................................................................................95
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11.2
IRC..........................................................................................................................95
11.3
Independent Data Monitoring Committee ................................................................95
12.0
DATA HANDLING AND RECORDKEEPING............................................................96
12.1
eCRFs......................................................................................................................96
12.2
Record Retention .....................................................................................................97
13.0
STATISTICAL METHODS..........................................................................................98
13.1
Statistical and Analytical Plans ................................................................................98
13.1.1
Analysis Sets ...................................................................................................98
13.1.2
Analysis of Demographics and Other Baseline Disease Characteristics............99
13.1.3
Efficacy Analysis.............................................................................................99
13.1.3.1
Analyses for Primary Efficacy Endpoint ..................................................99
13.1.3.2
Analyses of Key Secondary Efficacy Endpoint ........................................99
13.1.3.3
Interim Analyses, Final Analysis, and Multiple Hierarchical Testing 
Procedure for Testing Primary and Key Secondary Efficacy Endpoints..100
13.1.3.4
Analyses of Other Secondary Efficacy Endpoints ..................................104
13.1.4
PK Analysis...................................................................................................107
13.1.5
PRO Analyses................................................................................................107
13.1.6
Safety Analysis..............................................................................................107
13.1.7
EFS Events Re-estimation at IA1...................................................................108
13.2
Determination of Sample Size................................................................................109
14.0
QUALITY CONTROL AND QUALITY ASSURANCE.............................................110
14.1
Study-Site Monitoring Visits .................................................................................110
14.2
Protocol Deviations................................................................................................111
14.3
Quality Assurance Audits and Regulatory Agency Inspections ..............................111
15.0
ETHICAL ASPECTS OF THE STUDY......................................................................112
15.1
IRB and/or IEC Approval ......................................................................................112
15.2
Subject Information, Informed Consent, and Subject Authorization .......................113
15.3
Subject Confidentiality ..........................................................................................114
15.4
Publication, Disclosure, and Clinical Trial Registration Policy...............................114
15.4.1
Publication.....................................................................................................114
15.4.2
Clinical Trial Registration..............................................................................115
15.4.3
Clinical Trial Results Disclosure....................................................................115
15.5
Insurance and Compensation for Injury..................................................................115
16.0
REFERENCES............................................................................................................116
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LIST OF IN-TEXT TABLES
Table 6.a
Primary and Secondary Endpoints for Disclosures .............................................51
Table 8.a
Concomitant Medications Excluded While Receiving Study Treatment (Single 
Agent Azacitidine or Combination Pevonedistat Plus Azacitidine).....................63
Table 8.b
Concomitant Medications and Procedures Permitted During the Study...............64
Table 9.a
IPSS-R Prognostic Score Values........................................................................71
Table 9.b
IPSS-R Cytogenetic Risk Groups.......................................................................71
Table 9.c
IPSS-R Prognostic Risk Categories/Scores.........................................................72
Table 9.d
Hematology Tests ..............................................................................................76
Table 9.e
Complete Serum Chemistry Panel......................................................................76
Table 9.f
Select Serum Chemistry Panel ...........................................................................76
Table 9.g
Urinalysis with Microscopic Analysis ................................................................77
Table 9.h
Response Criteria for Altering Natural History of MDS and CMML..................79
Table 9.i
Response Criteria for HI for MDS and CMML...................................................81
Table 9.j
Response Criteria for AML................................................................................82
Table 9.k
Primary Specimen Collection.............................................................................83
LIST OF IN-TEXT FIGURES
Figure 13.a
Multiple Hierarchical Testing Procedure at IA2 and FA for the US Submission
........................................................................................................................101
Figure 13.b
Multiple Hierarchical Testing Procedure at IA2 and FA for the ex-US 
Submission ......................................................................................................102
LIST OF APPENDICES
Appendix A
Treatment-Related Mortality Rates...................................................................123
Appendix B
Study Diagrams ...............................................................................................124
Appendix C
Schedule of Events...........................................................................................127
Appendix D
Responsibilities of the Investigator...................................................................134
Appendix E
Investigator Consent to Use of Personal Information........................................136
Appendix F
ECOG Scale for Performance Status ................................................................137
Appendix G
Definition of Postmenopausal ..........................................................................138
Appendix H
Methods of Contraception Considered to be Effective......................................139
Appendix I
Cockcroft-Gault Equation ................................................................................140
Appendix J
New York Heart Association Classification of Cardiac Disease........................141
Appendix K
CYP3A Inducers..............................................................................................142
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Appendix L
Modified Charlson Comorbidity Index.............................................................143
Appendix M
BSA Calculation ..............................................................................................144
Appendix N
Formula for ANC Calculation ..........................................................................145
Appendix O
Detailed Description of Amendments to Text...................................................146
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2.0
STUDY SUMMARY
Name of Sponsor(s):
Takeda Development Center Americas, Inc.
Compound:
Pevonedistat (TAK-924/MLN4924)
Title of Protocol: A Phase 3, Randomized, Controlled, 
Open-label, Clinical Study of Pevonedistat Plus Azacitidine 
Versus Single-Agent Azacitidine as First-Line Treatment 
for Patients With Higher-Risk Myelodysplastic Syndromes, 
Chronic Myelomonocytic Leukemia, or Low-Blast Acute 
Myelogenous Leukemia
IND No.: 78,427
EudraCT No.:
2017-000318-40
Study Number: Pevonedistat-3001
Phase: 3
Study Design:
General eligibility may be assessed before the formal Screening period if it is part of standard clinical practice. 
However, formal screening will occur during the Screening period, which may last up to 28 days before 
randomization. The sponsor’s project clinician (or designee) will confirm patient eligibility before randomization by 
the investigator.
Once enrolled, patients with myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), or 
low-blast acute myelogenous leukemia (AML) will be randomized at a 1:1 ratio to receive study drug (either 
single-agent azacitidine or the combination of pevonedistat and azacitidine) in 28-day treatment cycles. All patients 
will be stratified into 4 categories: low-blast AML, Revised International Prognostic Scoring System (IPSS-R) risk 
groups of very high, high, or intermediate for MDS or CMML [1]. Note that patients with higher-risk MDS (HR MDS) 
or CMML indeterminate cytogenetics findings at Screening should be assigned a cytogenetics prognostic variable of 2 
points, ie, intermediate, for determining overall Prognostic Risk Category/Score. Modifications to the dose and 
schedule may be allowed.
Patients, including those who achieve a complete remission (CR), may receive study treatment until they experience 
unacceptable toxicity, relapse, transformation to AML (in patients with HR MDS or CMML), or progressive disease 
(PD). Patients may be allowed to continue study treatment (either treatment arm) if they meet the criteria for PD based 
only on bone marrow blast count (without AML transformation in patients with HR MDS or CMML) if, in the clinical 
judgment of the investigator, the patient is still receiving clinical benefit from this treatment and the continuation is 
endorsed by the sponsor’s project clinician (or designee). Patients who meet the criteria for PD and continue on study 
under these conditions must be reconsented before continuing study treatment. Patients may choose to discontinue 
therapy at any time.
Patients will attend the End-of-Treatment (EOT) visit 30 days (+10 days) after the last dose of study drug or before the 
start of subsequent antineoplastic therapy if that occurs sooner.
Following the EOT visit, patients with HR MDS or CMML will enter event-free survival (EFS) follow-up, if their 
disease has not transformed to AML. Patients will have monthly assessments to include physical exam, clinical blood 
tests, health-related quality of life (HRQOL) assessments, hospitalization assessment, and disease assessment. 
Patients who discontinue study treatment without evidence of progression (ie, PD or transformation to AML) will 
have a bone marrow aspirate and hematology tests (see Table 9.d), at time of suspected progression and at the time of 
suspected transformation to AML if this event occurs later (specimens sent to central laboratory). Patients who 
discontinue treatment while in CR or partial remission (PR) will also have a bone marrow aspirate and hematology 
tests done at the time of suspected relapse (specimens sent to central laboratory). Patients will continue monthly EFS 
follow-up study visits until their disease transforms to AML. Patients who have started subsequent therapy will have 
EFS follow-up but will not be required to have monthly visits; at the time of suspected transformation to AML, they 
will have a bone marrow aspirate and hematology tests (specimen sent to central laboratory).
Following the EOT visit, patients with low-blast AML will enter response follow-up, if they have no evidence of PD 
and they have not started subsequent therapy. Patients will have monthly assessments to include physical exam, 
clinical blood tests, HRQOL assessments, hospitalization assessment, and disease assessment. Patients who 
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discontinue study treatment while not in CR and without evidence of PD will have a bone marrow aspirate and 
hematology tests done at the time of suspected PD (specimen sent to central laboratory). Patients who discontinue 
treatment while in CR will also have a bone marrow aspirate done at the time of suspected relapse (specimen sent to 
central laboratory). Patients will continue monthly response follow-up visits, until they relapse from CR or meet the 
criteria for PD.
Following the EFS and response follow-up visits, patients with HR MDS or CMML who discontinue study treatment 
because of transformation to AML, or patients with low-blast AML who discontinue study treatment because of PD, 
will enter overall survival (OS) follow-up and will be contacted every 3 months until death to document subsequent 
therapies and survival status.
Disease response assessments for all HR MDS and CMML patients will be based on the Modified International 
Working Group (IWG) response criteria for MDS [2]. Disease response assessments for patients with low-blast AML 
will be based on the Revised Recommendations of the IWG for Diagnosis, Standardization of Response Criteria, 
Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia [3]. Formal disease 
assessments for study endpoints will be determined based on local bone marrow aspirate blast counts (blast counts 
from the bone biopsy may be used in the event the aspirate sample is inadequate and a biopsy was done), clinical 
laboratory evaluations performed at a central laboratory (local laboratory results may be used for time-sensitive 
clinical decisions), and local transfusion data.
Inpatient hospital admissions related to HR MDS or CMML, or low-blast AML, as well as transfusion independence, 
will be monitored as secondary efficacy endpoints. Red blood cell (RBC) and platelet transfusion independence 
requires that the patient receive no RBC or platelet transfusions, respectively, for a period of at least 8 weeks during 
the time period from the first dose of study drug administration through 30 days after the last dose of any study drug. 
Treatment-emergent resistance also will be monitored.
A bone marrow aspirate and biopsy will be collected at Screening, and bone marrow aspirates will be collected during 
treatment and follow-up for blast count evaluation (to inform disease burden assessment).
Bone marrow aspirates and blood will be obtained at Screening and at additional time points for assessing response 
and/or for translational research purposes. Samples will be collected and analyzed (at a central laboratory) from 
patients in both treatment arms. Bone marrow aspirates and blood collected at Screening will be used to analyze tumor 
cytogenetics, baseline somatic mutations, and other molecular characteristics such as gene expression profile and 
epigenetic status. Bone marrow aspirates and blood collected at the specified time points during treatment and/or at 
relapse will be used to evaluate depth and duration of response by following parameters such as residual tumor cells, 
residual mutation load, and changes in epigenetic modifications. Such analysis will also be used to identify 
treatment-emergent mutations. Developing potential biomarkers of pevonedistat-mediated activity may require 
analysis of the data from this study in combination with data from other clinical studies of pevonedistat.
Sparse sampling for the determination of pevonedistat plasma concentrations and, if appropriate, its metabolites will 
be collected from each patient in the Combination Pevonedistat Plus Azacitidine Arm to contribute to a population 
pharmacokinetic (PK) analysis of pevonedistat co-administered with azacitidine.
Adverse events and Eastern Cooperative Oncology Group (ECOG) performance status (PS) will be assessed, and 
electrocardiograms, clinical laboratory values, and vital signs will be obtained, to evaluate the safety and tolerability 
of the study drug treatments. Toxicity will be evaluated according to National Cancer Institute Common Terminology 
Criteria for Adverse Events, version 4.03, effective date 14 June 2010 [4].
Patient-reported outcomes (PROs) will be evaluated using the European Organization for Research and Treatment of 
Cancer Quality of Life Questionnaire (EORTC QLQ-C30), version 3.0 and EuroQoL 5 dimensions 5 levels (a quality 
of life questionnaire of the “EuroQoL Group Association” that was expanded to a 5-level instrument) (EQ-5D-5L) 
questionnaires.
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Primary Objective:

To determine whether the combination of pevonedistat and azacitidine improves EFS when compared with 
single-agent azacitidine. (An event is defined as death or transformation to AML in patients with MDS or CMML,
whichever occurs first, and is defined as death in patients with low-blast AML.)
Key Secondary Objective:

To determine whether the combination of pevonedistat and azacitidine improves OS when compared with 
single-agent azacitidine.
Other Secondary Objectives:

To determine whether the combination of pevonedistat and azacitidine improves 6-month and 1-year survival 
rates when compared with single-agent azacitidine.

To determine in patients with HR MDS, patients with HR CMML, and patients with HR MDS/CMML whether 
the combination of pevonedistat and azacitidine delays time to AML transformation when compared with 
single-agent azacitidine.

To determine whether the combination of pevonedistat and azacitidine, when compared with single-agent 
azacitidine, improves the rate of CR (CR in patients with HR MDS or CMML, or low-blast AML), CR+complete 
remission with incomplete blood count recovery (CRi) in patients with low-blast AML, CR+marrow CR (in 
patients with HR MDS or CMML), CR+PR+hematologic improvement (HI) (in patients with HR MDS or 
CMML), CR+marrow CR+PR (in patients with HR MDS or CMML), CR+marrow CR+PR+HI (in patients with 
HR MDS or CMML), overall response, overall response by Cycle 6, and overall response 2. Overall response in 
patients with HR MDS or CMML is defined as CR+PR; overall response in patients with low-blast AML is 
defined as CR+CRi+PR. Overall response 2 in patients with HR MDS or CMML is defined as CR+PR+HI; 
overall response 2 in patients with low-blast AML is defined as CR+CRi+PR.

To determine whether the combination of pevonedistat and azacitidine, when compared with single-agent 
azacitidine, improves duration of CR (CR for HR MDS or CMML, or low-blast AML), CR+CRi for low-blast 
AML, overall response (CR+PR for HR MDS or CMML, CR+CRi+PR for low-blast AML), and overall response 
2 (CR+PR+HI for HR MDS or CMML, CR+CRi+PR for low-blast AML).

To determine whether the combination of pevonedistat and azacitidine improves rate of transfusion independence 
when compared with single-agent azacitidine. RBC and platelet transfusion independence requires that the patient 
receive no RBC or platelet transfusions for a period of at least 8 weeks during the time period from the first dose 
of study drug administration through 30 days after the last dose of any study drug.

To determine whether the combination of pevonedistat and azacitidine increases the duration of RBC transfusion 
independence, platelet transfusion independence, or platelet and RBC transfusion independence, when compared 
with single-agent azacitidine.

To determine whether the combination of pevonedistat and azacitidine improves time to first CR or PR (for HR 
MDS or CMML, or low-blast AML) and to first CR or CRi (for low-blast AML) when compared with 
single-agent azacitidine.

To determine in patients with HR MDS, patients with HR MDS/CMML, and patients with HR CMML whether 
the combination of pevonedistat and azacitidine improves rates of HI when compared with single-agent 
azacitidine.

To determine whether the combination of pevonedistat and azacitidine does not increase inpatient hospital 
admission(s) related to HR MDS, CMML, or low-blast AML when compared with single-agent azacitidine.

To determine whether the combination of pevonedistat and azacitidine delays time to PD, relapse after CR 
(low-blast AML), relapse after CR or PR (HR MDS/CMML), or death when compared with single-agent 
azacitidine.

To determine whether the combination of pevonedistat and azacitidine maintains overall health status/quality of 
life and fatigue domain scores as measured by the PRO instrument EORTC QLQ-C30 when compared with 
single-agent azacitidine.

To collect plasma concentration-time data for pevonedistat to contribute to future population PK analyses of 
pevonedistat.
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
To compare ORR, EFS, and OS in patients who have TP53 mutations, 17p deletions, and/or are determined to be 
in an adverse cytogenetic risk group at Baseline, across treatment arms.
Subject Population: Male or female patients aged 18 years or older with HR MDS or CMML, or low-blast AML.
Number of Subjects:
Estimated total: approximately 450 patients (randomized in 
a 1:1 ratio)
Number of Sites:
Estimated total: approximately 120 study centers 
globally
Dose Level(s):
28-day treatment cycles
Single-agent arm: 
Azacitidine (75 mg/m2 [intravenous (IV) or 
subcutaneous (SC)]) on Days 1 through 5, Day 8, and 
Day 9
Combination arm:
Pevonedistat (20 mg/m2 via 60 (±10)-minute infusion) 
on Days 1, 3, and 5 
PLUS
Azacitidine (75 mg/m2 [IV or SC]) on Days 1 through 
5, Day 8, and Day 9 
Route of Administration:
Pevonedistat: IV
Azacitidine: IV or SC (per investigator’s choice)
Duration of Treatment:
Patients, including those who achieve a CR, may receive 
study treatment until they experience unacceptable toxicity, 
relapse, transformation to AML (for patients with HR MDS 
or CMML), or PD (for patients with low-blast AML), the 
sponsor terminates the study, or discontinuation due to 
other reasons.
A minimum of 6 cycles of treatment is strongly encouraged.
Period of Evaluation:
Up to approximately 6 years
Main Criteria for Inclusion:

Morphologically confirmed diagnosis of MDS or nonproliferative CMML (ie, with white blood cell count 
<13,000/µL) or low-blast AML based on 1 of the following:
French-American-British Classifications [5]:
–
Refractory anemia with excess blasts (RAEB), defined as having 5% to 20% myeloblasts in the bone 
marrow.
–
CMML with 10% to 19% myeloblasts in the bone marrow and/or 5% to 19% blasts in the blood.
OR
World Health Organization (WHO) Classifications [6]:
–
Refractory anemia with excess blasts-1 (RAEB-1), defined as having 5% to 9% myeloblasts in the bone 
marrow).
–
Refractory anemia with excess blasts-2 (RAEB-2), defined as having 10% to 19% myeloblasts in the 
bone marrow and/or 5% to 19% blasts in the blood).
–
Chronic myelomonocytic leukemia-2 (CMML-2), defined as having 10% to 19% myeloblasts in the 
bone marrow and/or 5% to 19% blasts in the blood.
–
Chronic myelomonocytic leukemia-1 (although CMML-1 is defined as having <10% myeloblasts in the 
bone marrow and/or <5% blasts in the blood, these patients may enroll only if bone marrow blasts are 
≥5%).
–
WHO-defined AML with 20% to 30% myeloblasts in the bone marrow (defined in this protocol as 
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low-blast AML) and <30% myeloblasts in peripheral blood who are deemed by the investigator to be 
appropriate for azacitidine-based therapy.

All patients with MDS or CMML must also have one of the following Prognostic Risk Categories, based on the 
IPSS-R [1]:
–
Very high (>6 points).
–
High (>4.5-6 points).
–
Intermediate (>3-4.5 points): a patient determined to be in the Intermediate Prognostic Risk Category is only 
allowable in the setting of ≥5% bone marrow myeloblasts.

ECOG PS of 0, 1, or 2.

Patients with AML (20%-30% blasts) must have a treatment-related mortality (TRM) score ≥4 for intensive, 
induction chemotherapy as calculated using the simplified model described by Walter and coworkers [7]; see 
Appendix A.
Calculation of TRM score:
–
0 for (age <61 years), +2 for (age 61-70 years), +4 for (age >71 years).
–
+ 0 for (PS=0), +2 for (PS=1), +4 for (PS >1).
–
+ 0 for (platelets <50,000/µL), +1 for (platelets >50,000/µL).

Clinical laboratory values within the following parameters (repeat within 3 days before the first dose of study 
drug if laboratory values used for randomization were obtained more than 3 days before the first dose of study 
drug):
–
Albumin >2.7 g/dL.
–
Total bilirubin ≤upper limit of the normal range (ULN) except in patients with Gilbert’s syndrome. Patients 
with Gilbert’s syndrome may enroll if direct bilirubin ≤1.5ULN of the direct bilirubin.
–
Alanine aminotransferase and aspartate aminotransferase <2.5×ULN.
–
Creatinine clearance >50 mL/min.
–
Hemoglobin >8 g/dL. Patients may be transfused to achieve this value. Elevated indirect bilirubin due to 
posttransfusion hemolysis is allowed.
Main Criteria for Exclusion:

Previous treatment for HR MDS or CMML, or low-blast AML with chemotherapy or other antineoplastic agents 
including hypomethylating agents such as decitabine or azacitidine. Previous treatment is permitted with 
hydroxyurea and with lenalidomide, except that lenalidomide may not be given within 8 weeks before the first 
dose of study drug.

Acute promyelocytic leukemia as diagnosed by morphologic examination of bone marrow, by fluorescent in situ 
hybridization or cytogenetics of peripheral blood or bone marrow, or by other accepted analysis.

Patients with AML with a white blood cell count >50,000/ µL. Patients who are cytoreduced with leukapheresis 
or with hydroxyurea may be enrolled if they meet the eligibility criteria.

Eligible for intensive chemotherapy and/or allogeneic stem cell transplantation. The reason a patient is not 
eligible for intensive chemotherapy and/or allogeneic stem cell transplantation may consist of one or more of the 
following factors:
–
Age >75.
–
Comorbidities.
–
Inability to tolerate intensive chemotherapy (eg, patients with AML with 20%-30% blasts and TRM ≥4).
–
Physician decision (eg, lack of available stem cell donor).

Patients with either clinical evidence of or history of central nervous system involvement by AML.

Treatment with any investigational products or participation in any interventional studies within 14 days before 
the first dose of any study drug.

Diagnosed or treated for another malignancy within 2 years before randomization or previously diagnosed with 
another malignancy and have any evidence of residual disease. Patients with nonmelanoma skin cancer or 
carcinoma in situ of any type are not excluded if they have undergone resection.
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
Prothrombin time or activated partial thromboplastin time >1.5×ULN or active uncontrolled coagulopathy or 
bleeding disorder. Patients therapeutically anticoagulated with warfarin, direct thrombin inhibitors, direct factor 
Xa inhibitors, or heparin are excluded from enrollment.

Treatment with strong cytochrome P450 3A inducers within 14 days before the first dose of pevonedistat. 
Main Criteria for Evaluation and Analyses:
Primary Endpoint:

EFS: time from randomization to the date of an EFS event (defined as death or transformation to AML in patients 
with MDS or CMML, whichever occurs first, and defined as death in patients with low-blast AML).
Key Secondary Endpoint:

OS.
Other Secondary Endpoints:

Six-month and 1-year survival rates.

Thirty-day and 60-day survival rates.

Time to AML transformation in patients with HR MDS, patients with HR CMML, and patients with 
HR MDS/CMML.

Rate of CR (CR in patients with HR MDS or CMML, or low-blast AML), CR+CRi in patients with low-blast 
AML, CR+marrow CR (in patients with HR MDS or CMML), CR+PR+HI (in patients with HR MDS or 
CMML), CR+marrow CR+PR (in patients with HR MDS or CMML), CR+marrow CR+PR+HI (in patients with 
HR MDS or CMML), overall response, overall response by Cycle 6, and overall response 2. Overall response in 
patients with HR MDS or CMML is defined as CR+PR; overall response in patients with low-blast AML is 
defined as CR+CRi+PR. Overall response 2 in patients with HR MDS or CMML is defined as CR+PR+HI; 
overall response 2 in patients with low-blast AML is defined as CR+CRi+PR.

Duration of CR (CR for HR MDS or CMML, or low-blast AML), CR+CRi for low-blast AML, overall response 
(CR+PR for HR MDS or CMML, CR+CRi+PR for low-blast AML), and overall response 2 (CR+PR+HI for HR 
MDS or CMML, CR+CRi+PR for low-blast AML).

Rates of RBC and platelet transfusion independence.

Duration of RBC transfusion independence, platelet transfusion independence, and platelet and RBC transfusion 
independence.

Time to first CR or PR or CRi (for patients with low-blast AML)

Rates of HI in patients with HR MDS, patients with HR MDS/CMML, and patients with HR CMML.

Patients who have inpatient hospital admission(s) related to HR MDS, CMML (collected through transformation 
to AML or until initiation of subsequent therapy, whichever occurs first) or low-blast AML (collected through 
initiation of subsequent therapy).

Time to PD, relapse after CR (low-blast AML), relapse after CR or PR (HR MDS/CMML), or death.

HRQOL assessed using the EORTC QLQ-C30.

Plasma concentration-time data for pevonedistat.

ORR, EFS, and OS in patients who have TP53 mutations, 17p deletions, and/or are determined to be in an adverse 
cytogenetic risk group in both treatment arms.
There is 1 primary endpoint of EFS and 1 key secondary endpoint of OS. The study design employs an adaptive 
event-size re-assessment approach for EFS in patients with HR MDS and a multiple hierarchical testing procedure for 
type I error control.
There are 2 planned interim analyses (IAs) and 1 final analysis (FA). The first interim analysis (IA1) is to evaluate 
EFS for futility and perform EFS event size re-assessment for patients with HR MDS for the second interim analysis
(IA2). IA2 will be an EFS FA in patients with HR MDS (US submission) and the intent-to treat (ITT) population 
(ex-US submission). The FA will evaluate OS.
IA1 will be performed when approximately 74 EFS events have occurred in patients with HR MDS (around 
50% information relative to the minimal planned event size of 147 EFS events for patients with HR MDS for the EFS 
FA at IA2). The study will stop if the EFS hazard ratio is >1.0 in all 3 of the following populations: patients with HR 
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MDS, patients with HR MDS/CMML, and the ITT population. Otherwise, EFS event size re-estimation for patients 
with HR MDS will be performed using conditional power for the EFS FA that will be conducted at IA2.
IA2 (ie, EFS FA) will be performed when the approximate adaptive EFS event size (from a minimum of 147 to a 
maximum of 249), informed by the Independent Data Monitoring Committee, has occurred in patients with HR MDS. 
The FA will be performed when approximately 202 OS events have occurred in patients with HR MDS. Separate 
multiple hierarchical testing procedures for the US submission and the ex-US submission will be adopted to test the 
primary endpoint of EFS and the key secondary endpoint of OS in the HR MDS population (US submission), the ITT 
population (ex-US submission), and other disease populations at IA2 and FA, with each procedure having a total 
1-sided alpha of 0.025. The details are described in Section 13.1.3.3.
Cui-Hung-Wang (CHW) [8] weighted log-rank test statistics will be used for all the tests that compare the treatment 
groups to preserve type-I error rate when the EFS event size in patients with HR MDS is re-estimated for IA2 at IA1. 
EFS in the HR MDS population (US submission) and in the ITT population (ex-US submission) will be tested first, 
only at IA2, using the 1-sided alpha of 0.025. All other tests specified in the multiple hierarchical testing procedures 
that will be performed at IA2 and/or FA, including OS in the HR MDS population (US submission), OS in the ITT 
population (ex-US submission), OS in the low-blast AML population, and OS in the HR MDS/CMML population,
will use a 1-sided alpha of 0.0001 at IA2 and the remaining 1-sided alpha of 0.0249 at FA. The multiple testing 
procedure (multiple hypotheses and multiple looks) maintains control of the familywise type I error rate, as discussed 
in Glimm et al [9].
If the prespecified number of approximately 202 OS events for FA are expected (based on blinded study data) to be 
available close to the IA2, the IA2 (ie, EFS FA) and the FA (ie, OS FA) will be performed as a single analysis, when 
approximately 202 OS events and the adaptive EFS event size have occurred in patients with HR MDS. As originally 
planned, separate multiple hierarchical testing procedures for the US submission and the ex-US submission will be 
used to test the primary endpoint of EFS and the key secondary endpoint of OS in the HR MDS population (US 
submission), the ITT population (ex-US submission), and other disease populations at this single analysis, with a total 
1-sided alpha of 0.025 for each procedure.
Sample Size Justification: The total number of patients was calculated on the basis of maintaining 83% power to test 
the key secondary endpoint OS in patients with HR MDS at a 1-sided alpha level of 0.025, as well as sufficient 
representation of patients with low-blast AML. The study is also adequately powered to test the primary endpoint, 
EFS in both patients with HR MDS and the ITT population for full approval in the US submission and the ex-US 
submission respectively, as well as to test OS in the ITT population. 
A total of approximately 450 patients, including at least 350 patients with HR MDS or CMML and at least 
100 patients with low-blast AML, will be enrolled. Patients will be randomized in a 1:1 ratio to the 2 treatment arms, 
stratified by low-blast AML, IPSS-R risk group of very high, high, or intermediate for MDS/CMML [1]. Assuming an 
enrollment rate that increases from an initial 1 patient per month to 22 patients per month after the first 10 months, 
with a dropout rate of approximately 10%, the study will take approximately 27 months for patient accrual and an 
additional approximately 38 months for follow-up from the enrollment of the last patient.
Assuming an exponential distribution for EFS, an initial minimum of 147 EFS events from patients with HR MDS 
will be required to detect an optimistic hazard ratio of 0.585 (median EFS of 17.09 months in the combination arm 
versus 10 months in the azacitidine alone arm) with approximately 90% power at a 1-sided alpha of 0.025. A 
maximum of 249 EFS events from patients with HR MDS will be needed to detect a hazard ratio of 0.663 (median 
EFS of 15.08 months in the combination arm versus 10 months in the azacitidine alone arm), with approximately 90% 
power at a 1-sided alpha of 0.025. The number of EFS events from patients with HR MDS for the adaptive EFS FA 
falls between the minimum of 147 EFS events and the maximum of 249 EFS events. It is projected that the EFS event 
size from the ITT population ranges from approximately 158 (approximately 92% power, 1-sided alpha=0.025, hazard 
ratio=0.585, median EFS of 22.22 months in the combination arm versus 13 months in the azacitidine alone arm) to 
305 (approximately 95% power, 1-sided alpha=0.025, hazard ratio=0.663, median EFS of 19.61 months in the 
combination arm versus 13 months in the azacitidine alone arm).
Similarly, assuming an exponential distribution for OS, 202 OS events in patients with HR MDS will be needed to 
detect a hazard ratio of 0.663 (median OS of 36.95 months in the combination arm versus 24.5 months in the 
azacitidine alone arm), with approximately 83% power at a 1-sided alpha of 0.025. It is projected that approximately 
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280 OS events will occur to the ITT population, providing approximately 93% power to test OS in the ITT population 
(1-sided alpha=0.025, hazard ratio=0.663, median OS of 36.95 months in the combination arm versus 24.5 months in 
the azacitidine alone arm).
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3.0
STUDY REFERENCE INFORMATION
3.1
Study-Related Responsibilities 
The sponsor will perform all study-related activities with the exception of those identified in the 
Clinical Study Supplier List. The identified vendors for specific study-related activities will 
perform these activities in full or in partnership with the sponsor.
3.2
Coordinating Investigator 
Takeda will select a signatory coordinating investigator from the investigators who participate in 
the study. Selection criteria for this investigator will include significant knowledge of the study 
protocol, the study medication, their expertise in the therapeutic area and the conduct of clinical 
research as well as study participation. The signatory coordinating investigator will be required to 
review and sign the clinical study report and by doing so agrees that it accurately describes the 
results of the study.
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3.3
List of Abbreviations
Abbreviation
Term
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AML
acute myelogenous leukemia
ANC
absolute neutrophil count
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AUC
area under the plasma concentration-time curve
AUCt
area under the plasma concentration-time curve from time 0 to time t.
BCRP
breast cancer resistance protein
BSA
body surface area
BUN
blood urea nitrogen
CCR
conventional care regimen
CDL
cullin-dependent ubiquitin E3 ligase 
Cmax
maximum observed concentration
CMH
Cochran-Mantel-Haenszel
CMML
chronic myelomonocytic leukemia
CR
complete remission 
CRi
complete remission with incomplete blood count recovery
CRO
contract research organization
CHW
Cui-Hung-Wang (test)
CYP
cytochrome P450
DDI
drug-drug interaction
DLTs
dose-limiting toxicities
DME
drug-metabolizing enzyme
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EFS
event-free survival
EQ-5D-5L
EuroQoL 5 dimensions 5 levels (a quality of life questionnaire of the “EuroQoL Group 
Association” that was expanded to a 5-level instrument)
EORTC
European Organisation for the Research and Treatment of Cancer
EORTC QLQ-C30 
European Organisation for the Research and Treatment of Cancer Core Quality of Life 
Questionnaire
EOT
end of treatment 
EU
European Union
ex-US
all countries and regions excluding the United States
FA
final analysis
FAB
French-American-British
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Abbreviation
Term
FDA
[United States] Food and Drug Administration
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
G-CSF
granulocyte colony-stimulating factor
GLP
Good Laboratory Practice
HI
hematologic improvement
HIV
human immunodeficiency virus
HMA
hypomethylating agent
HR MDS
higher-risk myelodysplastic syndromes
HRQOL
health-related quality of life
HSCT
hematopoietic stem cell transplantation
IA
interim analysis
IA1
first interim analysis
IA2
second interim analysis
IB
Investigator’s Brochure
IC50
concentrations producing 50% inhibition 
ICF
informed consent form
ICH
International Council for Harmonisation
IDMC
independent data monitoring committee
IEC
independent ethics committee
IRC
independent review committee
IPSS-R
Revised International Prognostic Scoring System
IRB
institutional review board
ITT
intent-to-treat
ITD
internal tandem duplication
IV
intravenous(ly)
IWG
International Working Group
IWRS
interactive web response system 
K-M
Kaplan-Meier
LFT
liver function test
MDS
myelodysplastic syndromes
MedDRA
Medical Dictionary for Regulatory Activities
MRD
minimal residual disease
MTD
maximum tolerated dose
NAE
NEDD8-activating enzyme 
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NEDD8
neural precursor cell expressed developmentally down-regulated protein 8
NGS
next-generation sequencing
OATP
organic anion-transporting polypeptides 
OBF
O’Brien Fleming
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Abbreviation
Term
ORR
overall response rate
ORR 2
overall response rate 2
OS
overall survival
PBPK
physiologically based pharmacokinetic
PCR
polymerase chain reaction
PD
progressive disease; disease progression
P-gp
P-glycoprotein 
PK
pharmacokinetic(s)
PP
per protocol
PR
partial remission 
PRO
patient-reported outcome
PS
[Eastern Cooperative Oncology Group] performance status
PT
prothrombin time
PTA
posttrial access
PTE
pretreatment event
RAEB
refractory anemia with excess blasts
RAEB-t
refractory anemia with excess blasts in transformation
RBC
red blood cell
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous
SDV
source data verification
SmPC
Summary of Product Characteristics
SOC
system organ class
SOE
Schedule of Events
SUSARs
suspected unexpected adverse reactions
TDC
Takeda Development Center
TEAE
treatment-emergent adverse event
TRM
treatment-related mortality
ULN
upper limit of the normal range
US
United States
USP
United States Pharmacopeia
USPI
United States Prescribing Information
WBC
white blood cell
WHO
World Health Organization
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3.4
Corporate Identification 
TDC Japan
Takeda Development Center Japan
TDC Americas
Takeda Development Center Americas, Inc.
TDC Asia
Takeda Development Center Asia, Pte Ltd
TDC Europe
Takeda Development Centre Europe Ltd
TDC
TDC Americas, TDC Japan, TDC Asia, and/or TDC Europe, as applicable
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4.0
INTRODUCTION
4.1
Scientific Background
4.1.1
Diseases Under Treatment
Myelodysplastic syndromes (MDS) are a group of biologically and clinically heterogeneous 
hematopoietic disorders derived from an abnormal multipotent progenitor cell. The diagnosis of 
MDS is made based upon findings in the peripheral blood and bone marrow as interpreted within 
the clinical context. Most cases of MDS are diagnosed based upon the presence of 3 main features:

Otherwise unexplained quantitative changes in 1 or more of the blood and bone marrow 
elements (ie, red cells, granulocytes, platelets). 

Morphologic evidence of significant dysplasia (ie, ≥10 percent of erythroid precursors, 
granulocytes, or megakaryocytes) upon visual inspection of the peripheral blood smear, bone 
marrow aspirate, and bone marrow biopsy in the absence of other causes of dysplasia. 

Blast forms account for less than 20 percent of the total cells of the bone marrow aspirate and 
peripheral blood. Cases with higher blast percentages are considered to have acute 
myelogenous leukemia (AML). In addition, the presence of myeloid sarcoma or certain 
genetic abnormalities, such as those with t(8;21), inv(16), or t(15;17), are considered 
diagnostic of AML, irrespective of the blast cell count.
MDS are classified using the World Health Organization (WHO) classification system [6,10]
based upon a combination of morphology, immunophenotype, genetics, and clinical features. The 
WHO classification system was built upon the French-American-British (FAB) Cooperative 
Group classification [5].
MDS are commonly divided into lower- or higher-risk categories based on the Revised 
International Prognostic Scoring System (IPSS-R) for MDS, which is a scoring system useful for 
estimating overall survival (OS) and the risk of transformation to AML [1]. Overall, 
approximately 25% of patients with very high, high, or intermediate IPSS-R scores will transform 
to AML within 0.7 years, 1.4 years, and 3.2 years, respectively [1]. Median survival for patients 
with MDS varies from years to months and decreases with increasing IPSS-R score.
Because MDS are heterogeneous diseases, varied treatment options exist. Most patients with MDS 
are managed with noncurative treatment strategies to control symptoms, improve quality of life, 
improve OS, and decrease progression to AML. Treatment of patients with lower-risk MDS (often 
defined as patients with <5% myeloblasts and/or normal or good risk cytogenetics and few 
cytopenias) focuses on minimizing blood product transfusions and maximizing quality of life 
through use of supportive care (eg, antibiotics as needed for infections, red blood cell [RBC] 
transfusions), growth factors such as erythropoiesis stimulating factors or immunosuppressive 
drugs. Treatment for patients with higher-risk disease often includes DNA hypomethylating 
agents (HMAs; azacitidine and decitabine) [11]. Rarely, intensive chemotherapy is used in 
patients with higher-risk MDS (HR MDS), but it generally results in significant toxicity and 
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modest responses 
(uptodate.com/contents/treatment-of-high-or-very-high-risk-myelodysplastic-syndromes, 
Treatment of high or very high risk myelodysplastic syndromes, Accessed 08 December 2014) 
[12-14]. 
Hypomethylating agents produce objective hematologic responses in approximately half of MDS 
patients, delay leukemic progression, improve quality of life, and, for azacitidine only, prolong 
survival in patients with HR MDS. Nevertheless, treatment with HMAs is not curative, and most 
patients relapse within 2 years. Lenalidomide, an immunomodulatory thalidomide congener, 
significantly improves RBC transfusion-independence rates and increases hemoglobin, but it is 
approved only for use in patients with the 5q syndrome subtype of low-risk MDS [12,13,15-17].
The only known curative therapy for MDS is allogeneic stem cell transplantation. However, only a 
minority of patients (typically with HR MDS) undergo this procedure because of contraindications 
and the limited availability of appropriate stem cell donors [18]. Even in these patients, 
treatment-related mortality (TRM) and morbidity and high relapse rates compromise long-term 
disease-free survival 
(uptodate.com/contents/treatment-of-high-or-very-high-risk-myelodysplastic-syndromes, 
Treatment of high or very high risk myelodysplastic syndromes, Accessed 08 December 2014) 
[13,19,20]. More-recent therapeutic approaches to MDS patients with higher-risk disease have 
involved combining drugs with HMAs, either to take advantage of synergistic properties of, for 
example, histone deacetylase inhibition combined with epigenetic modification, or to capitalize on 
nonoverlapping mechanisms of action [21,22].
As detailed by Zandberg et al, 2013 [23], chronic myelomonocytic leukemia (CMML) is a clonal 
stem cell disorder that displays features of both MDS and a myeloproliferative neoplasm. 
Diagnostic criteria for CMML include persistent peripheral blood monocytosis (>10×109/L), 
absence of the Philadelphia chromosome and/or BCR-ABL1 fusion gene, absence of 
platelet-derived growth factor receptor or gene rearrangement, fewer than 20% blasts in the blood 
and the bone marrow, and dysplasia of 1 or more myeloid lineages [24]. CMML was classified as 
an MDS in the FAB classification system in 1982 [5], but was subsequently reclassified as a mixed 
myelodysplastic/myeloproliferative disorder by the WHO classification system in 2001 [25]. Two 
subgroups of CMML were proposed based on the white blood cell (WBC), a myelodysplastic type
(WBC less than 13109/L), and a myeloproliferative type (WBC greater than 13109/L) [26]. 
CMML shares clinical and biological features with MDS, including development of cytopenias 
and bone marrow failure, risk of progression to AML, and overlapping recurring cytogenetic 
abnormalities. Like MDS, it has a variable clinical course, with reported rates of transformation to 
AML of 15% to 52% and a median OS of 12 to 18 months [27-29]. Treatment modalities for the 
2 diseases are also similar, including hematopoietic growth factors (erythropoiesis-stimulating 
agents and granulocyte colony-stimulating factor [G-CSF]), transfusion support, HMAs, and 
allogeneic hematopoietic stem cell transplantation (HSCT). 
Prognostic scoring systems for MDS, including the IPSS-R scoring system used in this study, have 
been routinely applied to patients with CMML and have been shown to be predictive of both 
transformation to AML and OS [30]. 
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Low marrow blast count (20%-30%) WHO-defined AML was previously classified as refractory 
anemia with excess blasts (RAEB) in transformation (RAEB-t). WHO criteria now define AML 
as >20% bone marrow blasts. In a phase 3 randomized trial, azacitidine significantly prolonged OS 
compared with conventional care regimens (CCRs) in patients with HR MDS [16]. A subgroup 
analysis of 113 elderly patients (median age 70 years) compared the effects of azacitidine versus 
CCRs on OS of these FAB-defined RAEB-t and WHO-defined AML [16]. Median OS for 
azacitidine-treated patients was 24.5 months compared with 16.0 months for CCR-treated patients 
(hazard ratio=0.47). Furthermore, azacitidine was associated with fewer total days in the hospital 
than CCR. In another phase 3 study, 191 patients with HR MDS by FAB criteria were randomly 
assigned to azacitidine or best supportive care [31]. Of these, 45 patients had WHO-defined AML. 
Response rates to azacitidine were similar in MDS and these low marrow blast AML patients. 
Azacitidine was associated with improvements in physical function, symptoms, and psychological 
state. Patients assigned to supportive care were permitted to cross over to azacitidine at the time of 
progression; this design limited survival analysis. Based on these studies, azacitidine-based 
therapy is a standard of care in low marrow blast count WHO-defined AML.
While HR MDS, CMML, and low marrow blast count AML can have differences in clinical 
presentation and disease course, the biology of this group of diseases share similarities including 
mutations in genes such as TP53, RUNX1, ASXL1, and TET2 [32-34]. This group of diseases, in 
addition to biological similarities, also shares, as previously discussed, sensitivity to azacitidine 
which results in clinical efficacy as demonstrated by significant improvements in overall response 
rates (ORRs), hematopoietic improvement and a significant improvement in OS compared with 
CCRs and with supportive care. The latter data, as well as preliminary clinical activity 
demonstrated by the combination of pevonedistat and azacitidine in previously untreated patients 
with AML (see Section 4.3), provide a compelling rationale to evaluate this combination in 
patients with HR MDS or CMML, or low marrow blast count AML. 
4.1.2
Study Drug: Pevonedistat
Pevonedistat (MLN4924; TAK-924) is a first-in-class small molecule inhibitor of the neural 
precursor cell expressed developmentally down-regulated protein 8 (NEDD8)-activating enzyme 
that is being developed for the treatment of malignancies. NEDD8-activating enzyme (NAE) is an 
E1 activating enzyme and is an essential component of the NEDD8 conjugation pathway, which 
controls the activity of a subset of ubiquitin E3 ligases, multiprotein complexes that transfer 
ubiquitin molecules to protein substrates that are then targeted to the proteasome for degradation. 
Cullin-dependent ubiquitin E3 ligases (CDLs) require conjugation to NEDD8 to be activated. 
CDLs control the timely ubiquitination and consequent proteasomal degradation of proteins with 
important roles in cell cycle progression and signal transduction, cellular processes that are 
integral to tumor cell growth, proliferation, and survival. Inhibitors of NAE activity may be of 
therapeutic value in the treatment of various cancers by disrupting proteasomal degradation of a 
variety of critical regulatory proteins. As detailed in Section 4.5, the nonclinical and preliminary 
clinical experience in AML with pevonedistat alone or in combination supports further evaluation 
in the subset of patients who are classified as HR MDS or CMML, or low-blast AML.
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4.2
Nonclinical Experience
4.2.1
Single-Agent Pevonedistat
Pevonedistat is a potent and selective inhibitor of NAE activity.
Pevonedistat treatment of cultured tumor cells resulted in growth inhibition of a wide variety of 
cell lines derived from acute leukemias, lymphomas, multiple myeloma, and a range of solid tumor 
types. Changes in protein levels observed in cultured cells treated with pevonedistat were 
consistent with the inhibition of NAE, in particular a decrease in NEDD8-cullin levels and a 
reciprocal increase in the levels of known CDL substrates, including NFE2-related factor 2 and 
chromatin-licensing and DNA-replication factor-1. In most cell lines evaluated, NAE inhibition by 
pevonedistat led to DNA re-replication and accumulation of cells in the S phase of the cell cycle; 
this resulted in DNA damage and subsequent cell death through apoptosis [35-37].
Pevonedistat demonstrated pharmacodynamic and antitumor activity in solid tumor, lymphoma, 
and AML xenograft models when administered to immunocompromised mice by the 
subcutaneous (SC) route. Very few preclinical models of HR MDS are available, and pevonedistat 
has not been tested specifically in HR MDS.
In vitro assay results indicated a low risk for human ether-à-go-go related gene channel inhibition 
by pevonedistat or its 3 major circulating metabolites. In a Good Laboratory Practice 
(GLP)-compliant cardiovascular safety pharmacology assessment in male beagle dogs dosed via 
intravenous (IV) infusion at 15, 30, or 40 mg/kg (300, 600, or 800 mg/m2, respectively), 
pevonedistat was not well tolerated at doses ≥30 mg/kg (≥600 mg/m2). Mortality and/or 
moribundity were observed within 24 hours postdose as a result of gastrointestinal injury 
(mucoid/soft feces, diarrhea with some macroscopic correlations [reddened mucosa]) at 40 mg/kg. 
In a separate GLP-compliant, 2-cycle, repeat-dose toxicology study in dogs, no test article-related 
effects were noted in the electrocardiogram (ECG) data.
The systemic toxicity of pevonedistat was assessed in GLP-compliant repeat-dose studies in rats 
and dogs. The dose-limiting toxicities (DLTs) in the 2-cycle studies for both species were 
gastrointestinal toxicity and bone marrow and lymphoid tissue depletion. Most adverse effects 
were resolving or had resolved after a 2-week recovery period. Pevonedistat did not result in 
lethality in either of the 5-cycle studies. The primary adverse test article-related effects in 
IV-dosed dogs included an acute phase response (increased body temperature, decreased albumin, 
increased globulin, increased monocytes and neutrophils, and increased fibrinogen levels); 
neutrophilic infiltrates in multiple tissues; and in males, vacuolation and degeneration of the 
seminiferous epithelium of the testes. Most adverse effects were reversing or had reversed after a 
2-week recovery period in both rats and dogs. Given that there were prominent effects on testes 
and ovaries noted at all doses tested in the GLP-compliant repeat-dose toxicology studies in both 
dogs and rats, pevonedistat likely represents a substantial reproductive and developmental hazard.
Detailed information regarding the nonclinical pharmacology and toxicology of pevonedistat may 
be found in the Investigator’s Brochure (IB).
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4.2.2
Pevonedistat With Azacitidine 
The combination of pevonedistat with azacitidine demonstrated synergistic or additive effects on 
viability of AML cell lines treated in vitro. Combination index analysis demonstrated synergy of 
pevonedistat with azacitidine in 2 AML cell lines (OCI-M2 and NB-4) and additivity in 
2 additional AML cell lines (THP-1 and HL60). The combination of pevonedistat and azacitidine 
in HL60 and OCI-M2 cell lines resulted in increased DNA damage (measured by phospho-H2AX) 
and apoptosis (measured by cleaved caspase-3) compared with the levels of these markers induced 
by single-agent pevonedistat or azacitidine.
The benefit of the combination of pevonedistat with azacitidine was confirmed in vivo with 
immunocompromised mice bearing HL-60, OCI-M2, and THP-1 SC tumor xenografts. 
Pevonedistat in combination with azacitidine demonstrated additive or synergistic antitumor 
activity and tumor regression in all 3 SC xenograft models, which represent both 
azacitidine-sensitive (OCI-M2) and azacitidine-insensitive (HL60 and THP-1) models. In 
OCI-M2, azacitidine and pevonedistat as single agents inhibited tumor growth, but the 
combination of these agents resulted in tumor regressions with a statistical assessment of synergy. 
In THP-1, although pevonedistat as a single agent inhibited tumor growth without causing 
regressions and azacitidine as a single agent had only a marginal effect on tumor growth, the 
combination caused regressions and delayed tumor regrowth following the treatment period. In 
HL60, tumor regressions were seen with the combination of pevonedistat and azacitidine at dose 
levels that had minimal or moderate antitumor activity as single agents. Furthermore, in a 
disseminated xenograft model in which HL60 cells were inoculated into immunocompromised 
mice by IV injection, pevonedistat and azacitidine as single agents both extended survival time 
compared with a control group, but the combination extended survival time longer than would be 
expected from an additive combination, thereby demonstrating a synergistic effect on survival.
Detailed information regarding the nonclinical pharmacology and toxicology of pevonedistat may 
be found in the IB.
4.3
Clinical Experience
As of 22 January 2018, pevonedistat has been administered to approximately 495 patients in 
clinical studies. These include 227 patients diagnosed with advanced malignancies including solid 
tumors, AML, melanoma, lymphoma, multiple myeloma, HR MDS, and acute lymphoblastic 
leukemia who participated in studies of single-agent pevonedistat. In completed combination 
studies, 64 elderly patients with treatment-naïve AML (Study C15009) were treated with 
pevonedistat plus azacitidine, and 64 patients with solid tumors received combination treatments 
with docetaxel, gemcitabine, or a combination of carboplatin and paclitaxel (Study C15010). In 
ongoing combination studies, 51 patients with advanced solid tumors have received a single IV 
dose of pevonedistat alone and in combination with the cytochrome P450 (CYP) 3A inhibitor 
probes itraconazole or fluconazole (36 of these 51 patients then continued receiving pevonedistat
plus standard of care, either docetaxel, or carboplatin plus paclitaxel) (Study C15011); 23 East 
Asian patients with WHO-defined AML or HR MDS have received a single IV dose of 
pevonedistat alone and in combination with azacitidine (Study Pevonedistat-1012); 6 patients with 
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advanced solid tumors have received a single dose of [14C]-pevonedistat (5 of these 6 patients then 
continued receiving pevonedistat plus standard of care, either docetaxel, or carboplatin plus 
paclitaxel) (Study Pevonedistat-1013); and 58 patients with HR MDS, CMML, or low-blast AML 
have received combination treatment with azacitidine and pevonedistat (Study 
Pevonedistat-2001).
Pevonedistat has reported single-agent clinical activity in a phase 1 study (Study C15003) in 
patients with relapsed/refractory AML. In Study C15003, a total of 66 patients with AML were 
treated in a variety of patient settings, including after relapse following allogeneic transplant as 
well as with therapy-related AML, and primary refractory AML. In the phase 1 trial, 7 responses 
(2 complete remission [CR] and 5 partial remission [PR]) were observed among 
55 response-evaluable patients with AML who received pevonedistat monotherapy. Investigators 
should note that some patients may benefit from continued treatment even though their bone 
marrow blast counts may fluctuate over the course of the first 4 cycles. For example, 2 of the 
7 responders to pevonedistat given as a single agent in Study C15003 had asymptomatic, transient 
increases in bone marrow blasts after achieving a response. In these 2 cases, bone marrow blasts 
increased from less than 5% to more than 20%, and then went down. In addition, another 
responder in that study had an asymptomatic, transient increase in bone marrow blasts before 
achieving a response. In that case, bone marrow blasts almost doubled before response. These 
3 patients were allowed to remain on study because their investigators felt they were clinically 
benefiting from continued treatment despite changes in their bone marrow blast counts.
Pevonedistat has clinical activity when administered in combination with azacitidine. Study 
C15009 evaluated the combination of escalating doses of pevonedistat plus azacitidine in 
64 treatment-naïve patients with AML. The maximum tolerated dose (MTD) was determined to be 
20 mg/m2 pevonedistat in combination with 75 mg/m2 azacitidine. A total of 61 patients were 
treated at the MTD. ORR in the 64-patient intent-to-treat (ITT) cohort was 50% (20 CR, 
5 complete remission with incomplete blood count recovery [CRi], 7 PR) with an 8.3 month 
median duration of remission. Pevonedistat PK was not altered by the addition of azacitidine. The 
nature and frequency of the reported toxicities (excluding DLTs) were similar to previous reports 
for azacitidine alone. [38]. 
Additional efficacy and safety information from Study C15009 is provided in Section 4.6.2. 
Refer to the IB, which will be updated regularly throughout the duration of this study, for further 
details on the clinical development program for pevonedistat.
4.4
PK of Pevonedistat
4.4.1
Nonclinical PK and Risk Assessment for Drug-Drug Interactions
The absorption, distribution, metabolism, and excretion properties of pevonedistat have been 
studied in Sprague-Dawley rats, beagle dogs, cynomolgus monkeys, and chimpanzees. The whole 
blood clearance is low in all animal species, likely as a result of the extensive partitioning of 
pevonedistat into RBCs. The plasma terminal disposition half-life varied from short (less than 
1 hour in rats) to relatively long (15 hours in monkeys). The major elimination pathway of 
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pevonedistat in animals is through the hepatic route. Urinary excretion of unchanged pevonedistat 
was negligible (<5%) in rats and primates. After an IV dose of [14C] pevonedistat, radioactivity 
was primarily excreted in the feces in intact rats and in bile duct-cannulated rats; excretion was 
almost complete by 24 hours postdose. No plasma metabolite accounted for more than 10% of the 
total plasma radioactivity, suggesting potentially low systemic exposure to metabolites. 
In vitro, pevonedistat is a substrate for P-glycoprotein (P-gp) and breast cancer resistance protein
(BCRP) transporters and is metabolized via hydroxylation and oxidation, predominantly by 
CYP3A4, with a small contribution from CYP2D6 (approximately 3%). Study C15011 is an 
open-label, 2-arm, phase 1 study to assess the effects of multiple doses of fluconazole, a moderate 
CYP3A inhibitor, and itraconazole, a strong CYP3A/P-gp inhibitor, on the single-dose PK of 
pevonedistat in patients with advanced solid tumors. Preliminary data from 26 evaluable patients 
(13 from the itraconazole arm and 13 from the fluconazole arm) demonstrate that steady-state 
exposures to fluconazole had a minimal effect on the single-dose IV pevonedistat PK at 8 mg/m2, 
while mean systemic exposure to pevonedistat increased by approximately 23% in the presence of 
itraconazole. On the basis of these observations, additional patients were enrolled to evaluate the 
effects of itraconazole on pevonedistat PK at the clinical dose of 20 mg/m2. Preliminary data from 
11 patients who completed protocol-specified dosing and PK evaluations indicated that 
pevonedistat systemic exposures following IV administration at 20 mg/m2 in the presence of 
itraconazole were similar to that in the absence of itraconazole (geometric mean ratio of 0.996 with 
an associated 90% CI of 0.913 and 1.09). These findings with established moderate and strong 
CYP3A inhibitor probes indicate a minor contribution of CYP3A to pevonedistat metabolism in 
humans. Strong and moderate CYP3A inhibitors and P-gp inhibitors can be used in patients 
receiving pevonedistat.
On the basis of completed in vitro studies, pevonedistat is predominantly metabolized through 
CYP3A-mediated pathways, as evidenced by the findings in human hepatic S9 fractions and 
recombinant CYP isozyme incubations. The contribution of CYP3A to pevonedistat clearance is 
minor on the basis of preliminary results of Study C15011. The effect of rifampin, a strong CYP3A 
inducer, on pevonedistat PK was evaluated in Study Pevonedistat-1015 (P1015).
Co-administration of rifampin did not result in clinically meaningful alteration of pevonedistat 
systemic exposures. Based on findings from Study P1015, as of Amendment 07, administration of 
pevonedistat with strong CYP3A inducers is permitted in the ongoing and planned clinical studies.
In vitro, pevonedistat is a substrate for the drug efflux transporters P-gp and BCRP and is also a 
weak inhibitor of BCRP-mediated transport (concentrations producing 50% inhibition [IC50] of 
6.3 M). Additional transport studies with organic anion-transporting polypeptides (OATP) in 
sandwich-cultured human hepatocytes showed that pevonedistat can inhibit the hepatic uptake of 
estrone-3-sulfate (IC50 of 29.1 M) while inhibition of OATP-mediated uptake of simvastatin and 
lovastatin (IC50 of 0.4-4.9 M and 0.9 M, respectively) was observed in some, but not all, donors. 
On the basis of these data, pevonedistat at clinically relevant concentrations is unlikely to affect 
the PK of other drugs that are known BCRP or OATP substrates (IC50 >10-fold the unbound Cmax
even with the lowest estimated value). In addition, the effect of BCRP inhibition is not expected to 
be clinically meaningful. Refer to Section 4.6.3 for a summary of potential clinical drug-drug 
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interactions (DDIs), and Sections 8.4 and 8.5 for excluded and permitted concomitant medications 
in this study.
Additional details on nonclinical PK information are provided in the IB.
4.4.2
Clinical PK
Clinical PK data are summarized in Section 5.2 of the IB. Single- and multiple-dose PK of 
pevonedistat have been evaluated in adult patients with solid tumors or hematologic malignancies. 
In these studies, pevonedistat was administered IV at dose levels of 25 to 278 mg/m2 and with 
various daily or intermittent dosing schedules within 21-day treatment cycles. Plasma 
concentrations of pevonedistat declined in a multi-exponential manner at the end of a 1-hour IV 
infusion, with little or no notable drug accumulation upon repeat dosing. This observation is 
consistent with a mean terminal elimination half-life of approximately 10 hours (range, 
7.7-15.2 hours) estimated across doses and schedules. Pevonedistat PK was linear over the dose 
range studied based on an area under the plasma concentration-time curve (AUC) from time 0 to 
24 hours that increased proportionately with dose. Consistent with in vitro data, pevonedistat was 
also found to extensively partition in human blood (mean blood-to-plasma concentration ratio of 
~65) with observed concentrations of pevonedistat in whole blood and plasma declining in parallel 
over 24 hours. Upon exploration of the effects of patient-specific covariates on pevonedistat 
population PK, body size and age influenced clearance of pevonedistat, while only body size was 
important for all volume of distribution parameters. Additionally, data are available in 
29 treatment-naïve, elderly AML patients who received IV pevonedistat at 20 mg/m2 (n=26) and 
30 mg/m2 (n=3) on Days 1, 3, and 5 in combination with IV/SC azacitidine 75 mg/m2 on a 
5-on/2-off (weekend)/2-on schedule (Study C15009) [39]. These data indicate that pevonedistat 
PK remains unaffected by 5 continuous days of azacitidine dosing when compared with 
single-agent pevonedistat data from the earlier study in AML patients (Study C15003).
4.5
Rationale for the Proposed Study
MDS include a heterogeneous group of myeloid disorders characterized by ineffective 
hematopoiesis and transformation to AML. Treatment with azacitidine increases OS in patients 
with HR MDS relative to conventional care [16]. Consequently, azacitidine is approved in many 
countries as a single agent in HR MDS. 
Pevonedistat is an investigational, first-in-class inhibitor of the NAE that has reported single-agent 
clinical activity in a phase 1 study in relapsed/refractory AML patients [40]. Based on nonclinical 
studies in AML models that demonstrated a synergistic lethality in cell lines and tumor regression 
in murine xenografts when pevonedistat was combined with azacitidine, pevonedistat has been 
studied in combination with azacitidine in treatment-naïve elderly AML patients who are unlikely 
to benefit from standard induction therapy (Study C15009). Results demonstrate that 20 mg/m2
pevonedistat plus azacitidine is generally well tolerated and demonstrates signs of clinical activity 
[39,41]. 
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4.5.1
Rationale for Study Population
Given the overlapping treatments and pathophysiology between HR MDS and AML, this phase 3 
study will evaluate event-free survival (EFS) (in HR MDS or CMML, an event is defined as 
transformation to AML or death; in-low-blast AML, an event is defined as death) of the 
combination of pevonedistat and azacitidine compared with single-agent azacitidine as a treatment 
for HR MDS or CMML, or low-blast AML. Patients with CMML are included because CMML 
shares clinical and biological features with MDS, has a similar variable clinical course, and 
treatment modalities for the 2 diseases are also similar (see Section 4.1.1). Patients with CMML 
were also included in randomized studies of azacitidine conducted in the United States (US) and 
the European Union (EU) with similar response rates to MDS patients [16,31]. The rationale for 
including low marrow blast count (20%-30%) WHO-defined AML is based on the fact that it had 
been previously classified as RAEB-t, which was part of the MDS spectrum, and that it is often 
treated with azacitidine-based therapy (see Section 4.1.1).
4.5.2
Rationale for the Combination of Pevonedistat Plus Azacitidine
The rationale for combining pevonedistat with azacitidine in patients with AML and MDS is 
2-fold; namely, the single-agent activity observed with azacitidine [16] and pevonedistat [42] in 
patients with AML or related diseases such as MDS, and the preclinical evidence supporting the 
improved benefit of pevonedistat administered in combination with azacitidine in AML xenograft 
models; see Section 4.2.2 and the IB for more information. 
4.5.3
Rationale for Dose and Schedule of Study Drugs
The choice of doses and schedules for this study was based on Study C15009, which established 
the MTD of pevonedistat as 20 mg/m2 given on Days 1, 3, and 5, in combination with 75 mg/m2
azacitidine given on Days 1 through 5, 8, and 9, in 28-day treatment cycles. The DLTs supporting 
this determination were elevations in liver function tests (LFTs); see Section 4.3 and the IB for 
more information. 
The commonly used schedule of azacitidine administration in the US is a 5-on/2-off 
(weekend)/2-on schedule to avoid the logistical limitations associated with administering drugs to 
patients during the weekend. According to oncologist/hematologist surveys conducted by the 
sponsor, of the patients treated with azacitidine for AML in the US, approximately 70% follow this 
schedule. Garcia-Delgado et al conducted a retrospective evaluation of 3 schedules of azacitidine 
administration to 240 patients with WHO-defined MDS or AML with 20%-30% bone marrow 
blasts. Patients were treated with azacitidine, on 1 of the following 3 dosage regimens: 
5 consecutive days (AZA 5); 7 days including a 2-day break (AZA 5-2-2); or 7 consecutive days 
(AZA 7)—all 28-day cycles. ORRs for the AZA 5, AZA 5-2-2, and AZA 7 schedules were 39.4%, 
67.9%, and 51.3%, respectively, and median OS durations were 13.2, 19.1, and 14.9 months, 
respectively. These results suggest better effectiveness and tolerability profiles for 7-day schedules 
and at least comparable and possibly superior efficacy of the AZA 5-2-2 schedule compared with 
the AZA 7 schedule [43].
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In this study, azacitidine may be administered using either the SC or IV route of administration, 
given that comparable systemic exposures (AUC48) to pevonedistat were achieved following 
either route by which azacitidine was given in Study C15009. Furthermore, it has been shown that 
azacitidine exposures and efficacy are comparable regardless of the route of azacitidine 
administration [44-46]. 
As detailed in Section 4.3, some patients in Study C15003 (single-agent pevonedistat in patients 
with relapsed/refractory AML) derived clinical benefit from continuing study treatment despite 
increases in their bone marrow blast counts while on treatment. Standard MDS guidelines [47] also 
recommend treatment for 6 cycles without altering dose or frequency of azacitidine regardless of 
cytopenias. Patients with HR MDS or CMML may be allowed to continue study treatment (either 
treatment arm) if they meet the criteria for progressive disease (PD) based only on bone marrow 
blast count (without AML transformation) if, in the clinical judgment of the investigator, the 
patient is still receiving clinical benefit from this treatment and the continuation is endorsed by the 
sponsor’s project clinician (or designee). Patients with low-blast AML in this study may also be 
allowed to continue study treatment (either treatment arm), even if they meet the criteria for PD 
based only on bone marrow blast counts, if, in the clinical judgment of the investigator, the patient 
is still receiving clinical benefit from this treatment, and the continuation is endorsed by the 
sponsor’s project clinician (or designee). Patients who meet the criteria for PD and continue on 
study under these conditions must be reconsented before continuing study treatment. If a patient 
has <50% increase in blast count from pretreatment, then this is stable disease and the patient 
should remain on study. 
4.5.4
Rationale for Molecular Analyses
Analysis of Biomarkers in Bone Marrow Aspirate
Both AML and MDS are heterogeneous diseases with respect to both tumor biology and clinical 
outcome. Various studies confirm that survival for individual patients in both diseases is heavily 
influenced by the specific molecular pathology of their tumors. Along with age and PS, 
cytogenetics are a key clinical predictor, and cytogenetic findings are incorporated into risk 
categorization schemes to guide treatment. 
The European LeukemiaNet integrates cytogenetics and molecular features of 3 key AML genes 
(FLT3 internal tandem duplication [ITD], CEBP, and NPM1) to classify patients into 3 prognostic 
risk groups [48]. As more genomic data from AML patients—from those who are newly 
diagnosed as well as those who have relapsed after standard of care therapy—become available, 
additional mutations in genes such as ASXL1 and TET2 are also being shown to have prognostic 
value [49,50]. Several novel risk-categorization schema have been proposed that include 
mutational status of these and other genes [51]. The IPSS-R for MDS now incorporates 
cytogenetics into the scoring system as a way to determine the risk of transformation to AML [1]. 
Additionally, there are several recurrent somatic mutations which are drivers of MDS 
pathogenesis and can be associated with clinical phenotype (eg, RNA splicing factor mutations in 
ring-sideroblasts) [52,53]. The assessment of mutations in several genes with known prognostic 
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significance is now more routinely incorporated into clinical practice, though this list will likely 
expand with increased knowledge of the genomic landscape of these diseases.
Mutational data are increasingly being used as a complementary tool to influence the selection of 
the most appropriate therapy, such as the consideration of small molecule FLT3 inhibitors for 
AML patients with tumor samples that test positive for the FLT3 ITD oncogene. The FLT3 ITD 
mutation is observed in approximately 30% of all AML cases [54]. Additional targeted therapies 
designed against specific AML mutations are currently in development. These include targeted 
agents against mutations in IDH1 and 2 present in approximately 8.5% and 7.5% of AML patients 
respectively [55]. It is likely that acquired mutations could also predict response to specific 
interventions, such as treatment with HMAs [56]. For example, it has recently been shown that 
mutations in TET2 are associated with sensitivity to azacitidine, whereas patients with the 
wild-type TET2 gene have been shown to be resistant to azacitidine [56-59]. In MDS, TP53 
mutations are associated with complex karyotype, elevated bone marrow blast percentage, and 
severe thrombocytopenia. However, in multivariate analysis, the presence of this abnormality has 
also been shown to have independent prognostic significance [56,60]. In a study published by 
Bejar et al [56], TP53 mutation status was the most significant predictor of mortality after HSCT. 
Additionally, TP53 mutations have also been shown to be independently prognostic in MDS 
patients treated with HMAs such as azacitidine. While TP53-mutated MDS patients initially 
respond well to HMAs, their duration of response is significantly shorter than wild-type patients 
[60]. In AML patients as well, though TP53 is associated with older age, genomic complexity, 
specific DNA copy number alterations, and a monosomal karyotype, in multivariable analysis, 
TP53 alterations are the most important prognostic factor in complex karyotype-AML, 
outweighing all other variables [61]. Based on these reports, finding therapies for AML and MDS 
patients with TP53 mutations that can improve duration of response and OS represents an unmet 
medical need.
Epigenetic changes have also been implicated in the pathogenesis of AML and MDS. For example, 
accumulation of abnormal methylation is a dynamic process in MDS, with increasing levels of 
methylation associated with progression to RAEB and AML [62]; hence, it is likely that aberrant 
methylation actively contributes to MDS progression [63]. In recent years, recurrent somatic
mutations in genes encoding proteins involved in DNA methylation and demethylation and in 
covalent histone modifications have been reported in several myeloid malignancies [63]. 
Azacitidine is a DNA methyltransferase inhibitor and could potentially target epigenetic changes
in AML and MDS. Evaluating epigenetic modifications in bone marrow cells at Baseline and at 
specified time points after treatment has the potential to identify changes in epigenetic status that 
might correlate with response to the combination of pevonedistat and azacitidine. Throughout this 
study, Baseline assessments are defined as those performed at the closest time before the start of 
study drug administration.
Leukemic cells that remain in the bone marrow following treatment are a major cause of disease 
relapse. Minimal residual disease (MRD) testing provides the sensitivity and specificity to identify 
the presence of these residual cells and determine the depth and duration of response achieved 
following therapy. Studies have shown that the sensitive detection of a leukemia-specific marker 
(eg, a mutation in the gene encoding nucleophosmin, NPM1) could improve prognostication by 
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identifying submicroscopic disease during remission [64]. Measurement of MRD is receiving 
recognition as a potential tool to assess the quality of response after chemotherapy and to plan 
postremission strategies. Though polymerase chain reaction (PCR) and multiparametric flow 
cytometry have become the most popular methods to investigate MRD in AML [65] and 
techniques such as next-generation sequencing (NGS) are also being explored in both AML and 
MDS [33,48,66]. 
In this study, the baseline molecular alterations to be evaluated from bone marrow aspirate 
samples collected at Screening or before the administration of study drug may include, but are not 
limited to, cytogenetic abnormalities, changes in gene expression, DNA mutations, and epigenetic 
alterations. Molecular techniques such as, but not limited to, targeted sequencing using NGS will 
be used for these analyses. Correlative analyses of bone marrow molecular characteristics will be 
done to identify biomarkers linked to response to and/or safety of the combination of pevonedistat 
and azacitidine. 
Similar analyses will be conducted in bone marrow samples from patients who initially respond to 
therapy and subsequently relapse. These analyses will allow the evaluation of potential 
mechanisms of treatment-emergent resistance, such as somatic mutations in NAE subunits and key 
signaling pathways, or change in pathway activity, in tumors that initially respond to therapy and 
then exhibit PD.
Changes in epigenetic status in the tumor cells following treatment with the combination of 
pevonedistat and azacitidine may be assessed by comparing epigenetic modification in bone 
marrow aspirate samples obtained at Screening and after treatment.
MRD assessments may be conducted on bone marrow aspirates collected at predefined early 
(eg, following Cycle 2 and Cycle 4) and late time points (eg, following Cycle 6 and Cycle 9) 
during the study. MRD or depth-of-response analysis may be done using Flow, proteomic, or 
NGS-based methods.
Analysis of Biomarkers in Blood
Though researchers have routinely analyzed bone marrow aspirates for cytogenetic and molecular 
abnormalities in patients with HR MDS, CMML and AML, several new methodologies are also 
being developed to analyze these aberrations in cells isolated from blood [67,68]. Based on these 
current developments, blood samples will also be collected at predefined time points and may be 
used for analysis of baseline molecular alterations (including cytogenetic abnormalities), depth of 
response, epigenetic alterations and changes in immune profile following therapy.
Analysis of Biomarkers in Buccal Epithelial Cell Samples
In this study, buccal epithelial cell samples will be collected at Screening. The DNA from the 
buccal epithelial cell samples will be used for characterization of genotype variations in genes 
encoding drug-metabolizing enzymes (DMEs) or transporters that might be implicated in 
pevonedistat disposition. It may also be used in the interpretation of the tumor DNA sequencing 
data.
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It should be noted that the overall study results will dictate the extent to which some of the 
biomarker analyses described above will be conducted.
4.5.5
Rationale for Health-Related Quality of Life Assessments
When caring for patients with advanced and life threatening diseases such as cancer, preserving 
their health-related quality of life (HRQOL) and reducing symptom burden are among the most 
important therapeutic goals. Furthermore, patient-reported outcomes (PROs), such as physical 
functioning and symptoms, are increasingly important in clinical research, including in oncology 
[69] and hematology [70]. However, there are limited data on PROs among patients with MDS, 
CMML, and AML. In previous randomized clinical trials among patients with MDS, patients on 
the azacitidine arm experienced improvement in HRQOL as assessed by the European 
Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC 
QLQ-C30) PRO instrument [71]. It is expected that the clinical activity of the combination of 
pevonedistat with azacitidine will lead to an improvement in patients’ HRQOL, as well as other 
symptoms and reduce the impact on HRQOL for patients with MDS, CMML, and AML.
To compare the impact of treatment between the 2 patient groups in this study, HRQOL will be 
assessed by 2 instruments: EORTC QLQ-C30 and EuroQoL 5 dimensions 5 levels (a quality of 
life questionnaire of the “EuroQoL Group Association” that was expanded to a 5-level instrument) 
(EQ-5D-5L). Data from these 2 instruments will facilitate assessment of important general, 
cancer-specific, and MDS-specific HRQOL domains and items, and ascertainment of how these 
may be correlated with certain clinical outcomes.
The EORTC QLQ-C30 [72], designed to assess HRQOL in a wide range of cancer patient 
populations, has been administered in multiple randomized clinical trials of patients with MDS 
[71,73]. The EORTC QLQ-C30 instrument has been recommended for use in oncology trials [74]
and is widely utilized in clinical trials and in global registries. Furthermore, regulatory agencies 
and health technology assessment bodies are increasingly considering PROs, such as physical 
functioning and symptoms, in their deliberations. Supplemental items from the EORTC item bank 
can also be included to cover relevant concepts not measured by the core EORTC QLQ-C30 
questionnaire.
The EQ-5D-5L [75] is a self-reported preference-based measure of health developed to describe 
and value health across a wide range of disease areas and to inform economic evaluations. It is 
widely accepted by health technology assessment agencies worldwide.
Refer to Section 9.4.12 for additional details on the components and administration of these 
questionnaires. 
4.6
Potential Risks and Benefits
4.6.1
Azacitidine
In clinical studies, adverse reactions to azacitidine were qualitatively similar between the IV and 
SC routes of administration [44]. In clinical studies with SC administration of azacitidine, adverse 
reactions of neutropenia, thrombocytopenia, anemia, nausea, vomiting, diarrhea, constipation, and 
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injection site erythema/reaction tended to increase in incidence with higher doses of azacitidine. 
Adverse reactions that tended to be more pronounced during the first 1 to 2 cycles of SC treatment 
compared with later cycles included thrombocytopenia, neutropenia, anemia, nausea, vomiting, 
injection site erythema/pain/bruising/reaction, constipation, petechiae, dizziness, anxiety, 
hypokalemia, and insomnia. There did not appear to be any adverse reactions that increased in 
frequency over the course of treatment.
Adverse reactions that appeared to be specifically associated with the IV route of administration 
included infusion site reactions (eg, erythema or pain) and catheter site reactions (eg, infection, 
erythema, or hemorrhage).
Adverse reactions identified during postmarketing use of azacitidine include interstitial lung 
disease, tumor lysis syndrome, injection site necrosis, and Sweet’s syndrome (acute febrile 
neutrophilic dermatosis).
Refer to the VIDAZA (azacitidine) US Prescribing Information (USPI) [44],or the EU Summary 
of Product Characteristics (SmPC) [76], as applicable, for the most recent information regarding 
the anticipated risks and benefits of azacitidine.
4.6.1.1
Anemia, Neutropenia, and Thrombocytopenia
Azacitidine causes anemia, neutropenia, and thrombocytopenia. Monitor complete blood counts 
frequently for response and/or toxicity, at a minimum, before each dosing cycle. After 
administration of the recommended dosage for the first cycle, adjust dosage for subsequent cycles 
based on nadir counts and hematologic response (see Section 8.3.2.1).
4.6.1.2
Severe Pre-existing Hepatic Impairment
Caution is needed in patients with liver disease when administering azacitidine. Patients with 
extensive tumor burden due to metastatic disease have been reported to experience progressive 
hepatic coma and death during azacitidine treatment, especially in such patients with baseline 
albumin <30 g/L [77]. Azacitidine is contraindicated in patients with advanced malignant hepatic 
tumors. 
4.6.1.3
Renal Abnormalities
Patients with renal impairment should be closely monitored for toxicity because azacitidine and its 
metabolites are primarily excreted by the kidneys. Renal abnormalities ranging from elevated 
serum creatinine to renal failure and death have been reported in patients treated with IV 
azacitidine in combination with other chemotherapeutic agents for non-MDS conditions. Renal 
tubular acidosis, defined as a fall in serum bicarbonate to <20 mEq/L in association with an 
alkaline urine and hypokalemia (serum potassium <3 mEq/L), developed in 5 patients with 
CMML treated with azacitidine and etoposide.
4.6.2
Pevonedistat Plus Azacitidine
Study C15009 evaluated the combination of escalating doses of pevonedistat on Days 1, 3, and 
5 plus 75 mg/m2 azacitidine administered (IV or SC) on a 5-on/2-off (weekend)/2-on schedule in 
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28-day cycles in treatment-naïve patients with AML, aged ≥60 years, who are unlikely to benefit 
from standard induction therapy [38]. 
A total of 64 patients were treated (ITT population) at 2 dose levels (median age 75 years [range 
61-89]; 53% male; 77% Eastern Cooperative Oncology Group [ECOG] performance status [PS] 
0/1, 22% ECOG PS 2; 56% de novo AML, 44% secondary AML). Median marrow blasts were 
38.5% (range 5-92), 50% of patients had intermediate-risk, 28% had adverse-risk, and 3% had 
favorable-risk cytogenetics. 
Pevonedistat dosing started at 20 mg/m2 (n=6) and increased to 30 mg/m2 (n = 3) in the absence of 
DLTs. During dose escalation, at the 30 mg/m2 dose level, 2 of the 3 patients experienced a DLT: 
1 patient had persistent Grade 2 bilirubin elevation, and 1 patient had reversible Grade 4 aspartate 
aminotransferase (AST) elevation. Transaminase and bilirubin elevations were transient and 
clinically inconsequential in both patients (resolving to Grade 1 or baseline levels within 1 week 
after withdrawal from study). The MTD was determined to be 20 mg/m2 pevonedistat in 
combination with 75 mg/m2 azacitidine. An additional 55 patients were treated at the MTD, for a 
total of 61 patients treated at the MTD.
Patients in the ITT cohort (n = 64) received a median of 4 cycles (range 1-37), and 23/64 patients 
(36%) received ≥6 cycles of pevonedistat+azacitidine. The most common adverse events (AEs) 
were constipation (48%), nausea (42%), fatigue (42%), and anemia (39%). Fifty-three patients 
(82%) experienced ≥Grade 3 AEs; the most frequent (≥15%) were anemia, febrile neutropenia 
(each 30%), thrombocytopenia (23%), neutropenia (20%), and pneumonia (17%). AST/alanine 
aminotransferase (ALT) elevations ≥Grade 3 were reported in 6% of patients. Forty-four patients 
(69%) experienced serious adverse events (SAEs); the most frequent (≥10%) were febrile 
neutropenia (25%) and pneumonia (14%). In addition to the 2 patients who withdrew because of 
DLTs, 2 patients withdrew from the study because of therapy-related toxicity (febrile neutropenia). 
In the MTD expansion cohort (n = 55), 2 additional patients experienced DLTs (≥Grade3 
transaminase elevation) and were successfully rechallenged with a reduced dose of pevonedistat. 
Both patients remained on study without further hepatic toxicity. There were 11 on-study deaths 
unrelated to study therapy. Pevonedistat pharmacokinetics (PK) was not altered by the addition of 
azacitidine.
ORR in the 64-patient ITT cohort was 50% (20 CR, 5 CRi, 7 PR), with a median duration of 
remission of 8.3 months (95% CI: 5.52, 12.06). Of the responding patients, 63% (20/32) responded 
within the first 2 cycles of treatment, 14 had responses lasting ≥4 cycles, 2 went on to have 
allogeneic stem cell transplant. In total, 3 patients proceeded to stem cell transplantation, as they 
met physiologic requirements and agreed to pursue the treatment. ORR was 52% (13/25; 7 CR, 3 
CRi, 3 PR) versus 49% (19/39; 13 CR, 2 CRi, 4 PR) for patients with low (<30%) versus high 
(≥30%) marrow blasts; 53% (19/36; 12 CR, 3 CRi, 4 PR) versus 46% (13/28; 8 CR, 2 CRi, 3 PR) 
for patients with de novo AML versus secondary AML; 44% (14/32; 9 CR, 1 CRi, 4 PR) versus 44% 
(8/18; 5 CR, 2 CRi, 1 PR) for patients with intermediate- versus adverse-risk cytogenetics; and 83% 
(19/23; 14 CR, 2 CRi, 3 PR) versus 32% (13/41; 6 CR, 3 CRi, 4 PR) for patients who received ≥6 
cycles versus <6 cycles of azacitidine, respectively. Responses were seen in patients with typically 
refractory disease. In total, 6 of 8 patients with a TP53 mutation achieved CR/CRi/PR, and 4 of 6 
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remained on study for >10 cycles. Among the entire cohort of 61 patients treated at the MTD 
(median follow-up of 21.2 months), survival was 52% at 6 months and 45% at 1 year; median OS 
was 7 months and 11.2 months versus 5.6 months for patients with secondary AML versus de novo 
AML. The median OS was 11.2 months versus 5.2 months for patients with low (<30%) versus 
high (≥30%) marrow blasts and 16.1 months versus 5.3 months for patients aged 65 to 74 versus 
≥75 years, respectively.
The most detailed information on risks is provided in the IB and the Developmental Core Safety 
Information (DCSI) located within the IB.
Overall identified risks of pevonedistat include increased heart rate, diarrhea, nausea, vomiting, 
abnormal LFTs, pyrexia, myalgia, and musculoskeletal pain. 
Hepatotoxicity: Hepatotoxicity has been noted following administration of pevonedistat in patients 
with advanced malignancy, including elevations of liver transaminases (up to Grade 4), alkaline 
phosphatase (ALP; up to Grade 3), and bilirubin (up to Grade 3). Grade 1 through 4 increases in 
ALT and AST have been observed in patients receiving single-agent pevonedistat for relapsed 
and/or refractory AML. The patients experiencing these changes in laboratory values have been 
asymptomatic. This type of elevation in transaminases had been observed previously in patients 
treated with pevonedistat. The elevations in laboratory values have been reversible with dose 
modification including dose delay and reduction. Patients with elevated transaminases have been 
successfully rechallenged at lower doses. 
Some events are considered potential risks of pevonedistat because of the occurrence of these 
events in phase 1 clinical studies in which single-agent pevonedistat was administered at doses 
substantially higher than those being used in current clinical trials. Those events included 
multi-organ failure that could result in death, renal failure, cardiac arrhythmias (all
supraventricular and all except 1 unrelated: the case of atrial fibrillation assessed by the 
investigator as related occurred in a patient with cardiovascular risk factors), myelosuppression 
with increased susceptibility to infection, bleeding, anemia, acute phase response, gastrointestinal 
toxicity including or resulting in dehydration, electrolyte imbalance, and hypophosphatemia.
Other events, such as fatigue, chills, decreased appetite, febrile neutropenia, and gastrointestinal 
bleeding (all events assessed by an investigator as unrelated, the majority occurred in the setting of 
thrombocytopenia), are considered potential risks that are confounded by underlying disease or 
malignancy. 
Potential risks that are derived from findings in animal studies in rats and dogs include myocardial 
degeneration and thrombosis, cardiovascular changes that could result in tachycardia, decreased or 
increased systolic blood pressure, increased diastolic blood pressure, pulmonary hypertension, 
enteropathy (including dehydration and electrolyte loss) with secondary sepsis, effects on testes 
and ovaries that represent a reproductive hazard including sterility, increased developmental risk 
to fetus or embryo, decreased trabecular bone (graded minimal to moderate) was noted in the 
femur and in the sternum in rats at all dose groups (low, medium, high) (this finding was 
considered adverse in the high-dose group; however, no bone fractures were noted at any of the 
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doses), prolongation of the activated partial thromboplastin time (aPTT), and local tissue injury 
when administered SC. Additional details may be found in the current IB.
Based on the known individual safety profiles of pevonedistat and azacitidine, the following 
potential risks of combination therapy may apply: myelosuppression, gastrointestinal events, 
electrolyte imbalances, hypophosphatemia, decreased renal function, hepatotoxicity, cardiac 
arrhythmias, cardiomyopathies, musculoskeletal pain, bleeding, and injection site reactions.
In Study C15009, patients received azacitidine as either an IV infusion or SC injection. 
Preliminary data indicate that the route of azacitidine administration has no apparent effect on the 
safety profile of pevonedistat plus azacitidine. 
4.6.3
Potential for DDIs
No formal clinical assessments of DDIs between azacitidine and other agents have been conducted. 
Please consult the VIDAZAUSPI (Clinical Pharmacology [Section 12.3], Drug-Drug Interactions)
for additional information [44].
Pevonedistat PK in combination with azacitidine was assessed in 64 evaluable treatment-naïve 
patients with AML in Study C15009. Pevonedistat systemic exposures were not altered in the 
presence of azacitidine when compared with historical single agent data (Study C15003). The 
potential risk of DDIs between pevonedistat and concomitantly administered drugs is currently 
informed by available nonclinical and clinical data (see IB). Study C15011, a phase 1 DDI study, 
is currently ongoing. The study assesses the effect of multiple doses of fluconazole (a moderate 
CYP3A inhibitor) as well as the effect of multiple doses of itraconazole (a strong CYP3A inhibitor) 
on the PK, safety, and tolerability of a single dose of IV pevonedistat (see Section 4.4.1). Based on 
preliminary assessments, administration of pevonedistat with moderate and strong CYP3A 
inhibitors and P-gp inhibitors is permitted in this study. In Study P1015, co-administration of 
rifampin, a strong CYP3A inducer, with pevonedistat did not result in clinically meaningful 
alteration of pevonedistat systemic exposures. Therefore, the use of strong CYP3A inducers is 
now permitted in this study. As a general precaution, patients receiving concomitant medications, 
particularly those with narrow therapeutic indices, should be carefully monitored as the DDI 
potential between pevonedistat and other drugs has not been formally studied in humans. Patients 
should also be instructed to consult with the investigator before taking any new medications, 
including over-the-counter products and herbal supplements.
See Section 8.4 for information on concomitant medications that are prohibited and Section 8.5 for 
information on medications that are permitted during this study.
4.6.4
Summary of Risks and Benefits
Analyses of safety data from more than 130 patients treated with pevonedistat plus azacitidine at 
the dose and schedule to be used in this phase 3 study demonstrate that pevonedistat adds little 
toxicity to azacitidine alone and that toxicities are manageable. Efficacy data from a phase 1 study 
using this combination demonstrated a 50% ORR based on an ITT analysis (20 CR, 5 CRi, 7 PR), 
with an 8.3-month median duration of remission in untreated, older patients with AML for whom 
intensive induction chemotherapy was considered inappropriate. In patients receiving ≥6 cycles of 
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therapy (n = 23, 44%), ORR was 83%. In total, 6 out of 8 patients with a TP53 mutation achieved 
CR/CRi/PR, and 4 of 6 remained on study for >10 cycles. Baseline bone marrow blast percentage 
or cytogenetic/molecular risk did not influence ORR [38]. Thus, the benefit-risk ratio supports 
further study of the combination of pevonedistat and azacitidine in a randomized controlled trial in 
patients with HR MDS or CMML, or AML.
5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objectives
The primary objective is:

To determine whether the combination of pevonedistat and azacitidine improves EFS when 
compared with single-agent azacitidine. (An event is defined as death or transformation to 
AML in patients with MDS or CMML, whichever occurs first, and is defined as death in 
patients with low-blast AML.) 
5.1.2
Key Secondary Objective
The key secondary objective is:

To determine whether the combination of pevonedistat and azacitidine improves OS when 
compared with single-agent azacitidine.
5.1.3
Other Secondary Objectives
Other secondary objectives are:

To determine whether the combination of pevonedistat and azacitidine improves 6-month and 
1-year survival rates when compared with single-agent azacitidine.

To determine in patients with HR MDS, patients with HR CMML, and patients with 
HR MDS/CMML whether the combination of pevonedistat and azacitidine delays time to 
AML transformation when compared with single-agent azacitidine.

To determine whether the combination of pevonedistat and azacitidine, when compared with 
single-agent azacitidine, improves the rate of CR (CR in patients with HR MDS or CMML, or 
low-blast AML), CR+CRi in patients with low-blast AML, CR+marrow CR (in patients with 
HR MDS or CMML), CR+PR+hematologic improvement (HI) (in patients with HR MDS or 
CMML), CR+marrow CR+PR (in patients with HR MDS or CMML), CR+marrow 
CR+PR+HI (in patients with HR MDS or CMML), overall response, overall response by 
Cycle 6, and overall response 2. Overall response in patients with HR MDS or CMML is 
defined as CR+PR; overall response in patients with low-blast AML is defined as 
CR+CRi+PR. Overall response 2 in patients with HR MDS or CMML is defined as 
CR+PR+HI; overall response 2 in patients with low-blast AML is defined as CR+CRi+PR.
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
To determine whether the combination of pevonedistat and azacitidine, when compared with 
single-agent azacitidine, improves duration of CR (CR for HR MDS or CMML, or low-blast 
AML), CR+CRi for low-blast AML, overall response (CR+PR for HR MDS or CMML, 
CR+CRi+PR for low-blast AML), and overall response 2 (CR+PR+HI for HR MDS or CMML, 
CR+CRi+PR for low-blast AML). 

To determine whether the combination of pevonedistat and azacitidine improves rate of 
transfusion independence when compared with single-agent azacitidine. RBC and platelet 
transfusion independence requires that the patient receive no RBC or platelet transfusions for a 
period of at least 8 weeks during the time period from the first dose of study drug 
administration through 30 days after the last dose of any study drug.

To determine whether the combination of pevonedistat and azacitidine increases the duration 
of RBC transfusion independence, platelet transfusion independence, or platelet and RBC 
transfusion independence, when compared with single-agent azacitidine.

To determine whether the combination of pevonedistat and azacitidine improves time to first 
CR or PR or CRi (in patients with low-blast AML) when compared with single-agent 
azacitidine. 

To determine in patients with HR MDS, patients with HR MDS/CMML, and patients with HR 
CMML whether the combination of pevonedistat and azacitidine improves rates of HI when 
compared with single-agent azacitidine.

To determine whether the combination of pevonedistat and azacitidine does not increase 
inpatient hospital admission related to HR MDS or CMML, or low-blast AML when compared 
with single-agent azacitidine. 

To determine whether the combination of pevonedistat and azacitidine delays time to PD, 
relapse after CR (low-blast AML), relapse after CR or PR (HR MDS/CMML), or death when 
compared with single-agent azacitidine. 

To determine whether the combination of pevonedistat and azacitidine maintains overall 
health status/quality of life and fatigue domain scores as measured by the PRO instrument 
EORTC QLQ-C30 when compared with single-agent azacitidine.

To collect plasma concentration-time data for pevonedistat to contribute to future population 
PK analyses of pevonedistat.

To compare ORR, EFS, and OS in patients who have TP53 mutations, 17p deletions, and/or
are determined to be in an adverse cytogenetic risk group at Baseline, across treatment arms.
5.1.4
Safety Objective
The safety objective is:

To evaluate the safety of the combination of pevonedistat and azacitidine when compared with 
single-agent azacitidine.
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5.1.5
Exploratory Objectives 
The exploratory objectives are:

To explore the relationship between response with EFS and OS, including CR with EFS and 
OS, ORR by Cycle 6 and ORR with EFS and OS, and overall response rate 2 (ORR 2) by Cycle 
6 and ORR 2 with EFS and OS.

To explore the relationship between molecular characteristics in patients identified at 
Screening (such as somatic mutations, cytogenetic abnormalities, epigenetic modifications, 
gene expression patterns) with ORR, EFS, OS, and other clinical endpoints of interest, across 
treatment arms.

To determine impact of therapy on the depth and durability of response, immune repertoire and 
treatment emergent resistance by following genomic, epigenomic, and/or protein-based 
markers in bone marrow or blood and correlation with ORR, EFS, OS, and other clinical 
efficacy endpoints of interest, across treatment arms.

To explore in patients with HR MDS or CMML, or low-blast AML potential relationships 
between polymorphic variations in genes encoding DMEs or transporters that may be 
implicated in pevonedistat disposition and exposure to pevonedistat.

To explore the relationship between molecular markers associated with poor prognosis in 
HR MDS or CMML, or low-blast AML, including genes associated with transformation to 
AML, identified in bone marrow aspirates at Screening with ORR, EFS, OS, and other clinical 
endpoints of interest, across treatment arms.

To assess the time to improvement in functioning and symptoms as measured by the PRO 
instrument EORTC QLQ-C30, including the following EORTC QLQ-C30 scores: fatigue, 
physical functioning, role functioning, and dyspnea and using the supplemental items of the 
EORTC item bank: fatigue, shortness of breath, and physical functioning.

To evaluate health utilization and calculate utility values using the preference-based PRO 
instrument EQ-5D-5L.
5.2
Endpoints
5.2.1
Primary Endpoint
The primary endpoint is:

EFS: time from randomization to the date of an EFS event (defined as death or transformation 
to AML in patients with MDS or CMML, whichever occurs first, and defined as death in 
patients with low-blast AML).
5.2.2
Key Secondary Endpoint
The key secondary endpoint is:

OS. 
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5.2.3
Other Secondary Endpoints
Other secondary endpoints are:

Six-month and 1-year survival rates.

Thirty-day and 60-day survival rates.

Time to AML transformation in patients with HR MDS, patients with HR CMML, and patients 
with HR MDS/CMML.

Rate of CR (CR in patients with HR MDS or CMML, or low-blast AML), CR+CRi in patients 
with low-blast AML, CR+marrow CR (in patients with HR MDS or CMML), CR+PR+HI (in 
patients with HR MDS or CMML), CR+marrow CR+PR (in patients with HR MDS or 
CMML), CR+marrow CR+PR+HI (in patients with HR MDS or CMML), overall response, 
overall response by Cycle 6, and overall response 2. Overall response in patients with HR 
MDS or CMML is defined as CR+PR; overall response in patients with low-blast AML is 
defined as CR+CRi+PR. Overall response 2 in patients with HR MDS or CMML is defined as 
CR+PR+HI; overall response 2 in patients with low-blast AML is defined as CR+CRi+PR.

Duration of CR (CR for HR MDS or CMML, or low-blast AML), CR+CRi for low-blast AML, 
overall response (CR+PR for HR MDS or CMML, CR+CRi+PR for low-blast AML), and 
overall response 2 (CR+PR+HI for HR MDS or CMML, CR+CRi+PR for low-blast AML).

Rates of RBC and platelet transfusion independence.

Duration of RBC transfusion independence, platelet transfusion independence, and platelet 
and RBC transfusion independence.

Time to first CR or PR or CRi (for patients with low-blast AML). 

Rates of HI in patients with HR MDS, patients with HR MDS/CMML, and patients with 
HR CMML.

Patients who have inpatient hospital admission(s) related to HR MDS or CMML (collected 
through transformation to AML or until initiation of subsequent therapy, whichever occurs 
first) or low-blast AML (collected through initiation of subsequent therapy).

Time to PD, relapse after CR (low-blast AML), relapse after CR or PR (HR MDS/CMML), or 
death.

HRQOL assessed using the EORTC QLQ-C30.

Plasma concentration-time data for pevonedistat.

ORR, EFS, and OS in patients who have TP53 mutations, 17p deletions, and/or are determined 
to be in an adverse cytogenetic risk group in both treatment arms.
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5.2.4
Safety Endpoints 
The safety endpoints are:

AEs.

SAEs.

Results of clinical laboratory tests.

ECOG PS.
5.2.5
Exploratory Endpoints 
The exploratory endpoints are:

Correlation of response with EFS and OS:
–
CR with EFS and OS.
–
ORR by Cycle 6 and ORR with EFS and OS.
–
ORR 2 by Cycle 6 and ORR 2 with EFS and OS.

Identification of molecular abnormalities such as somatic mutations, cytogenetic abnormalities, 
as well as methylation and gene expression patterns in patients at Screening in both treatment 
arms and correlation with clinical efficacy.

Evaluation of changes in markers such as somatic mutations, cytogenetic abnormalities, 
methylation and proteomic signatures as well as immune repertoire in bone marrow aspirates 
or blood at specified times during therapy and at relapse, in both treatment arms, and 
correlation with clinical efficacy.

Association of polymorphic variants in DMEs or transporters, as applicable, with pevonedistat 
exposure and/or safety.

Relationship with molecular markers associated with poor prognosis in HR MDS or CMML, 
or low-blast AML such as FLT3 ITD, RUNX-1, EZH2, ASXL1, N-RAS, K-RAS, in both 
treatment arms and correlation with clinical efficacy.

Time to improvement in functioning and symptoms as measured by the PRO instrument 
EORTC QLQ-C30, including the following EORTC QLQ-C30 scores: fatigue, physical 
functioning, role functioning, and dyspnea and using the supplemental items of the EORTC 
item bank: fatigue, shortness of breath, and physical functioning.

Evaluation of health utilization and calculate utility values using a preference-based PRO 
instrument EQ-5D-5L.
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6.0
STUDY DESIGN
6.1
Overview of Study Design
This study is a multicenter, global, randomized, controlled, open-label, phase 3 clinical study of 
the combination of pevonedistat and azacitidine versus single-agent azacitidine administered in 
patients with HR MDS or CMML, or low-blast AML (see Section 7.1, inclusion criteria 2 and 3 for 
definitions) who have not previously received chemotherapy or other antineoplastic agents 
including HMAs such as decitabine or azacitidine. Patients with nonproliferative CMML 
(ie, WBC <13,000/µL) are included because these patients were also included in both randomized 
studies of azacitidine conducted in the US and EU and were shown to have response rates similar 
to MDS patients. 
General eligibility may be assessed before the formal Screening period if it is part of standard 
clinical practice. However, per the Schedule of Events (SOE) (Appendix C), formal screening will 
occur during the Screening period, which may last up to 28 days before randomization. The 
sponsor’s project clinician (or designee) will confirm patient eligibility before randomization by 
the investigator.
It is expected that approximately 450 patients, including at least 350 patients with HR MDS or 
CMML and at least 100 patients with low-blast AML, will be enrolled in this study. At enrollment, 
patients with HR MDS or CMML, or low-blast AML will be randomized at a 1:1 ratio to receive 
study drug (either single-agent azacitidine or the combination of pevonedistat and azacitidine) in 
28-day treatment cycles. All patients will be stratified into 4 categories: low-blast AML, IPSS-R 
risk groups of very high, high, or intermediate for MDS or CMML [1]. Note that patients with HR 
MDS or CMML with indeterminate cytogenetics findings at Screening should be assigned a 
cytogenetics prognostic variable of 2 points, ie, intermediate, for determining overall Prognostic 
Risk Category/Score; see Section 9.4.4. All patients will receive azacitidine (75 mg/m2 [IV or SC]) 
on Days 1 through 5, Day 8, and Day 9. Patients randomized to the combination arm will also 
receive pevonedistat (20 mg/m2 via 60 ([±10]-minute infusion) on Days 1, 3, and 5. Modifications 
to the dose and schedule may be allowed as detailed in the SOE (Appendix C) and Section 8.1.
Patients, including those who achieve a CR, may receive study treatment until they experience 
unacceptable toxicity, relapse, transformation to AML, or PD as defined in Section 9.4.20. Patients 
may be allowed to continue study treatment (either treatment arm) if they meet the criteria for PD 
based only on bone marrow blast count (without AML transformation in patients with HR MDS or 
CMML) if, in the clinical judgment of the investigator, the patient is still receiving clinical benefit 
from this treatment and the continuation is endorsed by the sponsor’s project clinician (or 
designee). Patients who meet the criteria for PD and continue on study under these conditions must 
be reconsented before continuing study treatment. Patients may choose to discontinue therapy at 
any time. 
Patients will attend the End-of-Treatment (EOT) visit 30 days (+10 days) after the last dose of 
study drug or before the start of subsequent antineoplastic therapy if that occurs sooner. 
Following the EOT visit, patients with HR MDS or CMML will enter EFS follow-up, if their 
disease has not transformed to AML. Patients will have monthly assessments to include physical 
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exam, clinical blood tests, HRQOL assessments, hospitalization assessment, and disease 
assessment as outlined in the SOE (Appendix C). Patients who discontinue study treatment 
without evidence of progression (ie, PD or transformation to AML) will have a bone marrow 
aspirate and hematology tests (see Table 9.d) sent to the central laboratory at time of suspected 
progression (see SOE [Appendix C] and Table A). Patients will continue monthly EFS follow-up 
study visits until their disease transforms to AML or they start subsequent therapy (see Study 
Diagram in Appendix B). Patients who have started subsequent therapy will have EFS follow-up 
but will not be required to have monthly visits; at the time of suspected transformation to AML 
they will have a bone marrow aspirate and hematology tests (specimens sent to central laboratory). 
Following the EOT visit, patients with low-blast AML will enter response follow-up, if they have 
no evidence of PD and they have not started subsequent therapy. Patients will have monthly 
assessments to include physical exam, clinical blood tests, HRQOL assessments, hospitalization 
assessment, and disease assessment as outlined in the SOE (Appendix C). Patients who 
discontinue study treatment while not in CR and without evidence of PD will have a bone marrow 
aspirate and hematology tests sent to the central laboratory at the time of suspected PD. Patients 
who discontinue treatment while in CR will also have a bone marrow aspirate and hematology 
tests performed at the time of suspected relapse sent to the central laboratory (see Table A). 
Patients will continue monthly response follow-up visits, until they relapse from CR or meet the 
criteria for PD (see Study Diagram in Appendix B).
Following the EFS and response follow-up visits, or the EOT visit (for patients with HR MDS or 
CMML who discontinue study treatment because of transformation to AML, or patients with 
low-blast AML who discontinue study treatment because of PD), patients will enter OS follow-up 
and will be contacted every 3 months until death to document subsequent therapies and survival 
status (see Study Diagram in Appendix B).
Disease response assessments for all HR MDS and CMML patients will be based on the Modified 
International Working Group (IWG) response criteria for MDS [2] as detailed in Section 9.4.20. 
Disease response assessments for patients with low-blast AML will be based on the Revised 
Recommendations of the IWG for Diagnosis, Standardization of Response Criteria, Treatment 
Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia as detailed 
in Section 9.4.20 [3]. Formal disease assessments for study endpoints will be determined based on 
local bone marrow aspirate blast counts (blast counts from the bone biopsy may be used in the 
event the aspirate sample is inadequate and a biopsy was done), clinical laboratory evaluations 
performed at a central laboratory (local laboratory results may be used for time-sensitive clinical 
decisions), and local transfusion data.
Inpatient hospital admissions related to HR MDS or CMML, or low-blast AML, as well as 
transfusion independence, will be monitored as secondary efficacy endpoints. RBC and platelet 
transfusion independence requires that the patient receive no RBC or platelet transfusions, 
respectively, for a period of at least 8 weeks. Treatment-emergent resistance will also be 
monitored.
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A bone marrow aspirate and biopsy will be collected at Screening, and bone marrow aspirates will 
be collected during treatment and follow-up for blast count evaluation (to inform disease burden 
assessment).
Bone marrow aspirates will be obtained at Screening and at additional time points described in 
Table A and in Section 9.4.24 for assessing response and/or for translational research purposes. 
Samples will be collected and analyzed from patients in both treatment arms and sent to a central 
laboratory. Bone marrow aspirates collected at Screening will be used to analyze tumor 
cytogenetics, baseline somatic mutations, and other molecular characteristics such as gene 
expression profile and epigenetic status. Bone marrow aspirates collected at the specified time 
points during treatment and/or at relapse will be used to evaluate depth and duration of response by 
following parameters such as residual tumor cells, residual mutation load, and changes in 
epigenetic modifications. Such analysis will also be used to identify treatment-emergent mutations. 
Developing potential biomarkers of pevonedistat-mediated activity may require analysis of the 
data from this study in combination with data from other clinical studies of pevonedistat.
Sparse sampling for the determination of pevonedistat plasma concentrations and, if appropriate, 
its metabolites will be collected from each patient in the Combination Pevonedistat Plus 
Azacitidine Arm as described in the SOE (Appendix C) to contribute to a population PK analysis 
of pevonedistat co-administered with azacitidine. 
AEs and ECOG PS will be assessed, and ECGs, clinical laboratory values, and vital signs will be 
obtained, to evaluate the safety and tolerability of the study drug treatments. Toxicity will be 
evaluated according to National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI CTCAE), version 4.03, effective date 14 June 2010 [4]. Dose modification guidelines 
are presented in Section 8.3. 
PROs will be evaluated using the EORTC QLQ-C30, version 3.0, and EQ-5D-5L questionnaires.
6.2
Number of Patients
Approximately 450 patients (randomized in a 1:1 ratio), including at least 350 patients with 
HR MDS or CMML and at least 100 patients with low-blast AML, will be enrolled in this study 
from approximately 120 study centers globally. Enrollment is defined as when the patient is 
randomized onto study treatment. Enrollment will be managed to ensure an appropriate 
distribution of patient with HR MDS or CMML, and low-blast AML.
6.3
Duration of Study
6.3.1
Duration of an Individual Patient’s Study Participation
Patients, including those who achieve a CR, may receive study treatment until they experience 
unacceptable toxicity, relapse, transformation to AML (for patients with HR MDS or CMML), PD 
(for patients with low-blast AML), the sponsor terminates the study, or discontinuation for any 
other reason outlined in Section 9.7.
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After discontinuing study treatment, patients will be followed until death for survival status, 
subsequent therapy, and disease status (for patients with HR MDS or CMML).
Patients will be followed for 30 days after the last dose of any study drug or the start of subsequent 
alternative anticancer therapy to permit the detection of any delayed treatment-related AEs.
6.3.2
End of Study/Study Completion Definition and Planned Reporting
The study will be considered complete after the final analysis (FA) for OS has been completed or 
the study has been terminated by the sponsor. The estimated time frame for study completion is 
approximately 65 months after the first patient is enrolled. Patients who are still receiving study 
treatment and continuing to derive clinical benefit may continue to receive pevonedistat at the 
discretion of the sponsor; the continuation of treatment may occur in a manner other than the study 
protocol and according to local regulations. 
6.3.3
Timeframes for Primary and Secondary Endpoints to Support Disclosures
Refer to Table 6.a for disclosures information for all primary and secondary endpoints.
Table 6.a
Primary and Secondary Endpoints for Disclosures
Endpoint
Definition
Maximum Time Frame (a)
Primary: 

EFS 
The time from randomization to the 
occurrence of an event.
For patients with HR MDS/CMML, an 
event is defined as death or 
transformation to AML; for patients 
with low-blast AML, an event is 
defined as death.
Up to 6 years
Secondary: 

OS 
The time from randomization to death 
from any cause.
Up to 6 years
Other Secondary: 
Up to 6 years

6 month and 1 year survival rates
Kaplan-Meier (K-M) estimates for 6 
month and 1 year survival rates.

30-and 60-day mortality rates
The proportion of patients who survive 
at most 30/60 days from the first dose of 
study drug.

Time to AML transformation
The time from randomization to documented 
AML transformation.

Rate of CR, CR+CRi, 
CR+marrow CR, CR+PR+HI, 
CR+marrow CR+PR,CR+ 
marrow CR+PR+HI, overall 
response, overall response by 
Cycle 6, and overall response 2
As evaluated by the independent review 
committee (IRC).
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Table 6.a
Primary and Secondary Endpoints for Disclosures
Endpoint
Definition
Maximum Time Frame (a)

Duration of CR, CR+CRi, 
overall response, and overall 
response 2 
CR, CR or PR, CR or PR or HI for HR MDS 
or CMML; CR or CRi, CR or CRi or PR for 
low-blast AML to first documentation of PD 
or transformation to AML.

Rate of RBCs and/or 
platelet-transfusion 
independence
Rate of RBCs and/or platelet-transfusion 
independence is defined as number of 
patients who become RBCs and/or platelet 
transfusion independent divided by the 
number of patients who are RBCs and/or 
platelet transfusion dependent at Baseline.

Duration of RBC transfusion 
independence, platelet 
transfusion independence, and 
platelet and RBC transfusion 
independence
The time from the first established RBC 
and/or platelet transfusion independence to 
the subsequent first RBC and/or platelet 
transfusion.

Time to first CR or PR or CRi
The time from randomization to first 
documented CR or PR or CRi, whichever 
occurs first.

Rates of HI (see Table 9.i)
Rates of HI as evaluated by IRC.

Percent of patients who have 
inpatient hospital admission(s) 
related to HR MDS or CMML, 
or low-blast AML
The ratio of the number of patients who have 
hospital admission(s) related to HR MDS or 
CMML, or low-blast AML over the number 
of patients in the intent-to-treat (ITT) 
population per treatment arm.

Time to PD, relapse after CR
(low-blast AML), relapse after 
CR or PR (HR MDS/CMML), or 
death
The time from randomization until PD, or 
relapse after CR or PR, or death due to any 
cause, whichever occurs first.

HRQOL
Measured by domains from EORTC 
QLQ-C30, EORTC supplemental items, and 
EQ-5D-5L.

Plasma concentration-time data 
for pevonedistat
Pevonedistat concentration at prespecified 
collection time.
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Table 6.a
Primary and Secondary Endpoints for Disclosures
Endpoint
Definition
Maximum Time Frame (a)

Determine ORR, EFS and OS in 
patients that have TP53
mutations, 17p deletions, and/or 
are determined to be in an 
adverse cytogenetic risk group in 
both treatment arms
Similar definition of ORR, EFS and OS as
above applied to patients that have TP53
mutations, 17p deletions, and/or are 
determined to be in an adverse cytogenetic 
risk group in both treatment arms.
Up to 6 years
AML= acute myelogenous leukemia, CMML= chronic myelomonocytic leukemia, CR=complete remission, 
EFS=event-free survival, EORTC QLQ-C30= European Organisation for the Research and Treatment of Cancer Core 
Quality of Life Questionnaire, EQ-5D-5L= EuroQoL 5 dimensions 5 levels (a quality of life questionnaire of the 
“EuroQoL Group Association” that was expanded to a 5-level instrument), HI= hematologic improvement, 
HR MDS= higher-risk myelodysplastic syndromes, HRQOL= health-related quality of life, ORR=overall response 
rate, OS=overall survival, PD=progressive disease, PR=partial remission, RBC=red blood cell.
(a) Time to last assessment for that endpoint across the entire study.
6.3.4
Total Study Duration
It is anticipated that this study will last for approximately 63 months.
7.0
STUDY POPULATION
7.1
Inclusion Criteria
Each patient must meet all of the following inclusion criteria to be enrolled in the study:
1. Male or female patients 18 years or older.
2. Morphologically confirmed diagnosis of MDS or nonproliferative CMML (ie, with WBC 
<13,000/µL) or low-blast AML based on 1 of the following:
FAB Classifications [5]:

RAEB, defined as having 5% to 20% myeloblasts in the bone marrow.

CMML with 10% to 19% myeloblasts in the bone marrow and/or 5% to 19% blasts in 
the blood.
OR
WHO Classifications [6]: 

Refractory anemia with excess blasts-1 (RAEB-1), defined as having 5% to 9% 
myeloblasts in the bone marrow.

Refractory anemia with excess blasts-2 (RAEB-2), defined as having 10% to 19% 
myeloblasts in the bone marrow and/or 5% to 19% blasts in the blood.
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
Chronic myelomonocytic leukemia-2 (CMML-2), defined as having 10% to 19% 
myeloblasts in the bone marrow and/or 5% to 19% blasts in the blood. 

Chronic myelomonocytic leukemia-1 (although CMML-1 is defined as having <10% 
myeloblasts in the bone marrow and/or <5% blasts in the blood, these patients may 
enroll only if bone marrow blasts ≥5%).

WHO-defined AML with 20% to 30% myeloblasts in the bone marrow (defined in this 
protocol as low-blast AML) and <30% myeloblasts in peripheral blood who are 
deemed by the investigator to be appropriate for azacitidine-based therapy.
3. All patients with MDS or CMML must also have one of the following Prognostic Risk 
Categories, based on the IPSS-R [1]:

Very high (>6 points).

High (>4.5-6 points).

Intermediate (>3-4.5 points): a patient determined to be in the Intermediate Prognostic 
Risk Category is only allowable in the setting of ≥5% bone marrow myeloblasts.
4. ECOG PS of 0, 1, or 2 (see Appendix F).
5. Patients with AML (20%-30% blasts) must have a TRM score ≥4 for intensive, induction 
chemotherapy) as calculated using the simplified model described by Walter and coworkers 
[7]; see Appendix A. 
Calculation of TRM score: 

0 for (age <61 years), +2 for (age 61-70 years), +4 for (age >71 years). 

+ 0 for (PS=0), +2 for (PS=1), +4 for (PS >1).

+ 0 for (platelets <50), +1 for (platelets >50). 
6. Female patients who:

Are postmenopausal (see Appendix G) for at least 1 year before the Screening visit, OR

Are surgically sterile, OR

If they are of childbearing potential, agree to practice one highly effective method of 
contraception and one additional effective (barrier) method (see Appendix H), at the 
same time, from the time of signing the informed consent through 4 months after the 
last dose of study drug, OR

Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, 
postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are 
not acceptable methods of contraception. Female and male condoms should not be used 
together.)
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Male patients, even if surgically sterilized (ie, status postvasectomy), who:

Agree to practice effective barrier contraception during the entire study treatment 
period and through 120 days (or if the drug has a very long half-life, for 90 days plus 
five half-lives) after the last dose of study drug, or

Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, 
postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are 
not acceptable methods of contraception. Female and male condoms should not be used 
together.)
7. Ability to undergo the study-required bone marrow sample collection procedures. 
8. Suitable venous access for the study-required blood sampling (ie, including PK and 
pharmacodynamic sampling).
9. Clinical laboratory values within the following parameters (repeat within 3 days before the 
first dose of study drug if laboratory values used for randomization were obtained more than 3 
days before the first dose of study drug):

Albumin >2.7 g/dL.

Total bilirubin ≤ the upper limit of the normal range (ULN) except in patients with 
Gilbert’s syndrome. Patients with Gilbert’s syndrome may enroll if direct bilirubin 
≤1.5×ULN of the direct bilirubin.

ALT and AST <2.5×ULN.

Creatinine clearance >50 mL/min (see Appendix I).

Hemoglobin >8 g/dL. Patients may be transfused to achieve this value. Elevated 
indirect bilirubin due to posttransfusion hemolysis is allowed.
10. Voluntary written consent must be given before performance of any study-related procedure 
not part of standard medical care, with the understanding that consent may be withdrawn by 
the patient at any time without prejudice to future medical care.
7.2
Exclusion Criteria
Patients meeting any of the following exclusion criteria are not to be enrolled in the study.
1. Previous treatment for HR MDS or CMML, or low-blast AML with chemotherapy or other 
antineoplastic agents including HMAs such as decitabine or azacitidine. Previous treatment is 
permitted with hydroxyurea and with lenalidomide, except that lenalidomide may not be given 
within 8 weeks before the first dose of study drug.
2. Acute promyelocytic leukemia as diagnosed by morphologic examination of bone marrow, by 
fluorescent in situ hybridization or cytogenetics of peripheral blood or bone marrow, or by 
other accepted analysis.
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3. Patients with AML with a WBC count >50,000/ µL. Patients who are cytoreduced with 
leukapheresis or with hydroxyurea may be enrolled if they meet the eligibility criteria.
4. Eligible for intensive chemotherapy and/or allogeneic stem cell transplantation. The reason a 
patient is not eligible for intensive chemotherapy and/or allogeneic stem cell transplantation 
may consist of one or more of the following factors: 

Age >75. 

Comorbidities.

Inability to tolerate intensive chemotherapy (eg, patients with AML with 20%-30% 
blasts and TRM ≥4).

Physician decision (eg, lack of available stem cell donor).
The reason a patient is not eligible should be documented in the electronic case report form
(eCRF).
5. Patients with either clinical evidence of or history of central nervous system involvement by 
AML.
6. Any serious medical or psychiatric illness that could, in the investigator’s opinion, potentially 
interfere with the completion of study procedures or could limit expected patient survival to 
less than 6 months.
7. Treatment with any investigational products or participation in any interventional studies
within 14 days before the first dose of any study drug. 
8. Known hypersensitivity to pevonedistat or its excipients.
9. Known hypersensitivity to azacitidine or its excipients.
10. Active uncontrolled infection or severe infectious disease, such as severe pneumonia, 
meningitis, or septicemia.
11. Major surgery within 14 days before first dose or a scheduled surgery during study period; 
insertion of a venous access device (eg, catheter, port) is not considered major surgery.
12. Diagnosed or treated for another malignancy within 2 years before randomization or 
previously diagnosed with another malignancy and have any evidence of residual disease. 
Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if 
they have undergone resection.
13. Life-threatening illness unrelated to cancer.
14. Prothrombin time (PT) or aPTT >1.5×ULN or active uncontrolled coagulopathy or bleeding 
disorder. Patients therapeutically anticoagulated with warfarin, direct thrombin inhibitors, 
direct factor Xa inhibitors, or heparin are excluded from enrollment.
15. Known human immunodeficiency virus (HIV) seropositive.
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16. Known hepatitis B surface antigen seropositive, or known or suspected active hepatitis C 
infection. Note: Patients who have isolated positive hepatitis B core antibody (ie, in the setting 
of negative hepatitis B surface antigen and negative hepatitis B surface antibody) must have an 
undetectable hepatitis B viral load.
17. Known hepatic cirrhosis or severe preexisting hepatic impairment.
18. Known cardiopulmonary disease defined as unstable angina, clinically significant arrhythmia, 
congestive heart failure (New York Heart Association Class III or IV; see Appendix J), and/or 
myocardial infarction within 6 months before first dose, or severe pulmonary hypertension. As 
an example, well-controlled atrial fibrillation would not be an exclusion whereas uncontrolled 
atrial fibrillation would be an exclusion.
19. Treatment with strong CYP3A inducers (see Appendix K) within 14 days before the first dose 
of pevonedistat. 
20. Female patients who are lactating and breastfeeding or have a positive serum pregnancy test 
during the Screening period or a positive urine pregnancy test on Day 1 before first dose of 
study drug.
21. Female patients who intend to donate eggs (ova) during the course of this study or for 4 months 
after receiving their last dose of study drug(s).
22. Male patients who intend to donate sperm or father a child during the course of this study or for 
6 months after receiving their last dose of study drug(s). 
8.0
STUDY DRUG
8.1
Study Drug Administration
All protocol-specific criteria for administration of study drug must be met and documented before 
drug administration. Study drug will be administered only to eligible patients under the 
supervision of the investigator or identified subinvestigator(s).
The first dose of study drug must be administered within 5 days of randomization on study. It is 
strongly recommended that dosing for both treatment arms occur on the days specified 
(ie, azacitidine dosing on Days 1-5, 8, and 9; pevonedistat dosing on Days 1, 3, and 5). However, 
dosing of either drug may be delayed for safety reasons or other unavoidable circumstances 
(eg, weather affecting clinic accessibility). If pevonedistat dosing is delayed, a minimum of 1 full 
calendar day between any 2 doses should be maintained. In each cycle, a maximum of 3 doses of 
pevonedistat and 7 doses azacitidine (as applicable) should not be exceeded. For the combination 
arm, pevonedistat and azacitidine should always be administered on the same day (eg, instead of 
pevonedistat dosing on Days 1, 3, and 5, it would be acceptable to dose on Days 1, 5, and 8). If 
dosing is adjusted, study procedures should be performed on the actual day of dosing. Actual start 
and stop times of the study drug administration, should be recorded accurately.
The amount of study drug (pevonedistat and/or azacitidine, as applicable) to be administered will 
be based on body surface area (BSA). BSA will be calculated using a standard formula (see 
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example in Appendix M) on Cycle 1 Day 1, and on Day 1 of subsequent cycles if the patient 
experiences a 5% change in body weight from the weight used for the most recent BSA 
calculation.
8.1.1
All Patients: Azacitidine Dosing
All patients will receive azacitidine (75 mg/m2 [IV or SC, per investigator’s choice]) on Days 1 
through 5, Day 8, and Day 9 of each treatment cycle. To the extent possible, the investigator
should maintain the same route of administration of azacitidine for the patient during the study. 
However, the investigator, without approval of the sponsor’s project clinician, may choose to 
switch the route of azacitidine administration at any time based on clinical or logistic reasons 
(eg, loss of IV access or occurrence of local irritation with SC administration). Please see the most 
recent VIDAZA (azacitidine) USPI [44] or EU SmPC [76], for details on azacitidine 
administration.
8.1.2
Additional Instructions for the Combination Arm: Pevonedistat Plus Azacitidine 
Dosing
Patients assigned to the Combination Pevonedistat Plus Azacitidine Arm will receive azacitidine 
as described in Section 8.1.1 and will also receive pevonedistat (20 mg/m2) via 60 (±10) minute 
infusion on Days 1, 3, and 5. All doses must be taken as outlined in the SOE (Appendix C).
Patients will receive pevonedistat diluted with 5% dextrose or 0.9% saline in a 250 mL bag via a 
60-minute IV infusion per the information provided in the Directions for Investigational Drug Use 
document located in the Pharmacy Manual. Pevonedistat should be administered through central 
or peripheral venous access. The infusion may be slowed or stopped and restarted for any 
associated infusion-related reactions. All infusion times must be recorded. The total time from 
drug reconstitution to end of infusion must not exceed 6 hours.
The entire content of the pevonedistat IV bag will be infused at a constant rate over 60 (±10) 
minutes. The start and end time of IV infusion should be recorded accurately, particularly in 
Cycle 1, when PK assessments are performed. To ensure that all the pevonedistat is administered, 
the infusion line will be flushed with 0.9% saline or 5% dextrose immediately after administration. 
The volume used for line flushing is not considered a part of the volume of the pevonedistat IV bag 
to be documented.
On Days 1, 3, and 5, when both study drugs are administered, azacitidine will be administered first 
followed by pevonedistat. The infusion of pevonedistat will begin between 15 and 60 minutes after 
completion of administration of SC azacitidine, and between 30 and 60 minutes after completion 
of administration of IV azacitidine
8.2
Reference/Control Therapy: Azacitidine 
Azacitidine is a chemical analogue of cytidine that is widely used for the treatment of patients with 
AML. A phase 3, randomized, open-label, international study compared azacitidine (75 mg/m2 SC 
daily for 7 days, every 28 days) with investigator-selected CCRs (eg, best supportive care, 
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low-dose cytarabine, or intensive chemotherapy) in 358 patients with HR MDS as defined at that 
time [16].
Approximately one third (n=113) of the patients in this study had RAEB-t (20%-30% bone 
marrow blasts); under the 2008 WHO-revised criteria, RAEB-t is now defined as AML [6]. A 
subanalysis of the study compared the relative efficacy and safety of azacitidine versus CCR in this 
patient subgroup (median age 70 years) [78]. Of these 113 patients with WHO-defined AML, 86% 
were considered unfit for intensive chemotherapy. Two-year OS rates were higher with azacitidine 
versus CCR in the patients considered unfit for intensive chemotherapy (51% vs 13%, respectively, 
p=0.0003). In addition, azacitidine was associated with fewer total days in the hospital (26.0 vs 
50.9 days per patient-year; relative risk=0.48; 95% CI 0.44-0.52; p<0.0001) than CCR. In patients 
with unfavorable cytogenetics, median OS in the azacitidine (n=14) and CCR (n=13) groups was 
12.3 and 5.3 months, respectively (hazard ratio=0.66; 95% CI 0.26-1.68; p=0.38), whereas the 
2-year OS rate was 38% for azacitidine, with no patients surviving more than 20 months in the 
CCR group (p=0.01) [78].
In a randomized phase 3 trial of azacitidine versus CCR in older patients with newly diagnosed 
AML, the median OS with azacitidine was 10.4 months, a 3.8 month (58%) increase over CCR. 
One-year survival with azacitidine was 47%, a 36% increase over CCR. Although the study did not 
reach statistical significance for its primary endpoint of OS (p=0.08), azacitidine demonstrated a 
clinically meaningful improvement. A sensitivity analysis of OS censoring at subsequent AML 
therapy demonstrated a statistically significant benefit for azacitidine versus CCR (12.1 vs 
6.9 months, respectively; p=0.0147) [79].
8.3
Dose Modification Guidelines
8.3.1
Criteria for Retreatment and Dose Delays
Retreatment Within a Cycle
If dosing of either drug is delayed for safety reasons, retreatment may be resumed upon resolution 
of the safety condition to ≤Grade 1. For pevonedistat, a minimum of 1 full calendar day between 
any 2 doses should be maintained. In each cycle, a maximum of 3 doses of pevonedistat and 
7 doses azacitidine (as applicable) should not be exceeded. If azacitidine is held for whatever 
reason, it may be resumed to complete a full treatment course as long as the full 7 doses are 
completed within the first 14 days of the cycle.
If dosing is interrupted within a cycle because of drug-related toxicity, and if the investigator and 
the sponsor’s project clinician (or designee) agree that it is in the patient’s interest to continue 
therapy with the study drug(s), then after recovery of the toxicity or toxicities in question 
to Grade 1 or to the patient’s baseline values, the dose of study drug may be reduced. For toxicity 
not related to drug (eg, disease-related toxicity), although a similar dose reduction is permitted, in 
general it is discouraged. If the reduced dose is well tolerated and the toxicity leading to dose 
reduction was ≤Grade 3, has resolved, and does not re-occur, the dose may resume at the original 
dose level in the next cycle after endorsement by the sponsor’s project clinician (or designee). For 
specific guidelines on azacitidine and pevonedistat dose reductions, see Sections 8.3.2 and 8.3.3. 
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Initiation of a New Cycle
Treatment with study drugs will be repeated every 28 days. It is strongly recommended that dosing 
for both treatment arms occur on the days specified. However, the initiation of a new cycle may be 
delayed for safety reasons or other unavoidable circumstances (eg, weather affecting clinic 
accessibility). For therapy to resume, nonhematologic toxicity considered related to treatment with 
study drugs must have resolved to ≤Grade 1, to the patient’s baseline values, or to a level 
considered acceptable by the investigator after discussion with sponsor’s project clinician (or 
designee). Criteria for dosing in a new cycle related to hematologic toxicities are detailed for 
azacitidine in Section 8.3.2.1 and for pevonedistat in Section 8.3.2.2.
If a patient fails to meet the criteria for retreatment, initiation of the next cycle of treatment may be 
delayed for up to 2 weeks. At the end of that time, the patient should be re-evaluated to determine 
whether the criteria for retreatment have been met. A dose reduction (as detailed in Sections 8.3.2
and 8.3.3) would be triggered if treatment is delayed for >2 weeks because of incomplete recovery 
from treatment-related toxicity. If the reduced dose is well tolerated and the toxicity leading to 
dose reduction was ≤Grade 3, has resolved, and does not reoccur, the dose may resume at the 
original dose level in the next cycle after endorsement by the sponsor’s project clinician (or 
designee).
Discontinuation of Treatment due to Study Drug–Related Toxicity
Study drug may be held for up to 6 weeks (42 days) because of study drug–related toxicity before 
a patient must be removed from protocol therapy.
8.3.2
Dose Modification for Hematologic Toxicities 
8.3.2.1
Azacitidine
Dose reduction or delays of azacitidine for hematologic toxicities (including fever and neutropenia) 
during the first 6 cycles of therapy are strongly discouraged, as it may impact patient outcome. 
Any potential dose reduction should be discussed and agreed first with the sponsor’s project 
clinician (or designee).
For hematologic AEs, the start of a new treatment cycle should be delayed and/or dose 
modifications should be considered if:

Absolute neutrophil count (ANC) is <500/µL. For patients with disease-related neutropenia, 
physician discretion may be used to initiate therapy with ANC ≥50% of baseline (baseline 
from the start of the previous cycle). In general, the use of growth factors should be restricted. 
However, to avoid dose delay, patients who experience Grade 4 neutropenia (ANC <500/µL) 
with or without fever may receive G-CSF or granulocyte macrophage colony-stimulating 
factor (GM-CSF) between days 28 to 42 days of azacitidine monotherapy or combination after 
discussion and agreement with the sponsor’s project clinician (or designee). Any use of growth 
factors will be documented in the eCRF. Patients who receive myeloid growth factors will not 
be included in assessment of neutrophil response during that cycle.
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
Platelet count is <20,000/µL. For patients with disease-related thrombocytopenia, physician 
discretion may be used to initiate therapy with platelet count ≥50% of baseline (baseline from 
the start of the previous cycle). If the above criteria are not met, the start of the new cycle will 
be delayed until the above criteria are met. If a low ANC or platelet count causes the delay of 
the start of the new cycle of more than 2 weeks, then the azacitidine dose will be decreased to 
50 mg/m2 when treatment is resumed.
If the reduced dose is well tolerated and the toxicity leading to dose reduction was ≤Grade 3, has 
resolved and does not reoccur, the dose may resume at the original dose level in the next cycle after 
endorsement by the sponsor’s project clinician (or designee).
If indicated, bone marrow evaluation will be performed to establish whether continued 
myelosuppression is related to persistent or progressing leukemic infiltration. 
8.3.2.2
Pevonedistat
It is not anticipated that pevonedistat dose modifications would be necessary because of 
myelosuppression. However, if clinically indicated in the opinion of the investigator, the 
pevonedistat dose may be reduced from 20 mg/m2 to 10 mg/m2. The pevonedistat dose may be 
re-escalated to 15 mg/m2 or 20 mg/m2 at the next cycle, if the toxicity has recovered to ≤Grade 1 or 
the patient’s baseline. 
Although leukostasis is not anticipated in this study, pevonedistat should be held for symptoms of 
leukostasis until the leukostasis is treated per institutional guidelines. Pevonedistat may be 
restarted when WBC count is <50,000/µL and following agreement by the sponsor’s project 
clinician (or designee).
8.3.3
Dose Modification for Nonhematologic Toxicities 
8.3.3.1
Azacitidine
Azacitidine Dose Adjustment Based on Renal Function and Serum Electrolytes
For renal toxicities, specifically elevated creatinine >Grade 1, azacitidine should be reduced in 
accordance with the prescribing information [44] and/or institutional guidelines. Similarly, if 
unexplained elevations in serum creatinine or blood urea nitrogen (BUN) occur, the next cycle 
should be delayed until values return to normal or baseline values, and the dose should be reduced 
by 50% on the next treatment course. 
If unexplained reductions in serum bicarbonate levels to <20 mEq/L occur, the azacitidine dose 
should be reduced by 50% on the next course. The azacitidine dose may be re-escalated back to 
75 mg/m2 at the next cycle, if the toxicity has recovered to ≤Grade 1 or the patient’s baseline 
status. 
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8.3.3.2
Pevonedistat
Pevonedistat Dose Adjustment Based on Serum Transaminases and Total Bilirubin
It is anticipated that LFTs (AST, ALT, and occasionally bilirubin) may be elevated for 
approximately 48 hours following the end of pevonedistat infusion on Cycle 1 Day 1. 
For elevated LFTs of Grade 2 or 3 that occur on or after Cycle 1 Day 3, pevonedistat should be 
held; once the elevated AST or ALT returns to ≤Grade 1, and/or elevated bilirubin returns to 
1.5ULN or the patient’s baseline level, pevonedistat dose may be resumed at 20 mg/m2. For 
pevonedistat, a minimum of 1 full calendar day between any 2 doses should be maintained, and a 
maximum of 3 doses of pevonedistat within the cycle must not be exceeded. 
For elevated LFTs of Grade 4 that occur on or after Cycle 1 Day 3, the pevonedistat dose should be 
held for the remainder of the cycle; if the elevated AST or ALT returns to ≤Grade 1, and/or 
elevated bilirubin returns to 1.5ULN or the patient’s baseline level, then pevonedistat may be 
restarted at the next cycle at a reduced dose of 10 mg/m2. If the toxicity remains at ≤Grade 1 or the 
patient’s baseline status at the 10 mg/m2 dose, then pevonedistat may be re-escalated to 15 mg/m2 
for the next cycle. After 1 cycle at 15 mg/m2, further re-escalation to 20 mg/m2 may occur only 
after the patient’s LFT (AST, ALT, and bilirubin) have been confirmed to be Grade 1, the same 
level as the patient’s baseline values, or a level considered acceptable by the investigator and the 
sponsor’s project clinician (or designee).
Pevonedistat Dose Adjustment Based on Hypophosphatemia
If hypophosphatemia is ≥Grade 3, study drug treatment should not be resumed until the 
hypophosphatemia is ≤Grade 2. Hypophosphatemia should be evaluated (including severity and 
etiology), monitored, and treated according to institutional guidelines. 
Pevonedistat Dose Adjustment for Other Toxicities
For other ≥Grade 2 nonhematologic toxicities potentially related to pevonedistat, the pevonedistat 
dose may be reduced from 20 mg/m2 to 10 mg/m2 at the discretion of the investigator as clinically 
indicated. If the toxicity returns to ≤Grade 1 or the patient’s baseline status, pevonedistat may be 
re-escalated to 15 mg/m2 or 20 mg/m2 at the next cycle.
8.4
Excluded Concomitant Medications and Procedures
Prohibited concomitant therapies include investigational agents, androgens, supraphysiologic 
doses of corticosteroids, erythropoietin, thrombopoietin agonists (eg, eltrombopag and 
romiplostim) or chemotherapeutic agents active against MDS, CMML, or low-blast AML.
The effect of rifampin, a strong CYP3A inducer, on pevonedistat PK was evaluated in 
Study P1015. The geometric mean AUC from time 0 to infinity of pevonedistat in the presence of 
rifampin was 79% of that in the absence of rifampin (90% CI: 69.2%, 90.2%). The result indicated 
that co-administration of rifampin did not result in clinically meaningful alteration of pevonedistat 
systemic exposures in the context of 28% of inter-individual variability in pevonedistat clearance. 
Based on these findings, CYP3A inducers are no longer included in the list of excluded 
concomitant medications.
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A physiologically based PK (PBPK) model accounting for hepatic uptake and metabolism of 
pevonedistat was developed to describe the PK of pevonedistat and the observed low sensitivity to 
DDIs with strong CYP3A/P-gp inhibitor (itraconazole) and strong inducer (rifampin). The 
pevonedistat PBPK model indicates that the systemic exposure of pevonedistat was not sensitive 
to the perturbations of enzyme activity when the hepatic uptake becomes the rate-determining step 
of its clearance. Considering the minimum effect on P-gp inhibition and hepatic uptake being the 
rate-determining step of pevonedistat clearance, the effect of BCRP inhibition is not expected to be 
clinically meaningful. Therefore, exclusion of BCRP inhibitors (eg, cyclosporine) is not deemed 
warranted in clinical studies of pevonedistat and BCRP inhibitors are no longer included in the list 
of excluded concomitant medications.
Medications that are generally excluded but are allowed with certain exceptions are listed in 
Table 8.a.
Table 8.a
Concomitant Medications Excluded While Receiving Study Treatment (Single 
Agent Azacitidine or Combination Pevonedistat Plus Azacitidine)
Therapy
Comment/Exceptions
Acetaminophen and acetaminophen-containing products
May be used judiciously but should not exceed a dose of 
2 g in 24 hours.
Systemic antineoplastic therapy, except for hydroxyurea
Hydroxyurea dosing during the study treatment phase 
may be adjusted to control the level of circulating blast 
counts to no lower than 10,000/µL while on study 
treatment. The dosing of hydroxyurea and changes to 
dosing of hydroxyurea must be recorded.
Any investigational agent, other than pevonedistat in the 
combination arm, for MDS, CMML, or low-blast AML, or 
commercially available agents used in MDS, CMML, or 
low-blast AML, including androgens, supraphysiologic 
doses of corticosteroids, erythropoietin, eltrombopag 
[Promacta], or romiplostim [Nplate]
AML=acute myelogenous leukemia, CMML=chronic myelomonocytic leukemia, MDS=myelodysplastic syndromes.
8.5
Permitted Concomitant Medications and Procedures 
Medications and procedures that are specifically permitted during the study are listed in Table 8.b.
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Table 8.b
Concomitant Medications and Procedures Permitted During the Study
Therapy
Comment
Antiplatelet agents (eg, aspirin, 
clopidogrel) and anticoagulants
May be used in patients who develop a thrombosis while on study. Note that 
patients with active uncontrolled coagulopathy or who are therapeutically 
anticoagulated with warfarin, direct thrombin inhibitors, direct Xa inhibitors or 
heparin are excluded from enrollment as per Section 7.2. 
Antiemetics for azacitidine
May be administered according to institutional guidelines.
Myeloid growth factors (eg, 
G-CSF, GM-CSF)
In general, the use of myeloid growth factors is discouraged and should be 
restricted. For patients in CR, CRi, or marrow CR, growth factors may be used in 
specific circumstances after discussion with the project clinician or designee. 
Use of growth factors may also be used in patients with Grade 3 or Grade 4 
febrile neutropenia after discussion and agreement with the project clinician or 
designee. Additionally to avoid dose delays, patients who experience Grade 4 
neutropenia (ANC <500/µL) with or without fever may receive G-CSF or 
GM-CSF between days 28-42 days of azacitidine monotherapy or combination 
after discussion and agreement with the sponsor’s project clinician (or designee). 
Patients who receive myeloid growth factors will not be included in assessment 
of neutrophil response.
Platelet transfusion
Permitted as medically necessary per institutional guidelines (eg, for platelets 
<10,000/µL in the absence of clinical bleeding); see Section 8.7.
Red blood cell transfusion
To be considered for all patients with anemia, especially those with hemoglobin 
values ≤8 g/dL; see Section 8.7.
G-CSF=granulocyte colony-stimulating factor, GM-CSF=granulocyte macrophage colony-stimulating factor.
8.6
Precautions and Restrictions
Concomitant medications and procedures that are excluded or must be used with caution are 
described in Sections 8.4 and 8.5, respectively.
Certain situations may warrant further caution, such as modifying the dose of study drug(s). Dose 
modification guidelines are provided in Section 8.3.
Refer to the package insert for VIDAZA USPI [44] or EU SmPC [76], for precautions and 
restrictions related to azacitidine use.
It is not known what effects pevonedistat has on human pregnancy or development of the embryo 
or fetus. Therefore, female patients participating in this study should avoid becoming pregnant, 
and male patients should avoid impregnating a female partner. Nonsterilized female patients of 
reproductive age group and male patients should use highly effective methods of contraception 
(see list provided in Appendix H) through defined periods during and after study treatment as 
specified below.
Female patients must meet 1 of the following:

Postmenopausal (see definition in Appendix G) for at least 1 year before the Screening visit, 
OR
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
Surgically sterile, OR

If they are of childbearing potential, agree to practice 1 highly effective method and 
1 additional effective (barrier) method of contraception at the same time, from the time of 
signing of the informed consent form (ICF) through 4 months after the last dose of study drug 
(whichever is longer), OR

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of 
the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 
methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable 
methods of contraception. Female and male condoms should not be used together.)
Female patients must agree to not donate eggs (ova) during the course of this study or for 4 months 
after receiving their last dose of study drug(s). 
Female patients should be advised not to breastfeed while undergoing treatment with azacitidine.
Male patients, even if surgically sterilized (ie, status postvasectomy) must agree to 1 of the 
following:

Agree to practice effective barrier contraception during the entire study treatment period and 
through 120 days (or if the drug has a very long half-life, for 90 days plus five half-lives) after 
the last dose of study drug, OR

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of 
the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 
methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable 
methods of contraception. Female and male condoms should not be used together.)
Male patients must agree to not donate sperm or father a child during the course of this study or for 
6 months after receiving their last dose of study drug(s).
Before starting treatment, male patients should be advised to seek counseling on sperm storage, 
and female patients should be advised to seek counseling on egg storage.
Nonclinical data suggest that male and female patients administered pevonedistat have a potential 
risk of infertility.
8.7
Management of Clinical Events
8.7.1
Azacitidine
The most common adverse drug reactions for azacitidine are described in Section 4.6.1. For the 
single-agent azacitidine treatment arm, refer to the VIDAZA USPI [44] or EU SmPC [76], as 
applicable, for details regarding the management of clinical events attributed to azacitidine.
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Guidance for Management of Necrotizing Fasciitis
Necrotizing fasciitis, including fatal cases, has been reported in patients treated with azacitidine. 
Azacitidine therapy should be discontinued in patients who develop necrotizing fasciitis, and 
appropriate treatment should be promptly initiated per institutional guidelines.
8.7.2
Combination Pevonedistat Plus Azacitidine
Common AEs reported for patients receiving the combination of pevonedistat and azacitidine are 
listed in Section 4.6.2. Also see the most recent IB. For the Combination Pevonedistat Plus 
Azacitidine Arm, follow the guidance in the following subsections of this protocol.
Guidance for Clinical Assessment and Management of Hemodynamic Compromise 
It is essential that the patients receiving the combination of pevonedistat and azacitidine are 
carefully evaluated at Screening and before each dose of study drug for early symptoms and signs 
of hemodynamic compromise and/or active infection. Particular attention should be given to fever, 
tachycardia, hypotension, orthostasis, tachypnea, recent nausea and vomiting, and clinical 
evidence of dehydration. Patients who experience an untoward reaction with the combination of 
pevonedistat and azacitidine should be followed closely on subsequent dosing.
For patients for whom there is a concern of dehydration, the following guidance for rehydration 
before pevonedistat dosing may be considered: 500 mL/hour of 0.5 N saline given over 
2 to 4 hours for a total of 1 to 2 L of fluid as clinically appropriate; each infusion of IV fluids 
should be recorded in the eCRFs.
For all patients with anemia, and especially for those with hemoglobin values ≤8 g/dL at Screening 
or during the conduct of the study, RBC transfusions should be considered before pevonedistat 
dosing based on the risk of inadequate oxygenation, underlying cardiopulmonary status, clinical 
judgment, and/or hospital guidelines. Similarly, for patients with clinically significant 
thrombocytopenia, especially those with platelet count <10,000/µL, a platelet transfusion should 
be considered. Any RBC or platelet transfusion must be recorded in the eCRFs.
Patients who experience signs and symptoms of hemodynamic compromise after pevonedistat 
dosing (eg, tachycardia, hypotension, orthostasis, changes in mental status, syncope, and dizziness) 
should be followed closely and managed with supportive care, including hospitalization, as 
clinically indicated.
Guidance Management of Leukostasis 
Pevonedistat treatment should be withheld for patients who develop symptoms of leukostasis (see 
Section 8.3.2.2). Treatment may include leukapheresis and hydroxyurea administration, per 
institutional guidelines. When the WBC of the patient is <50,000/L and symptoms are improved, 
pevonedistat treatment may be restarted after consulting with the sponsor’s project clinician (or 
designee). Azacitidine treatment may continue as clinically indicated.
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Guidance for Management of Extravasation
Based on nonclinical findings as detailed in the IB, pevonedistat is considered a nonvesicant drug. 
Although no published guidelines are available for extravasation of nonvesicants, the investigator 
is encouraged to follow institutional guidelines. Some general advice in case of extravasation 
includes immediately stopping drug infusion and elevating the affected limb to minimize swelling.
8.8
Blinding and Unblinding
This is an open-label study. Takeda’s staff or its designee that is directly involved in the study will 
be blinded to the treatment assignment of patients in the trial. The independent review committee 
(IRC) will be blinded to treatment assignments.
8.9
Description of Investigational Agents
Upon receipt of drug supply, contents must be verified promptly and the proper contacts notified 
of any discrepancies or damages as described in the Study/Pharmacy Manual.
8.9.1
Azacitidine
Azacitidine may be supplied by the site from commercial sources, depending on regional 
availability. Commercially available azacitidine is supplied as lyophilized powder in 100-mg 
single-use vials. Refer to the Study/Pharmacy Manual and the VIDAZA USPI [44] or EU SmPC 
[76], as applicable, for additional information regarding azacitidine.
8.9.2
Pevonedistat
The drug product is labeled Pevonedistat (TAK-924/MLN4924) Concentrate for Solution for 
Infusion.
Pevonedistat Concentrate for Solution for Infusion will be supplied by the sponsor as detailed in 
the Study/Pharmacy Manual. 
Each Pevonedistat Concentrate for Solution for Infusion vial contains 50 mg Pevonedistat, as free 
base, formulated with the following excipients: 
 
 and water for injection.
Details are available in the IB.
8.10
Preparation, Reconstitution, and Dispensation
Parenteral drug products should be inspected visually for particulate matter and discoloration 
before administration, whenever solution and container permit.
Before use, Pevonedistat Concentrate for Solution for Infusion vials should be brought to ambient 
conditions (15°C-30°C) by removing the vials from the refrigerator and placing them at room 
temperature. Accelerated warming methods such as a water bath must not be used. Pevonedistat 
Concentrate for Solution for Infusion is stable at ambient temperature for 6 hours before dilution. 
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If the drug product vial is not to be used within the 6-hour timeframe, the vial should be returned to 
storage. Each vial is for single use only.
Each Pevonedistat Concentrate for Solution for Infusion vial contains nominally 5 mL (50 mg) or 
4.4 mL (44 mg) Pevonedistat, as free base. Before injecting the drug product into the 250 mL IV 
bag containing a 5% dextrose or 0.9% saline solution, calculate the volume of drug product that 
will be administered and remove this volume from the 250 mL IV bag containing a 5% dextrose or 
0.9% saline solution (see Pharmacy Manual for details). Using sterile technique, the appropriate 
volume of drug is then withdrawn from vial(s) and injected into the 250 mL IV bag containing a 5% 
dextrose or 0.9% saline solution. The bag must be gently inverted repeatedly to mix the contents. 
The prepared Pevonedistat IV bag must be used within 6 hours if stored at room temperature or 
discarded. Alternatively, the prepared IV bag is chemically stable and may be stored for up to 18 
hours at 2°C to 8°C. After 18 hours of storage at 2°C to 8°C, the prepared IV bag must be used 
within 3 hours upon coming to room temperature or must be discarded. 
The vial must not be shaken at any time during dose preparation.
Discard bag, needle, and syringe in a proper biohazard container according to institutional 
guidelines.
Detailed reconstitution and dosage preparation instructions are provided in the Directions for Use 
located in the Pharmacy Manual.
Instructions for the preparation, reconstitution, and dispensation of azacitidine are provided in the 
VIDAZA USPI [44] or EU SmPC [76].
Pevonedistat is an anticancer drug, and as with other potentially toxic compounds, caution should 
be exercised when handling pevonedistat.
8.11
Packaging and Labeling
Pevonedistat Concentrate for Solution for Infusion will be provided in United States 
Pharmacopeia (USP) Type I glass vials. Each USP Type I glass vial nominally contains 5 mL or 
4.4 mL of compounded sterile solution, sealed with a Teflon-coated butyl rubber stopper and 
oversealed with an aluminum seal and a plastic cap.
Azacitidine is available as lyophilized powder in 100-mg, single-use vials from commercial 
supply with commercial packaging and labeling. Azacitidine may be sourced locally by the 
clinical sites when regulations allow for clinical site sourcing with appropriate labeling.
8.12
Storage, Handling, and Accountability
All investigational supplies are to be kept in a secure area with controlled access.
Vials of Pevonedistat Concentrate for Solution for Infusion are to be stored at 2°C to 8°C.
Details of the storage and handling of azacitidine are provided in the VIDAZA USPI [44] or EU 
SmPC [76]. 
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A drug dispensing log, including records of drug received from the sponsor and drug administered 
to the patients, will be provided and kept at the study site. Disposal instructions are provided in the 
Pharmacy Manual.
8.13
Other Protocol-Specified Materials
Refer to the Pharmacy Manual.
9.0
STUDY CONDUCT
This trial will be conducted in compliance with the protocol, Good Clinical Practice (GCP), 
applicable regulatory requirements, and International Council for Harmonisation (ICH) 
guidelines.
9.1
Study Personnel and Organizations
The contact information for the sponsor’s project clinician for this study, the central laboratory and 
any additional clinical laboratories or vendors participating on the study may be found in the Study 
Manual(s). A full list of investigators is available in the sponsor’s investigator database.
9.2
Arrangements for Recruitment of Patients
Recruitment and enrollment strategies for this study may include recruitment from the 
investigator’s local practice or referrals from other physicians. If advertisements become part of 
the recruitment strategy, they will be reviewed by the institutional review board 
(IRB)/independent ethics committee (IEC). It is not envisioned that prisoners (or other populations 
that might be subject to coercion or exploitation) will be enrolled into this study.
9.3
Treatment Group Assignments
Patient eligibility will be established before randomization into the study as patients will not be 
permitted to re-enroll. Confirmation of patient eligibility by the sponsor’s project clinician (or 
designee) following review and approval of a Patient Eligibility Checklist is required before 
randomization. A centralized randomization and stratification using an interactive web response 
system (IWRS) will be used. Patients will be randomized strictly sequentially at a center as they 
become eligible for randomization and will be stratified as detailed in Section 13.2. The study drug 
regimen must be initiated within 5 days of randomization on study. If a patient discontinues from 
the study, his/her randomization code will not be reused, and the patient will not be allowed to 
re-enter the study. 
9.4
Study Procedures
Refer to the SOE (Appendix C) for timing of assessments. Additional details are provided as 
necessary in the sections that follow and in the Study and Laboratory Manuals. When applicable, 
specific visit windows for study procedures are provided in the footnotes to the study schedules.
Nonessential protocol visits that do not require on-site sample collection and assessment may be 
completed via telemedicine (video or phone conversation between the patient and the treating 
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physician, if allowed per Health Authorities, privacy laws, and institutional and local guidelines) 
in situations where a site visit cannot be conducted, such as in a COVID-19 pandemic. 
9.4.1
Informed Consent
Each patient must provide written informed consent before any study-required procedures are 
conducted, unless those procedures are performed as part of the patient’s standard care.
Reconsent of Patients who Meet the Criteria for PD and Continue Study Treatment
Patients with HR MDS or CMML may be allowed to continue study treatment (either treatment 
arm) if they meet the criteria for PD based only on bone marrow blast count (without AML 
transformation) if, in the clinical judgment of the investigator, the patient is still receiving clinical 
benefit from this treatment, and the continuation is endorsed by the sponsor’s project clinician (or 
designee). Patients with low-blast AML in this study may also be allowed to continue study 
treatment (either treatment arm), even if they meet the criteria for PD based only on bone marrow 
blast counts if, in the clinical judgment of the investigator, the patient is still receiving clinical 
benefit from this treatment, and the continuation is endorsed by the sponsor’s project clinician (or 
designee). Patients who continue on study under these conditions must be reconsented before 
continuing study treatment.
9.4.2
Inclusion/Exclusion Confirmation
During Screening, a Patient Eligibility Checklist must be completed and submitted by the 
investigator for review and approval by the sponsor or designee before patient randomization. 
Completion of the eligibility checklist is necessary to verify that the patient has met all of the 
inclusion and exclusion criteria. Source documentation allows for independent verification that 
patient eligibility has been determined by the proper methodology. Unless specifically requested, 
additional source documentation does not need to be submitted with the checklist for the 
assessment of eligibility related to the other inclusion and exclusion criteria.
9.4.3
Patient Demographics
The date of birth, race, ethnicity, and sex of the patient are to be recorded during Screening.
9.4.4
Medical History and IPSS-R Risk Categorization
During Screening, a complete medical history will be compiled for each patient. The history will 
emphasize the background and progress of the patient’s MDS, CMML, or low-blast AML (see 
inclusion criteria 2 and 3, Section 7.1, for definitions), including an assessment of bone marrow 
morphology (see Section 9.4.24 for additional details on bone marrow sample collection and 
evaluation). Information regarding any prior therapy for MDS, CMML, or low-blast AML, 
including start and stop dates of each therapeutic agent and response to therapy, will be collected in 
the eCRF. In addition, all blood transfusions related to MDS, CMML, or low-blast AML that the 
patient received within 8 weeks before randomization will be recorded to document baseline 
transfusion dependence. 
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For patients with MDS or CMML (but not for patients with low-blast AML), screening 
assessments must include risk categorization (for both MDS and CMML patients) according to the 
IPSS-R [1]. Source documents supporting the prognostic risk category determination may be 
requested with the Patient Eligibility Checklist for review by the sponsor before randomization 
(see Section 9.4.2).
The IPSS-R Prognostic Score values based on specific criteria are provided in Table 9.a and the 
IPSS-R cytogenetic risk groups are provided in Table 9.b. Cytogenetic risk groups and bone 
marrow blast percentages will be based upon results from the local laboratory, while clinical lab 
values (hemoglobin, platelets and ANC) should be from the central laboratory results. Criteria and 
score values from these tables are used to determine the overall risk category as listed in Table 9.c. 
These 3 tables have been adapted from: www.mds-foundation.org/ipss-r-calculator/ (accessed 
05 January 2015), based on Greenberg et al., 2012 [1].
Additional details and instructions for determining the prognostic risk category are provided in the 
Study Manual.
Table 9.a
IPSS-R Prognostic Score Values
Prognostic Variable
0
0.5
1
1.5
2
3
4
Cytogenetics (a)
Very Good
Good
Intermediate
Poor
Very Poor
BM Blast %
≤2
>2 - <5
5-10%
>10%
Hemoglobin
≥10
8 - <10
<8
Platelets
≥100
50 - <100
<50
ANC
≥0.8
<0.8
Source: Greenberg et al., 2012 [1].
BM=bone marrow; ANC=absolute neutrophil count; IPSS-R=Revised International Prognostic Scoring System.
(a) Patients with indeterminate cytogenetics findings at Screening should be assigned a cytogenetics prognostic 
variable of 2 points (ie, intermediate) for determining overall Prognostic Risk Category/Score. 
Table 9.b
IPSS-R Cytogenetic Risk Groups
Cytogenetic prognostic subgroups
Cytogenetic abnormalities
Very good
-Y, del(11q)
Good
Normal, del(5q), del(20q), double including del(5q)
Intermediate
del(7q), +8, +19, i(17q), any other single or double independent clones
Poor
-7, inv(3)/t(3q)/del(3q), double including -7/del(7q),
Complex: 3 abnormalities
Very poor
Complex: >3 abnormalities
Sources: Greenberg et al., 2012 [1] and Schanz J et al., 2012 [80].
IPSS-R=Revised International Prognostic Scoring System.
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Table 9.c
IPSS-R Prognostic Risk Categories/Scores
Risk Category
Risk Score
Very low
≤1.5
Low
>1.5–3
Intermediate
>3–4.5
High
>4.5–6
Very high
>6
Source: Greenberg et al., 2012 [1]. 
IPSS-R=Revised International Prognostic Scoring System.
Risk status among patients with AML (favorable, intermediate, and poor risk categories), also 
have been defined according to cytogenetics and molecular abnormalities. For example, patients 
with TP53 mutations are classified as poor risk AML [48]. Cytogenetics, mutation analysis and 
molecular analysis will be done to assess these factors.
9.4.5
Modified Charlson Comorbidity Index Assessment
Patients will be assessed during Screening using the Modified Charlson Comorbidity Index (refer 
to Appendix L).
9.4.6
Physical Examination
A complete physical examination will be performed per standard of care at Screening and at the 
EOT visit. A symptom-directed physical examination will be completed per standard of care at the 
times specified in the SOE (Appendix C), and as clinically indicated.
9.4.7
Patient Height
Height will be measured only during Screening.
9.4.8
Patient Weight
Weight will be measured during Screening, within 3 days before Day 1 dosing in all cycles, and at 
the EOT visit. If the screening assessment was done within 3 days before Cycle 1 Day 1, an 
assessment at Cycle 1 Day 1 is not necessary. 
The amount of study drug (pevonedistat and/or azacitidine, as applicable) to be administered will 
be based on BSA. BSA will be calculated using a standard formula (see example in Appendix M) 
on Cycle 1 Day 1, and on Day 1 of subsequent cycles if the patient experiences a 5% change in 
body weight from the weight used for the most recent BSA calculation.
9.4.9
ECOG PS
ECOG PS will be assessed at the times specified in the SOE (Appendix C). Refer to Appendix F
for the PS grading scale.
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9.4.10
Vital Signs
Vital signs, including diastolic and systolic blood pressure, heart rate, and body temperature will 
be collected at Screening, predose on Days 1, 3, and 5 on each treatment arm of each treatment 
cycle, at EOT, and as clinically indicated. Diastolic and systolic blood pressure, and heart rate will 
be collected postdose on Days 1, 3, and 5 on each treatment arm of each treatment cycle. Vital sign 
measurements will be taken with the patient in the supine or sitting position.
9.4.11
Pregnancy Test
A serum pregnancy test will be performed for women of childbearing potential at Screening. A 
pregnancy test must also be performed for women of childbearing potential at every cycle 
(typically performed on Day 1 of the cycle; however, if a serum pregnancy test is used, this may be 
performed up to 3 days before Day 1) with negative results available before the first dose is 
administered in that cycle. A pregnancy test will also be performed for women of childbearing 
potential at the EOT visit to exceed the end of systemic exposure, which is 2 days for pevonedistat.
Pregnancy tests may also be repeated during the study if requested by an IEC/IRB or if required by 
local regulations.
9.4.12
PROs
To compare the impact of treatment between the 2 treatment arms in this study, patient-reported 
HRQOL will be assessed by 2 instruments: EORTC QLQ-C30, version 3.0, and EQ-5D-5L. 
The patient should be given the paper version of the questionnaires to complete at the scheduled 
visit before other clinical assessments are conducted. The questionnaires should be completed in 
the language most familiar to the respondent, at the scheduled visit, before the patient sees the 
investigator for clinical assessments. The patient should be given sufficient space and time to 
complete the questionnaires. The patient should complete the questionnaires on their own without 
any assistance from site staff or a caregiver. The questionnaires are intended to be self-reported 
and should not be interviewer-administered.
The study coordinator should check the questionnaire for completeness and encourage the patient 
to complete any missing responses. Detailed instructions relating to the administrative procedures 
of the questionnaires will be provided to the sites. Patient’s refusal to complete all or any part of a 
questionnaire should be documented in the eCRF. 
EORTC QLQ-C30
The EORTC QLQ C30 [72] was designated to assess HRQOL in a wide range of cancer patient 
populations and contains 30 items which incorporates 5 functional scales (physical, role, cognitive, 
emotional, and social), 9 symptom scales (fatigue, nausea and vomiting, pain, dyspnea, sleep 
disturbance, appetite loss, constipation, diarrhea, and financial difficulties), and a global quality of 
life/health status scale. Most of the 30 items have 4 response levels (not at all, a little, quite a bit, 
and very much), with 2 questions relying on a 7-point numeric rating scale. Supplemental items on 
symptoms (7 items) and functional impacts (3 items) from the EORTC item bank will also be 
included. The supplemental 10 items have 4 response levels (not at all, a little, quite a bit, and very 
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much). Raw scores are converted into scale scores ranging from 0 to 100. For the functional scales 
and the global health status scale, higher scores represent better HRQOL; whereas for the 
symptom scales lower scores represent better HRQOL. All items in this questionnaire relate to a 
recall period of 1 week.
EQ-5D-5L
The EQ-5D-5L is a self-administered, preference-based measure of health status. EQ-5D-5L 
includes 5 dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression) 
and 5 response levels for each domain (no problems, slight problems, moderate problems, severe 
problems, and extreme problems). Patients are asked to indicate their health state by selecting the 
most appropriate level of severity on each of the 5 dimensions. Patient responses to the 
5 dimensions of the EQ-5D-5L represent the patient’s health state that is transformed to a utility 
score using preferably country-specific value sets. There is also a visual analogue scale used by 
respondents to rate their health on a scale from best (100) to worst (0).
9.4.13
Hospitalization Assessment
During study treatment and EFS and response follow-up periods (ie, through transformation to 
AML for HR MDS and CMML patients, through progression for low-blast AML patients, or until 
initiation of subsequent therapy for all patients, whichever occurs first), all hospitalizations since 
the previous assessment will be collected from all patients as indicated in the SOE (Appendix C). 
Examples of data to be collected are number and duration of inpatient hospitalizations, location of 
admission (eg, intensive care unit, hospital floor bed), and reason(s) for admission and primary 
diagnosis at discharge. Transfusion data will also be collected. For example, the number of 
patients who received packed RBCs and number of units received, number of patients who 
received a platelet transfusion and number of units received, and location of transfusion (inpatient 
vs outpatient).
9.4.14
Concomitant Medications and Procedures
All concomitant medications and procedures (excluding transfusions) will be recorded from the 
time of the first dose of any study drug through 30 days after the last dose of any study drug. RBC 
and platelet transfusions will be recorded from 8 weeks before randomization through 30 days 
after the last dose of any study drug. See Section 8.4 and Section 8.5 for additional details 
regarding excluded and permitted concomitant medications and procedures. 
9.4.15
AEs
Monitoring of AEs, serious and nonserious, will be conducted throughout the study as specified in 
the SOE. Refer to Section 10.0 for details regarding definitions, documentation, and reporting of 
pretreatment events (PTEs), AEs, and SAEs.
9.4.16
Enrollment
Enrollment is achieved when the patient is randomized onto study treatment.
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Procedures for completion of the enrollment information are described in the IWRS and Study 
Manual(s).
9.4.17
ECGs
A 12-lead ECG will be administered at the time points specified in the SOE (Appendix C). 
Additional ECGs may be performed as clinically indicated.
9.4.18
Chest X-ray 
A chest x-ray will be performed during Screening. If a chest x-ray or chest computed tomography 
scan was done within 2 months before randomization, the chest x-ray does not need to be done 
during Screening.
9.4.19
Clinical Laboratory Evaluations
Handling and shipment of clinical laboratory samples will be outlined in the Laboratory Manual. 
Clinical laboratory evaluations will be performed by a central laboratory. The central laboratory 
results also should be used for determination of eligibility criteria by the sponsor’s project clinical 
(or designee) before randomization. For dosing decisions, local hematology and chemistry 
laboratory results may be used; however, samples must still be sent to the central laboratory as 
well. Local laboratory evaluations may be done more frequently at the investigator’s discretion, 
for instance management of anemia. Reasons that central laboratory results may not be available 
include, but are not limited to, the following:

Samples are not able to be analyzed by central laboratory (for various reasons).

Laboratory-dependent decisions needed for patient treatment have to be made before the 
availability of central lab results.
In the instance when a local laboratory is used and central laboratory results are subsequently 
available, a retrospective review will be completed by the sponsor’s project clinician (or designee) 
to determine any significant difference between those results. In the event of a significant 
difference, the sponsor may provide further advice to the clinical site.
9.4.19.1
Clinical Chemistry, Hematology, and Urinalysis
Blood samples for analysis of the hematological and clinical chemistry parameters shown in 
Table 9.d, Table 9.e, and Table 9.f and urine samples for analysis of the parameters shown in 
Table 9.g will be obtained as specified in the SOE (Appendix C).
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Table 9.d
Hematology Tests
Hematology
Hematocrit
Hemoglobin
Leukocytes with differential, including percent circulating blasts
Neutrophils (ANC); ANC will be calculated from the leukocyte count with differential count; see Appendix N
Platelet (count)
Coagulation testing (PT and aPTT) will be done at Screening and sent to the central laboratory.
Blood samples for analysis of reticulocyte counts and ferritin levels will be obtained as specified in 
the SOE (Appendix C) and sent to the central laboratory.
Table 9.e
Complete Serum Chemistry Panel
Serum Chemistry
Albumin
ALP
ALT
AST
Bilirubin (total)
BUN
Calcium
Carbon dioxide (CO2)
Chloride 
Creatinine 
Direct bilirubin 
Glucose
Lactate dehydrogenase
Magnesium
Phosphate
Potassium
Sodium
Urate
Blood phosphate tests will be performed on Day 5 of each treatment cycle or the day on which the 
third dose of pevonedistat is given if it is not Day 5 (to be performed by the central laboratory).
Table 9.f
Select Serum Chemistry Panel
Select Serum Chemistry
ALP
ALT
AST
Bilirubin (total)
BUN
Creatinine
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Table 9.g
Urinalysis with Microscopic Analysis
Urinalysis
Bilirubin
Glucose
Ketones
Leukocytes
Nitrite
Occult blood
pH
Protein
Specific gravity
Turbidity and color
Microscopic assessment of leukocytes, erythrocytes, 
bacteria, casts, and crystals
9.4.20
Disease Assessment
Formal disease assessments for study endpoints will be determined based on local bone marrow 
aspirate blast counts (blast counts from the bone biopsy may be used in the event the aspirate 
sample is inadequate and a biopsy was done), clinical laboratory evaluations performed at a central 
laboratory (local laboratory results may be used for time-sensitive clinical decisions), and local 
transfusion data. The investigator’s assessment of disease will be entered into the eCRF for each 
time point.
Transformation to AML may occur in both MDS and CMML. In this study, transformation to 
AML is defined, according to WHO Classification [81] as a patient having ≥20% blasts in the 
blood or marrow AND increase of blast count by 50%. To illustrate: 

For patients with 5% to 9% blasts pretreatment: a ≥50% increase to >10% blasts constitutes 
progression of MDS.

For patients with 10% to 19% blasts pretreatment: a ≥50% increase to >20% blasts constitutes 
transformation to AML.
Note: The principal investigator should make all efforts to perform the disease assessment by a 
bone marrow examination and hematology tests. However, in the exceptional circumstance that it 
is not possible to have a bone marrow examination from patients for disease assessment, 
transformation to AML will also be defined as >20% blasts in peripheral blood AND an increase 
of blast count by 50% from pretreatment.
Note that, according to the WHO Classification [81]: 
The blast percentage and assessment of degree of maturation and dysplastic abnormalities 
in the neoplastic cells should be determined, if possible, from a 200-cell leukocyte 
differential performed on a peripheral blood smear and a 500-cell differential performed on 
marrow aspirate smears stained with Wright Giemsa or May-Grunwald Giemsa. The blast 
percentage should be correlated with an estimate of the blast count from the marrow biopsy 
section. In addition to myeloblasts, the monoblasts and promonocytes in acute 
monoblastic/monocytic and acute and chronic myelomonocytic leukemia and the 
megakaryoblasts in acute megakaryoblastic leukemia are considered as ‘blast equivalents’ 
when the requisite percentage of blasts is calculated for the diagnosis of AML.
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As defined in Table 9.h and Table 9.i, additional assessment(s) of disease response for patients 
with MDS or CMML are based on the criteria outlined in the Modified IWG Response Criteria for 
MDS [2]; and additional assessments of disease response for patients with low-blast AML are 
based on the criteria outlined in the Revised Recommendations of the IWG for Diagnosis 
Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for 
Therapeutic Trials in Acute Myeloid Leukemia (Table 9.j).
Note that standard MDS guidelines [47] also recommend treatment for 6 cycles without altering 
dose or frequency of azacitidine regardless of cytopenias. Therefore, in this study, patients with 
HR MDS or CMML may be allowed to continue study treatment (either treatment arm), even if 
they meet the criteria for PD based only on bone marrow blast counts (without AML 
transformation), if, in the clinical judgment of the investigator, the patient is still receiving clinical 
benefit from this treatment, and the continuation is endorsed by the sponsor’s project clinician (or 
designee). Patients who meet the criteria for PD and continue on study under these conditions must 
be reconsented before continuing study treatment.
Investigators should note that some AML patients may benefit from continued treatment even 
though their bone marrow blast counts may fluctuate over the course of the first 4 cycles. For 
example, 2 of the 6 responders in the single-agent pevonedistat study in relapsed/refractory AML 
had asymptomatic transient increases in bone marrow blasts after achieving a response. In these 
2 cases, bone marrow blasts increased from less than 5% to more than 20%, and then decreased. In 
addition, another responder in that study had an asymptomatic transient increase in bone marrow 
blasts before achieving a response. In that case, bone marrow blasts almost doubled before 
response. These 3 patients were allowed to remain on study because their investigators felt they 
were clinically benefiting from continued treatment despite changes in their bone marrow blast 
counts. Therefore, patients with low-blast AML in this study may be allowed to continue study 
treatment (either treatment arm), even if they meet the criteria for PD based only on bone marrow 
blast counts, if, in the clinical judgment of the investigator, the patient is still receiving clinical 
benefit from this treatment and the continuation is endorsed by the sponsor’s project clinician (or 
designee). Patients who meet the criteria for PD and continue on study under these conditions must 
be reconsented before continuing study treatment. If a patient has <50% increase in blast count 
from pretreatment, then this is stable disease and the patient should remain on study.
A minimum of 6 cycles of treatment is strongly encouraged. If early removal from the study 
is being considered for toxicity or stable disease, contact the sponsor’s project clinician (or 
designee) to discuss before the patient is removed from the study.
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Table 9.h
Response Criteria for Altering Natural History of MDS and CMML
Category
Response Criteria
CR
Bone marrow: ≤5% myeloblasts with normal maturation of all cell lines (a) 
Persistent dysplasia will be noted (a)
Peripheral blood (b)
Hgb ≥11 g/dL
Platelets ≥100109/L
Neutrophils ≥1.0109/L
Blasts 0%
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: Any HI responses (see Table 9.i) will be noted separately, in addition to 
marrow CR
Stable disease
Failure to achieve at least PR, but no evidence of progression for >8 weeks
If a patient has <50% increase in blast count from pretreatment, then this is stable disease and 
the patient should remain on study.
Failure
Death during treatment or PD (as defined below), or progression to AML or a more advanced 
MDS or CMML FAB/WHO 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 
Note: Transient cytopenias during chemotherapy courses should not be considered 
relapse, as long as they recover to the previous levels.
Reduction in Hgb concentration by ≥1.5 g/dL or transfusion dependence
Cytogenetic response
Complete
Disappearance of the chromosomal abnormality without appearance of new ones
Partial
At least 50% reduction of the chromosomal abnormality 
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Table 9.h
Response Criteria for Altering Natural History of MDS and CMML
Category
Response Criteria
Progressive disease 
(PD)
Note: Transient cytopenias during chemotherapy courses should not be considered PD, 
as long as they recover to the previous levels. Progression based on blood values should 
not be considered at all until after the post-Cycle 4 marrow draw.
If a patient has ≥50% increase in blast count from pretreatment (without AML 
transformation) but is still deriving benefit from this treatment (eg, improvement in 
peripheral blood counts), the patient may continue on study as agreed by the investigator and 
the sponsor’s project clinician (or designee).
For patients with:
Less than 5% blasts: ≥50% increase in blasts to >5% blasts
5% - 9% blasts: ≥50% increase to >10% blasts
10% - 19% blasts: ≥50% increase to >20% blasts
20% - 30% blasts: see Table 9.j “Response Criteria for AML”
Any of the following:
At least 50% decrement from maximum remission/response in granulocytes or platelets
Reduction in Hgb by ≥2 g/dL
New transfusion dependence
Survival
Endpoints:
Overall: death from any cause
Event free: failure or death from any cause
PFS: PD, or transformation to AML, or death from MDS
DFS: time to relapse or transformation to AML
Cause-specific death: death related to MDS
To convert hemoglobin from grams per deciliter to grams per liter, multiply grams per deciliter by 10.
AML=acute myelogenous leukemia, CMML=chronic myelomonocytic leukemia, CR=complete remission, 
DFS=disease-free survival, FAB=French-American-British, Hgb=hemoglobin, HI=hematologic improvement, 
MDS=myelodysplastic syndromes, PFS=progression-free survival, PR=partial remission, WHO=World Health 
Organization.
(a) Dysplastic changes should consider the normal range of dysplastic changes. 
(b) 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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Table 9.i
Response Criteria for HI for MDS and CMML
HI (a)
Response Criteria (Responses Must be At Least 8 Weeks in Duration)
Erythroid response (pretreatment, <11 
g/dL)
Hgb 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 Hgb of ≤9.0 g/dL pretreatment will count in the RBC transfusion 
response evaluation.
Platelet response (pretreatment, 
<100109/L)
Absolute increase of ≥30109/L for patients starting with >20109/L 
platelets
Increase from <20109/L to >20109/L and by at least 100% 
Neutrophil response (pretreatment, 
<1.0109/L)
At least 100% increase and an absolute increase >0.5109/L
Progression or relapse after HI (b)
At least 1 of the following:
At least 50% decrement from maximum response levels in granulocytes 
or platelets
Reduction in Hgb by ≥1.5 g/dL
Transfusion dependence
To convert hemoglobin levels from grams per deciliter to grams per liter, multiply grams per deciliter by 10.
Hgb=hemoglobin, HI=hematologic improvement, RBC=red blood cell.
(a) Pretreatment counts will be the average of screening and Cycle 1 Day 1 predose samples. 
(b) In the absence of another explanation, such as acute infection, a course of chemotherapy, gastrointestinal bleeding, 
hemolysis, and so forth. The 2 kinds of erythroid and platelet responses should be reported overall as well as by the 
individual response pattern. 
The revised recommendations of the IWG for Diagnosis, Standardization of Response Criteria, 
Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia 
will be used for assessment of disease response [3]. Investigators are encouraged to consult the 
reference for more detailed explanation of response criteria.
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Table 9.j
Response Criteria for AML
Category
Response Criteria
Morphologic 
Complete remission 
(CR)
A CR designation requires that the patient achieve the morphologic leukemia-free state and 
have an ANC of more than 1,000/µL and platelets of ≥100,000/µL. A morphologic 
leukemia-free state requires less than 5% blasts in an aspirate sample with marrow spicules 
and with a count of at least 200 nucleated cells. Hemoglobin concentration or hematocrit has 
no bearing on remission status, although the patient must be independent of transfusions. 
There should be no residual evidence of extramedullary leukemia.
Morphologic complete 
remission with 
incomplete blood 
count recovery (CRi)
After chemotherapy, some patients fulfill all of the criteria for CR except for residual 
neutropenia (<1000/µL) or thrombocytopenia (<100,000/µL).
Cytogenetic CR
Reversion to a normal karyotype at CR or CRi
Partial remission (PR)
This designation requires all of the hematologic values for a CR but with a decrease of at 
least 50% in the percentage of blasts to 5% to 25% in the bone marrow aspirate. Thus, if the 
pretreatment bone marrow blast percentage was 50% to 100%, the percentage of blasts must 
decrease to a value between 5% and 25%; if the pretreatment blast percentage was 20% to 
less than 49%, they must decrease by at least half to a value of more than 5%. A repeat bone 
marrow aspiration after several weeks may be required to distinguish between a PR and 
increased blasts caused by bone marrow regeneration. A value of ≤5% blasts may also be 
considered a PR if Auer rods are present.
Progressive disease 
(PD)
Because the IWG criteria for AML do not provide a standardized definition for PD, [3] in 
this protocol, PD is defined as one of the following:

>50% increase in bone marrow blasts from baseline value to >30% blasts.

>50% increase in circulating blasts from baseline value to >30% blasts in peripheral 
blood (in the exceptional case when bone marrow examination is not possible). 

Development of biopsy-proven extramedullary disease, or new sites of extramedullary 
leukemia.
Relapse after CR
Relapse after CR is defined as a reappearance of leukemic blasts in the peripheral blood 
or >5% blasts in the bone marrow not attributable to any other cause (eg, bone marrow 
regeneration after consolidation therapy). In the setting of recent treatment, if there are no 
circulating blasts and the bone marrow contains 5% to 20% blasts, a repeat bone marrow 
performed at least a week later is necessary to distinguish relapse from bone marrow 
regeneration.
AML= acute myelogenous leukemia, ANC= absolute neutrophil count, IWG= International Working Group.
9.4.21
Biomarker, Pharmacodynamic, and PK Samples
9.4.21.1
Primary Specimen Collection
The primary specimen collection is displayed in Table 9.k.
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Table 9.k
Primary Specimen Collection
Specimen Name is 
Procedure in SOE 
(Appendix C) or 
Table A
Primary 
Specimen
Primary 
Specimen 
Derivative 1
Primary 
Specimen 
Derivative 
2
Description of Intended Use
Sample 
Collection
Fresh bone marrow 
aspirate sample for 
cytogenetics
Fresh bone 
marrow
N/A
N/A
Central cytogenetic analysis in 
fresh bone marrow aspirate 
samples
Mandatory
Fresh bone marrow 
aspirate sample for 
cytogenetics at relapse
Fresh bone 
marrow
N/A
N/A
Central cytogenetic analysis in 
fresh bone marrow aspirate 
samples
Mandatory
Fresh bone marrow 
aspirate sample for 
molecular analysis
Fresh Bone 
Marrow
Frozen cell 
pellet
DNA
Molecular analysis in fresh bone 
marrow aspirate samples
Mandatory
RNA
Frozen cell 
pellets
N/A
Fresh bone marrow 
aspirate sample for 
molecular analysis at 
relapse
Fresh Bone 
Marrow
Frozen cell 
pellet
DNA
Molecular analysis in fresh bone 
marrow aspirate samples
Mandatory
RNA
Frozen cell 
pellets
N/A
Buccal epithelial cells 
sample for DNA
Buccal Swab
DNA
N/A
Biomarker measurements in 
buccal epithelial cells
Mandatory
Plasma samples for 
pevonedistat PK
Plasma
N/A
N/A
Pharmacokinetic measurements
Mandatory
Whole blood sample 
for molecular analysis
Blood
Frozen cell 
pellet
DNA
Molecular analysis in fresh 
blood samples
Mandatory
RNA
Frozen cell 
pellets
N/A
Whole blood sample 
for molecular analysis 
at relapse
Blood
Frozen cell 
pellet
DNA
Molecular analysis in fresh 
blood samples
Mandatory
RNA
Frozen cell 
pellets
N/A
9.4.22
PK Measurements
Blood samples (approximately 3 mL each) for the determination of pevonedistat (and its 
metabolites, if appropriate) plasma concentrations will be collected from all patients in the 
Combination Pevonedistat Plus Azacitidine Arm at the time points indicated in the SOE 
(Appendix C). The exact date and time of each sample collection, as well as the actual start and 
stop times of the study drug administration, should be recorded accurately, and particular care 
should be given to the recording of blood sampling times that occur close to the infusion.
To ensure that the measurements are representative of plasma exposure, blood draws will be 
conducted in the arm opposite to a patient’s IV infusion. In the case that only a single arm is 
available, blood should be drawn as distal to the site of IV infusion as feasible, and the site of 
blood draw should be documented.
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Details regarding the preparation, handling, and shipping of samples are provided in the 
Study Manual. 
9.4.23
Biomarker Measurements in Buccal Epithelial Cells 
Buccal epithelial cell samples will be collected from patients in the Single-Agent Azacitidine Arm 
as well as patients in the Combination Pevonedistat Plus Azacitidine Arm as detailed in Table A). 
These samples (in addition to bone marrow aspirate and blood samples described in Section 9.4.24) 
will be used to identify biomarkers that are predictive of efficacy and/or safety of the combination 
of pevonedistat and azacitidine. Buccal epithelial cell samples will be used for the analysis of 
genotype variations in genes encoding DMEs or drug transporters that might be implicated in 
pevonedistat disposition. These samples may also be used in the interpretation of the tumor DNA 
sequencing data. This is a mandatory sample. 
Details regarding the preparation, handling, and shipping of these samples are provided in the 
Laboratory Manual.
9.4.24
Bone Marrow Aspirate and Biopsy Collection and Analysis
Bone Marrow Sample Collection for Disease Assessment
Bone marrow aspirates and biopsies will be required during the study as detailed in Table A. 
In addition, a bone marrow assessment will be performed for disease assessment at relapse (or 
suspected relapse) or PD, and if otherwise clinically indicated (eg, major changes in the patient’s 
underlying hematological disease are suspected). Note that the detection of circulating blasts is not 
by itself a sufficient criterion for relapse, but should trigger a bone marrow examination to 
determine whether a relapse has occurred. Other examples of triggers for ad hoc bone marrow 
examination may include a 50% reduction from maximum remission/response in granulocytes or 
platelets or a reduction in hemoglobin by ≥2 g/dL that is not considered drug related (eg, do not 
recover), or the hematologic values prompt new or more frequent transfusion support than the 
patient’s baseline status. 
A bone marrow biopsy (in addition to bone marrow aspirate) is required only at Screening to 
confirm the diagnosis. However, a bone marrow biopsy may be collected with bone marrow 
aspirate in accordance with institutional guidelines. If a biopsy was done within 28 days before 
enrollment, this archival biopsy may be used and does not need to be repeated. Similarly if 
cytogenetic and mutation analysis was done within 28 days before enrollment, these results also 
may be used. A fresh bone marrow aspirate obtained at Screening or anytime before the first 
administration of study drug will be used for baseline molecular characterization. If a bone marrow 
biopsy is not collected routinely per country/institutional guidelines, it is not required.
Bone marrow samples will be analyzed locally at the clinical site to: 

Determine blast count on aspirate samples: Samples will be evaluated locally for blast count 
per institutional standard practice to inform disease burden assessment. Samples will also be 
sent to a central laboratory for possible confirmation of bone marrow blast count, if required. 
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
Analyze cytogenetics for IPSS-R score determination and disease response assessment for 
patients with HR MDS and CMML. Cytogenetics will also be assessed for patients with 
low-blast AML. A portion of the bone marrow aspirate sample at Screening will also be sent to 
each site’s preferred cytogenetic laboratory for cytogenetics assessment according to 
institutional guidelines (by karyotype and/or fluorescence in situ hybridization). Chromosomal 
abnormalities and translocations that are routinely assessed for the diagnosis of MDS and 
AML and are included in the IPSS-R Prognostic Risk Score include, for example, trisomy 8, 
del(5)q, monosomy 7, del(20)(q), +6, +13, +21, t(5;12)(q33;p13), other 12p changes, 
t(3;5)(q25;q34), inv(3)(q21q26), rearrangements involving 1q, 11q23, 17p-/-17 and X 
chromosome. Note that bone marrow aspirates also must be sent to a central laboratory to 
assess cytogenetics at Screening and when additional marrow aspirates are performed. 
However, if local cytogenetics was done during the 28 days before randomization and before 
the screening marrow, it need not be repeated from the screening marrow (see Table A).

Analyze mutations: If mutation analysis is routinely done at the site, the data will be collected 
by the sponsor for analysis. Mutations such as TP53, FLT3, CEBPA, NPM1, ASXL1, TET2, 
RUNX1, DNMT3A, SRSF1, and SF3B1 are associated with clinical outcome in both MDS and 
AML [56]. If these data are available at the site, they will be collected. Analysis could be done 
by PCR or by other molecular techniques such as NGS. 
The bone marrow pathology reports, screening cytogenetics reports, and screening mutation 
analysis reports from the local laboratories will be submitted to the sponsor.
In addition to submitting bone marrow samples to the local laboratory (as per institutional 
guidelines), samples should be submitted to the central laboratory, as follows:

Whenever a bone marrow aspirate is collected: 
–
a peripheral blood smear will be sent to the central laboratory.
–
2 to 3 unstained aspirate smears (either uncharged or charged slides) should be submitted 
to the central laboratory.
–
1 aspirate smear from the local analysis should be submitted to the central laboratory.

Whenever a bone marrow biopsy is collected, it should be submitted to the central laboratory.
Acceptable bone marrow biopsy samples in order of preference are as follows:
1. 5 unstained slides (charged slides) from core biopsy specimen 3 to 5 microns thick. 
2. Formalin-fixed paraffin embedded tissue block.
3. Core biopsy in formalin-filled container. 
These bone marrow samples that are being sent to the central laboratory are for:

Bone marrow samples will also be sent to a central laboratory, in addition to those sent for 
local laboratory examination, for possible evaluation of blast count, if required. The procedure 
for handling, preparation and shipment of samples is outlined in the Laboratory Manual. 
Samples will be evaluated by the central laboratory at each time point (including any 
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unscheduled samples) and results will be reported to the sponsor. This evaluation will not be a 
real-time confirmation of progression, and results will not be routinely available to the clinical 
sites. Clinical decisions will be based on local laboratory blast count results. Discrepancies 
between local study site results and central laboratory results will be reviewed by the sponsor. 
Following Cycle 4, bone marrow collection will be performed only as clinically indicated in 
patients who achieve CR. In all other patients who do not achieve CR, bone marrow assessments 
will be performed as described in Table A. Additional bone marrow aspirates may be performed if 
warranted by changes in peripheral blood counts.
Details regarding the preparation, handling, and shipping of these samples are provided in the 
Laboratory Manual.
Fresh Bone Marrow Aspirate Sample Collection for Molecular Analysis
Fresh bone marrow aspirate samples will be collected as described in Table A and will be sent to a 
specialty laboratory for molecular characterization to:

Identify biomarkers that are predictive of efficacy and/or safety of the combination of 
pevonedistat and azacitidine: A portion of the bone marrow aspirate sample obtained at 
Screening will be sent to a specialty lab for baseline molecular characterization of the patient’s 
MDS, CMML or low-blast AML.

Evaluate changes in epigenetic patterns: Changes in epigenetic patterns (eg, methylation) 
following drug treatment will be determined by comparing epigenetic modifications in bone 
marrow aspirate samples obtained at Screening and after treatment (end of Cycle 2). 
Epigenetic changes might also be determined by evaluating changes in gene expression 
between bone marrow aspirate samples collected at Screening and after treatment.

Determine depth and durability of response over time. Analysis will be done for disease burden 
following treatment using either flow cytometry, NGS, or proteomic based approaches. 

Evaluate mechanisms of treatment-emergent resistance: Bone marrow aspirates obtained at 
relapse will be evaluated for potential mechanisms of treatment-emergent resistance, such as 
somatic mutations in NAE subunits and key signaling pathways, or change in pathway activity. 
Blood Sample Collection for Biomarker Analysis:

Fresh blood samples will be collected as described in the SOE (Appendix C) and may be sent 
to a specialty laboratory for molecular characterization similar to that being proposed for the 
bone marrow aspirate sample.
Details regarding the preparation, handling, and shipping of these samples are provided in the 
Laboratory Manual.
9.5
Completion of Study Treatment (for Individual Patients)
A patient has completed the treatment if they discontinue treatment for any of the reasons listed in 
Section 9.7. Note that PD includes transformation to AML, relapse after CR for patients with 
low-blast AML, or other PD as defined in Section 9.4.20.
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As detailed in Section 4.3, some patients in Study C15003 (single-agent pevonedistat in patients 
with relapsed/refractory AML) derived clinical benefit from continuing study treatment despite 
changes in their bone marrow blast counts. Standard MDS guidelines [47] also recommend 
treatment for 6 cycles without altering dose or frequency of azacitidine regardless of cytopenias. 
Therefore, in this study, patients may be allowed to continue study treatment (either treatment 
arm), even if they meet the criteria for PD based only on bone marrow blast counts (without AML 
transformation), if, in the clinical judgment of the investigator, the patient is still receiving clinical 
benefit from this treatment, and the continuation is endorsed by the sponsor’s project clinician (or 
designee). If a patient has <50% increase in blast count from pretreatment, then this is stable 
disease and the patient should remain on study. If a patient has ≥50% increase in blast count from 
pretreatment (without AML transformation), but is still deriving benefit, the patient may continue 
on study as agreed by the investigator and the sponsor’s project clinician (or designee). Patients 
who meet the criteria for PD and continue on study under these conditions must be reconsented 
before continuing study treatment.
A minimum of 6 cycles of treatment is strongly encouraged. If early removal from the study is 
being considered for toxicity or stable disease, contact the sponsor’s project clinician (or designee) 
to discuss before the patient is removed from the study.
Patients will attend an EOT visit 30 days (+10 days) after the last dose of study drug or before the 
start of subsequent antineoplastic therapy if that occurs sooner; refer to the SOE (Appendix C) for 
EOT visit assessments. All patients will then continue to be followed as specified in the SOE 
(Appendix C): 

Patients with HR MDS or CMML at study enrollment who have not transformed to AML and 
have not started subsequent therapy following the EOT visit will enter EFS follow-up. If a 
patient with HR MDS or CMML at study enrollment subsequently transforms to AML (as 
defined in Section 9.4.20) the patient will then enter OS follow-up. 

Patients with low-blast AML at study enrollment who have not progressed and have not started 
subsequent therapy following the EOT visit will enter response follow-up. If a patient with 
low-blast AML subsequently progresses or relapses (as defined in Section 9.4.20) or initiates 
subsequent therapy during the response follow-up period, the patient will then enter OS 
follow-up period.

Patients with HR MDS or CMML at study enrollment that has transformed to AML and 
patients with low-blast AML at study enrollment who have experienced PD or relapse after CR 
at the time of the EOT visit will enter OS follow-up immediately. 
9.6
Completion of Study (for Individual Patients)
Patients will be considered to have completed the study if they are followed until death or until the 
sponsor terminates the study.
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9.7
Discontinuation of Treatment With Study Drug and Patient Replacement
Treatment with study drug must be discontinued for any of the following reasons: 

Study drug–related toxicity causing a study drug hold of >6 weeks (see Section 8.3.1).

Unacceptable toxicity.

Transformation to AML (in patients with HR MDS or CMML).

PD.
Note: Patients may be allowed to continue study treatment (either treatment arm) if they meet the 
criteria for PD on the basis of only bone marrow blast count (without AML transformation in 
patients with HR MDS or CMML) if, in the clinical judgment of the investigator, the patient is still 
receiving clinical benefit from this treatment and the continuation is endorsed by the sponsor’s 
project clinician (or designee). Patients who meet the criteria for PD and continue on study under 
these conditions must be reconsented before continuing study treatment. 

Disease relapse.
Treatment with study drug may also be discontinued for any of the following reasons: 

AE.

Protocol deviation.

Subsequent anticancer therapy.

Initiation of HSCT.

Study terminated by sponsor.

Withdrawal by subject.

Lost to follow-up.

Other.
Once study drug has been discontinued, all study procedures outlined for the EOT visit will be 
completed as specified in the SOE (Appendix C). The primary reason for study drug 
discontinuation will be recorded on the eCRF. Further details should be recorded in the eCRF.
Patients who are randomized to a treatment arm but do not receive study drug for any reason will 
not be replaced.
9.8
Withdrawal of Patients From Study
A patient may be withdrawn from the study for any of the following reasons:

Lost to follow-up.

Study terminated by sponsor.

Withdrawal by subject.
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
Death.

Other.
The sponsor or its designee must be notified in writing if a patient is withdrawn from study 
treatment or from the study. The reason(s) for withdrawal must be documented in the patient’s 
medical records. The investigators will make every reasonable effort to keep each patient on the 
study until all planned treatments and assessments have been performed. If a patient discontinues 
study treatment, every attempt should be made to follow the patient until death or administrative 
study closure. Final treatment assessments will be performed before any other therapeutic 
intervention if possible. Additionally, any planned alternative treatments should be documented on 
the patient’s medical records and eCRF.
The consequence of study withdrawal is that no new information will be collected from the 
withdrawn patient and added to the existing data or any database
9.9
Study Compliance
Study drug will be administered or dispensed only to eligible patients under the supervision of the 
investigator or identified subinvestigator(s). The appropriate study personnel will maintain records 
of study drug receipt and dispensing.
9.10
Posttreatment Follow-up Assessments (EFS Follow-up, Response Follow-up, and 
OS Follow-up) 
Patients who discontinue study treatment will complete the EOT visit 30 days (+10) after the last 
dose of study drug. Patients will continue to be followed for EFS, Response, and OS endpoints as 
detailed in the SOE (Appendix C) and Table A. All subsequent therapies for MDS, CMML, and/or 
AML (as applicable) will be recorded, regardless if they are initiated before or after PD or 
transformation to AML.
Following the EOT visit, patients with HR MDS or CMML will enter EFS follow-up, if their 
disease has not transformed to AML. Patients will have monthly assessments to include physical 
exam, clinical blood tests, HRQOL assessments, hospitalization assessment, and disease 
assessment as outlined in the SOE (Appendix C). Patients who discontinue study treatment 
without evidence of progression (ie, PD or transformation to AML) will have a bone marrow 
aspirate and hematology tests (see Table 9.d) (all sent to the central laboratory) at the time of 
suspected progression. Patients who discontinue treatment while in CR or PR also will have a bone 
marrow aspirate and hematology tests (all sent to the central laboratory) at the time of suspected 
relapse (see SOE [Appendix C] and Table A). Patients will continue monthly EFS follow-up study 
visits until their disease transforms to AML (see Study Diagram in Appendix B). Patients who 
have started subsequent therapy will have EFS follow-up but will not be required to have monthly 
visits; at the time of suspected transformation to AML they will have a bone marrow aspirate and 
hematology tests (all sent to the central laboratory). 
Following the EOT visit, patients with low-blast AML will enter response follow-up, if they have 
no evidence of disease progression and they have not started subsequent therapy. Patients will 
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have monthly assessments to include physical exam, clinical blood tests, HRQOL assessments, 
hospitalization assessment, and disease assessment as outlined in the SOE (Appendix C). Patients 
who discontinue study treatment while not in CR and without evidence of PD will have a bone 
marrow aspirate and hematology tests (all sent to central laboratory) at the time of suspected PD. 
Patients who discontinue treatment while in CR also will have a bone marrow aspirate and 
hematology tests (all sent to central laboratory) performed at the time of suspected relapse (see 
Table A). Patients will continue monthly response follow-up visits, until they relapse from CR or 
meet the criteria for PD (see Study Diagram in Appendix B).
Following the EFS and response follow-up visits, or the EOT visit (for patients with HR MDS or 
CMML who discontinue study treatment because of transformation to AML, or patients with 
low-blast AML who discontinue study treatment because of PD), patients will enter OS follow-up 
and will be contacted every 3 months until death to document subsequent therapies and survival 
status (see Study Diagram in Appendix B).
Note: Related SAEs must be reported to Takeda Department of Pharmacovigilance or designee. 
This includes deaths that the investigator considers related to study drug that occur during the 
posttreatment follow-up. Refer to Section 10.0 for details regarding definitions, documentation, 
and reporting of SAEs. 
9.11
Posttrial Access
9.11.1
Posttrial Access
If a posttrial access (PTA) program should become an option for a patient, after Final Analysis (FA) 
is completed, and if the responsible investigator and the sponsor agree that the patient would 
derive benefit from – or would be harmed without – continued treatment, then pevonedistat may be 
provided through the PTA program (where permitted by local regulations).
9.11.2
Duration of PTA
If a PTA program should become an option for a patient, as described in Section 9.11.1, the 
sponsor may continue to provide pevonedistat to that patient through the PTA program. Continued 
access to pevonedistat for participants will be terminated for those individuals who no longer 
benefit from treatment (eg, their disease has progressed or treatment is no longer tolerable), the 
benefit-risk no longer favors the individual, an appropriate alternative therapy becomes available, 
or pevonedistat becomes available either commercially or via another access mechanism. PTA 
may be terminated in a country or geographic region where the development of pevonedistat has 
been suspended or stopped by the sponsor or where pevonedistat can no longer be supplied.
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10.0
ADVERSE EVENTS
10.1
Definitions
10.1.1
PTE Definition
A PTE is any untoward medical occurrence in a patient or subject who has signed informed 
consent to participate in a study but before administration of any study medication; it does not 
necessarily have to have a causal relationship with study participation.
10.1.2
AE Definition
AE means any untoward medical occurrence in a patient or subject administered a pharmaceutical 
product; the untoward medical occurrence does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product whether or not it is related to the medicinal product. This includes any 
newly occurring event, or a previous condition that has increased in severity or frequency since the 
administration of study drug.
An abnormal laboratory value will not be assessed as an AE unless that value leads to 
discontinuation or delay in treatment, dose modification, therapeutic intervention, or is considered 
by the investigator to be a clinically significant change from baseline.
10.1.3
SAE Definition
SAE means any untoward medical occurrence that at any dose:

Results in death.

Is life-threatening (refers to an AE in which the patient was at risk of death at the time of the 
event. It does not refer to an event which hypothetically might have caused death if it were 
more severe).

Requires inpatient hospitalization or prolongation of an existing hospitalization (see 
clarification in the paragraph in Section 10.2 on planned hospitalizations).

Results in persistent or significant disability or incapacity. (Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions).

Is a congenital anomaly/birth defect.

Is a medically important event. This refers to an AE that may not result in death, be 
immediately life threatening, or require hospitalization, but may be considered serious when, 
based on appropriate medical judgment, may jeopardize the patient, require medical or 
surgical intervention to prevent 1 of the outcomes listed above, or involves suspected 
transmission via a medicinal product of an infectious agent. Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at home, 
blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
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development of drug dependency or drug abuse; any organism, virus, or infectious particle 
(eg, prion protein transmitting transmissible spongiform encephalopathy), pathogenic or 
nonpathogenic, is considered an infectious agent.
In this study, intensity for each AE, including any lab abnormality, will be determined using the 
NCI CTCAE, version 4.03, effective date 14 June 2010 [4]. Clarification should be made between 
an SAE and an AE that is considered severe in intensity (Grade 3 or 4), because the terms serious 
and severe are NOT synonymous. The general term severe is often used to describe the intensity 
(severity) of a specific event; the event itself, however, may be of relatively minor medical 
significance (such as a Grade 3 headache). This is NOT the same as serious, which is based on 
patient/event outcome or action criteria described above, and is usually associated with events that 
pose a threat to a patient’s life or ability to function. A severe AE (Grade 3 or 4) does not 
necessarily need to be considered serious. For example, a WBC count of 1000/mm3 to less than 
2000 is considered Grade 3 (severe) but may not be considered serious. Seriousness (not intensity) 
serves as a guide for defining regulatory reporting obligations.
10.2
Procedures for Recording and Reporting AEs and SAEs
All AEs spontaneously reported by the patient and/or in response to an open question from study 
personnel or revealed by observation, physical examination, or other diagnostic procedures will be 
recorded on the appropriate page of the eCRF (see Section 10.3 for the period of observation). Any 
clinically relevant deterioration in laboratory assessments or other clinical finding is considered an 
AE. When possible, signs and symptoms indicating a common underlying pathology should be 
noted as 1 comprehensive event.
Regardless of causality, SAEs and serious PTEs (as defined in Section 10.1) must be reported (see 
Section 10.3 for the period of observation) by the investigator to the Takeda Global 
Pharmacovigilance department or designee within 24 hours of becoming aware of the event. This 
will be done by transmitting an electronic data capture (EDC) SAE report. If transmission of an 
EDC SAE report is not feasible, then a facsimile of the completed Takeda paper-based SAE form 
will be sent. A sample of the paper-based SAE form and processing directions are in the Study 
Manual. Information in the SAE report or form must be consistent with the data provided on the 
eCRF.
If information not available at the time of the first report becomes available at a later date, the 
investigator will transmit a follow-up EDC SAE report (or a paper-based SAE form if an EDC 
SAE report is not feasible) or provide other documentation immediately within 24 hours of receipt. 
Copies of any relevant data from the hospital notes (eg, ECGs, laboratory tests, discharge 
summary, postmortem results) should be sent to the addressee, if requested.
All SAEs and serious PTEs should be followed up until resolution or permanent outcome of the 
event. The timelines and procedure for follow-up reports are the same as those for the initial report.
Planned hospital admissions or surgical procedures for an illness or disease that existed before the 
patient was enrolled in the trial are not to be considered AEs unless the condition deteriorated in an 
unexpected manner during the trial (eg, surgery was performed earlier or later than planned).
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For both serious and nonserious AEs, the investigator must determine both the severity (toxicity 
grade) of the event and the relationship of the event to study drug administration. For serious PTEs, 
the investigator must determine both the severity (toxicity grade) of the event and the causality of 
the event in relation to study procedures.
Severity (toxicity grade) for each AE, including any lab abnormality, will be determined using the 
NCI CTCAE, version 4.03, effective date 14 June 2010 [4]The criteria are provided in the Study 
Manual.
Relationship of the event to study drug administration (ie, its causality) will be determined by the 
investigator responding yes (related) or no (unrelated) to this question: “Is there a reasonable 
possibility that the AE is associated with the study drug?”
10.3
Monitoring of AEs and Period of Observation
AEs, both nonserious and serious, will be monitored throughout the study as follows: 

AEs 
–
Nonserious PTEs related to study screening procedures will be reported from the time of 
the signing of the ICF up to first dose of study drug and recorded in the eCRFs.
–
Treatment-emergent adverse events (TEAEs) will be reported from the first dose of any 
study drug through 30 days after administration of the last dose of any study drug and 
recorded in the eCRFs. TEAEs should be monitored until they are resolved or are clearly 
determined to be due to a patient’s stable or chronic condition or intercurrent illness(es).

SAEs
–
Serious PTEs will be reported to the Takeda Department of Pharmacovigilance or designee 
from the time of the signing of the ICF up to first dose of study drug, and will also be 
recorded in the eCRF.
–
Related and unrelated treatment-emergent SAEs will be reported to the Takeda 
Department of Pharmacovigilance or designee from the first dose of study drug through the 
EOT visit, 30 (+10) days after administration of the last dose of study drug, and recorded in 
the eCRF. After this period, only related SAEs must be reported to the Takeda Department 
of Pharmacovigilance or designee. SAEs should be monitored until they are resolved or are 
clearly determined to be due to a patient’s stable or chronic condition or intercurrent 
illness(es). 
10.4
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events
If a woman becomes pregnant or suspects that she is pregnant while participating in this study, she 
must inform the investigator immediately and permanently discontinue study drug. The sponsor 
must also be contacted immediately by faxing a completed Pregnancy Form to the Takeda Global 
Pharmacovigilance department or designee (see Section 10.2). The pregnancy must be followed 
for the final pregnancy outcome.
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If a female partner of a male patient becomes pregnant during the male patient’s participation in 
this study, the sponsor must also be contacted immediately by faxing a completed Pregnancy Form 
to the Takeda Global Pharmacovigilance department or designee (see Section 10.2). Every effort 
should be made to follow the pregnancy for the final pregnancy outcome.
10.5
Procedures for Reporting Product Complaints or Medication Errors (Including 
Overdose)
A product complaint is a verbal, written, or electronic expression that implies dissatisfaction 
regarding the identity, strength, purity, quality, or stability of a drug product. Individuals who 
identify a potential product complaint situation should immediately report this via the phone 
numbers or e-mail addresses provided below.
A medication error is a preventable event that involves an identifiable patient and that leads to 
inappropriate medication use, which may result in patient harm. Whereas overdoses and 
underdoses constitute medication errors, doses missed inadvertently by a patient do not. 
Individuals who identify a potential medication error (including overdose) situation should 
immediately report this via the phone numbers or e-mail addresses provided below.
Call center
Phone number
E-mail
Fax
Dohmen Life 
Science 
Services
1-844-662-8532 
Non-toll-free number: 
1-510-740-1273 
GlobalOncologyMedinfo@takeda.com 
1-800-881-6092
Product complaints in and of themselves are not AEs. If a product complaint results in an SAE, an 
SAE form should be completed and sent to Cognizant (refer to Section 10.2).
10.6
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, including the European 
Medicines Agency, investigators and IRBs or IECs, as applicable, in accordance with national 
regulations in the countries where the study is conducted. Relative to the first awareness of the 
event by/or further provision to the sponsor or sponsor’s designee, SUSARs will be submitted to 
the regulatory authorities as an expedited report within 7 days for fatal and life-threatening events 
and 15 days for other serious events, unless otherwise required by national regulations. The 
sponsor will also prepare an expedited report for other safety issues where these might materially 
alter the current benefit-risk assessment of an investigational medicinal product or that would be 
sufficient to consider changes in the investigational medicinal product’s administration or in the 
overall conduct of the trial. The investigational site also will forward a copy of all expedited 
reports to his or her IRB or IEC in accordance with national regulations. 
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11.0
STUDY-SPECIFIC COMMITTEES
11.1
Takeda Safety Monitoring
Safety data will be reviewed and assessed periodically by a Global Pharmacovigilance Safety 
Team and a cross-functional Safety Management Team throughout the conduct of the study. These 
cross-functional reviews will include a Global Safety Lead from the study team, as well as 
representation from other departments at Takeda such as Clinical Research, Pharmacovigilance, 
Biostatistics, Clinical Pharmacology, and Clinical Operations.
11.2
IRC
An IRC will be blinded to treatment arm and review all disease evaluation data from the study and 
determine disease status (response categories, transformation to AML, etc), according to the 
Modified IWG Response Criteria for MDS for patients with MDS or CMML and the Revised 
Recommendations of the IWG for Diagnosis Standardization of Response Criteria, Treatment 
Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia for 
patients with low-blast AML. Data from the IRC will not be provided to the investigator during the 
conduct of the study.
Details of the IRC will be captured in a charter.
11.3
Independent Data Monitoring Committee 
An independent data monitoring committee (IDMC) supported by at least 1 independent 
statistician will review safety and efficacy data at the 2 planned interim analyses (IAs). The IDMC 
will review the outcomes at the first interim analysis (IA1) and the second interim analysis (IA2), 
and make recommendations on study conduct if needed. If the prespecified number of 
approximately 202 OS events for FA are expected (based on blinded study data) to be available 
close to the IA2, the IA2 (ie, EFS FA) and the FA (ie, OS FA) will be performed as a single 
analysis, when approximately 202 OS events and the adaptive EFS event size have occurred in 
patients with HR MDS. In this case, since the study will reach FA and the data will no longer be 
blinded after FA, an IDMC recommendation will not be necessary for this single analysis of IA2 
and FA.
The adaptation decision rule used to re-estimate the number of EFS events for the EFS FA, will be 
prespecified and will be included in the IDMC charter only—not described in the protocol or 
statistical analysis plan (SAP). Therefore, the study team and the investigational site personnel will 
not have knowledge of the adaptation decision rule. (See Section 13.0 for more information on the 
statistical analyses.)
The IDMC will provide a recommendation regarding study continuation based on the safety and 
efficacy parameters. If the study is terminated early based on the IDMC recommendation, the 
sponsor will notify the appropriate regulatory authorities. In addition, the IDMC will periodically 
review safety data at regularly scheduled meetings prespecified in the IDMC charter. 
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Study accrual will not be interrupted because of the scheduled safety reviews. The IDMC or 
pevonedistat study team may request an ad hoc meeting for any reason, including a significant 
unexpected safety event, unplanned unblinding of study results, follow-up of an observation 
during a planned IDMC meeting, or a report external to the study, such as publication of study 
results from a competing product. At each review, subject incidence rates of AEs (including all 
SAEs, treatment-related AEs, serious treatment-related events, and events requiring the 
discontinuation of study therapy) will be tabulated by system organ class (SOC), preferred term, 
and severity grade. Listings and/or narratives of on-study deaths and other serious and significant 
AEs, including any early withdrawals due to AEs, will be provided. Records of all meetings will 
be archived. The IDMC will communicate major safety concerns and recommendations regarding 
study modification or termination to the sponsor. Further details will be provided in the IDMC 
charter. 
12.0
DATA HANDLING AND RECORDKEEPING 
The full details of procedures for data handling will be documented in the Data Management Plan. 
If selected for coding, AEs, PTEs, medical history, and concurrent conditions will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA). Drugs will be coded using the WHO 
Drug Dictionary.
12.1
eCRFs 
Completed eCRFs are required for each subject who signs an ICF.
The sponsor or its designee will supply investigative sites with access to eCRFs and will make 
arrangements to train appropriate site staff in the use of the eCRF. These forms are used to transmit 
the information collected in the performance of this study to the sponsor, contract research 
organization (CRO) partners, and regulatory authorities. Investigative sites must complete eCRFs 
in English.
After completion of the enrollment process, computer logic checks will be run to identify items, 
such as inconsistent dates, missing data, and questionable values. Queries may be issued by 
Takeda personnel (or designees) and will be answered by the site.
Any change of, modification of, or addition to the data on the eCRFs should be made by the 
investigator or appropriate site personnel. Corrections to eCRFs are recorded in an audit trail that 
captures the old information, the new information, identification of the person making the 
correction, the date the correction was made, and the reason for change.
The principal investigator must review the eCRFs for completeness and accuracy and must sign 
and date the appropriate eCRFs as indicated. Furthermore, the principal investigator must retain 
full responsibility for the accuracy and authenticity of all data entered on the eCRFs.
eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The sponsor or its designee will be permitted to review the subject’s medical 
and hospital records pertinent to the study to ensure accuracy of the eCRFs. The completed eCRFs 
are the sole property of the sponsor and should not be made available in any form to third parties, 
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except for authorized representatives of appropriate governmental health or regulatory authorities, 
without written permission of the sponsor.
12.2
Record Retention
The following procedure is applied for the countries except for Japan. The investigator agrees to 
keep the records stipulated in Section 12.1 and those documents that include (but are not limited to) 
the study-specific documents, the identification log of all participating subjects, medical records, 
temporary media such as thermal sensitive paper, source worksheets, all original signed and dated 
ICFs, subject authorization forms regarding the use of personal health information (if separate 
from the ICFs), electronic copy of eCRFs, including the audit trail, and detailed records of drug 
disposition to enable evaluations or audits from regulatory authorities, the sponsor or its designees. 
Any source documentation printed on degradable thermal sensitive paper should be photocopied 
by the site and filed with the original in the subject’s chart to ensure long term legibility. 
Furthermore, ICH E6 Section 4.9.5 requires the investigator to retain essential documents 
specified in ICH E6 (Section 8) until at least 2 years after the last approval of a marketing 
application for a specified drug indication being investigated or, if an application is not approved, 
until at least 2 years after the investigation is discontinued and regulatory authorities are notified. 
In addition, ICH E6 Section 4.9.5 states that the study records should be retained until an amount 
of time specified by applicable regulatory requirements or for a time specified in the Clinical Study 
Site Agreement between the investigator and sponsor.
Refer to the Clinical Study Site Agreement for the sponsor’s requirements on record retention. The 
investigator should contact and receive written approval from the sponsor before disposing of any 
such documents.
The following procedure is applied for Japanese sites only.
The investigator and the head of the institution agree to keep the records stipulated in Section 12.1
and those documents that include (but are not limited to) the study-specific documents, the 
identification log of all participating subjects, medical records, temporary media such as thermal 
sensitive paper, source worksheets, all original signed and dated ICFs, subject authorization forms 
regarding the use of personal health information (if separate from the ICFs), electronic copy of 
eCRFs, including the audit trail, and detailed records of drug disposition to enable evaluations or 
audits from regulatory authorities, the sponsor or its designees. Any source documentation printed 
on degradable thermal sensitive paper should be photocopied by the site and filed with the original 
in the subject’s chart to ensure long term legibility. Furthermore, ICH E6 Section 4.9.5 requires the 
investigator and the head of the institution to retain essential documents specified in ICH E6 
(Section 8) until at least 2 years after the last approval of a marketing application for a specified 
drug indication being investigated or, if an application is not approved, until at least 2 years after 
the investigation is discontinued and regulatory authorities are notified. In addition, ICH E6 
Section 4.9.5 states that the study records should be retained until an amount of time specified by 
applicable regulatory requirements or for a time specified in the Clinical Study Site Agreement 
between the investigator and/or the head of the institution and sponsor.
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Refer to the Clinical Study Site Agreement for the sponsor’s requirements on record retention. The 
investigator and the head of the institution should contact and receive written approval from the 
sponsor before disposing of any such documents.
13.0
STATISTICAL METHODS
13.1
Statistical and Analytical Plans
In general, summary tabulations will be presented by treatment arm and will display the number of 
observations, mean, standard deviation, median, minimum, and maximum for continuous 
variables, and the number and percentage per category for categorical data. The Kaplan-Meier 
(K-M) survival curves and 25th, 50th (median), and 75th percentiles (if estimable) will be 
provided along with their 95% CIs for time-to-event data.
Deviations from the statistical analyses outlined in this protocol will be indicated in the SAP; any 
further modifications will be noted in the final clinical study report.
Study Pevonedistat-3001 is a phase 3 study with 1 primary endpoint of EFS, 1 key secondary 
endpoint of OS, and adaptive event size re-estimation for EFS in patients with HR MDS [82]. 
There are 2 planned IAs and 1 FA. IA1 will evaluate futility for EFS and perform EFS event size 
re-estimation for patients with HR MDS for IA2. IA2 will be an EFS FA for patients with 
HR MDS (US submission) and the ITT population (ex-US submission). The FA will evaluate OS.
13.1.1
Analysis Sets
The populations used for analysis will include the following:

Safety population: The safety population is defined as all patients who receive at least 1 dose 
of pevonedistat plus azacitidine or azacitidine alone. Patients will be analyzed according to the 
actual treatment they received. Patients who received any dose of pevonedistat will be 
included in the Combination Pevonedistat Plus Azacitidine Arm, and patients who did not 
receive any dose of pevonedistat and received at least 1 dose of azacitidine will be included in 
the Single-Agent Azacitidine Arm, regardless of their randomized treatment.

Intent-to-treat (ITT) population: The ITT population is defined as all patients who are 
randomized. Patients in this population will be analyzed according to the treatment they were 
randomized to receive, regardless of any dosing errors.

Per-protocol (PP) population: The PP population is a subgroup of the ITT population, 
consisting of all patients who receive at least 1 dose of study drug and do not have major 
protocol deviations, as determined by the study clinician. All decisions to exclude patients 
from the PP population will be made before the unblinding of the study.

Response-evaluable population: The response-evaluable population is defined as patients 
who receive at least 1 dose of study drug, have a disease assessment at Screening (baseline 
evaluation), and at least 1 postbaseline disease assessment.
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13.1.2
Analysis of Demographics and Other Baseline Disease Characteristics
Demographics and baseline characteristics will be summarized descriptively, including gender, 
age, race, weight, height, and other parameters as appropriate. No inferential statistics will be 
carried out.
13.1.3
Efficacy Analysis
All available efficacy data will be included in data listings and tabulations. Data that are 
potentially spurious or erroneous will be examined according to standard data management 
operating procedures. In general, missing data will be treated as missing, and no data imputation 
will be applied, unless otherwise specified. 
All primary efficacy evaluations for the primary and key secondary efficacy endpoints will be 
conducted using patients with HR MDS, the ITT population, and other disease subpopulations 
(patients with low-blast AML, patients with HR MDS/CMML, and patients with HR CMML). In 
addition, sensitivity analysis may be performed using the PP population or response-evaluable 
population, when appropriate.
13.1.3.1
Analyses for Primary Efficacy Endpoint
EFS
The analysis of the primary endpoint, EFS, will use IRC assessment. The analysis of EFS for the 
US submission will be based on patients with HR MDS; the analysis for the ex-US submission will 
be based on the ITT population. For patients with HR MDS or CMML, an event is defined as death 
or transformation to AML, whichever occurs first; for patients with low-blast AML, an event is 
defined as death. EFS is defined as the time from randomization to the occurrence of an event. 
Detailed rules of handling missing assessments and censoring for the analysis of EFS will be 
described in the SAP. The Cui-Hung-Wang (CHW) [8] weighted log-rank test statistic will be used 
to maintain a strong control of type I error. In addition, an unadjusted stratified Cox model will be 
used to estimate the hazard ratio and its 95% CIs for the treatment effect. The K-M survival curves 
and K-M medians (if estimable), along with their 2-sided 95% CIs, will also be provided for each 
treatment group.
Sensitivity analyses for EFS will include:

EFS assessed by investigator.

EFS assessed by IRC in the PP population.
Subgroup analyses will be performed for EFS relative to baseline stratification factors and 
demographic data such as sex, race, and age, as appropriate. Details of the subgroups will be 
specified in the SAP.
13.1.3.2
Analyses of Key Secondary Efficacy Endpoint
The analysis of the key secondary endpoint, OS for the US submission will be based on patients 
with HR MDS; the analysis for the ex-US submission will be based on the ITT population. OS is 
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defined as the time from randomization to death from any cause. Patients without documentation 
of death at the time of the analysis will be censored at the date last known to be alive. The CHW 
test statistic will be used to compare the treatment and control groups with respect to OS. In 
addition, an unadjusted stratified Cox model will be used to estimate the hazard ratio and its 
95% CIs for the treatment effect. The K-M survival curves and K-M medians (if estimable), along 
with their 95% CIs, will also be provided for each study group. Subgroup analyses for OS will be 
performed relative to baseline stratification factors and demographic data such as sex, race, and 
age, as appropriate. Details of the subgroups will be specified in the SAP. To adjust for the 
potential confounding effects of subsequent therapies after patients discontinue study therapy, 
additional sensitivity analyses for OS, such as marginal structural models (MSM) or inverse 
probability of censoring weight (IPCW) Cox models, may be conducted when appropriate.
13.1.3.3
Interim Analyses, Final Analysis, and Multiple Hierarchical Testing Procedure for 
Testing Primary and Key Secondary Efficacy Endpoints
There are 2 planned IAs and 1 FA. IA1 is planned to evaluate EFS for futility, and re-assess the 
EFS event size for patients with HR MDS for IA2. IA2 will be an FA of EFS in patients with 
HR MDS (for the US submission) and the ITT population (for the ex-US submission). The FA will 
evaluate OS.
IA1 will be performed when approximately 74 EFS events have occurred in patients with 
HR MDS (around 50% information relative to the minimal planned event size of 147 EFS events 
for patients with HR MDS for the EFS FA at IA2). The study will stop if the EFS hazard ratio 
is >1.0 in all 3 of the following populations: patients with HR MDS, patients with HR
MDS/CMML, and the ITT population. Otherwise, EFS event size re-estimation for patients with 
HR MDS will be performed using conditional power for the EFS FA that will be conducted at IA2.
IA2 (ie, EFS FA) will be performed when the approximate adaptive EFS event size (from a 
minimum of 147 to a maximum of 249), informed by the IDMC, has occurred in patients with HR 
MDS. The FA will be performed when approximately 202 OS events have occurred in patients 
with HR MDS. Separate multiple hierarchical testing procedures for the US submission and the 
ex-US submission will be adopted to test the primary endpoint of EFS and the key secondary 
endpoint of OS in the HR MDS population (US submission), the ITT population (ex-US 
submission), and other disease populations at IA2 and FA, with each procedure having a total 
1-sided alpha of 0.025, as depicted on Panel A of Figure 13.a (US submission testing procedure) 
and on Panel A of Figure 13.b (ex-US submission testing procedure).
If the prespecified number of approximately 202 OS events for FA are expected (based on blinded 
study data) to be available close to the IA2, the IA2 (ie, EFS FA) and the FA (ie, OS FA) will be 
performed as a single analysis, when approximately 202 OS events and the adaptive EFS event 
size have occurred in patients with HR MDS. As originally planned, separate multiple hierarchical 
testing procedures for the US submission and the ex-US submission will be used to test the 
primary endpoint of EFS and the key secondary endpoint of OS in the HR MDS population (US 
submission), the ITT population (ex-US submission), and other disease populations at this single 
analysis, with a total 1-sided alpha of 0.025 for each procedure. The 2 hierarchical testing 
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procedures originally specified at IA2 and FA will be performed as a single testing procedure, as 
depicted on Panel B of Figure 13.a (US submission testing procedure) and on Panel B of 
Figure 13.b (ex-US submission testing procedure).
Figure 13.a
Multiple Hierarchical Testing Procedure at IA2 and FA for the US 
Submission
CMML=chronic myelomonocytic leukemia, EFS=event-free survival, FA=final analysis, HR MDS=higher-risk 
myelodysplastic syndromes, IA2=second interim analysis, IA2/FA=IA2 and FA are performed as a single analysis, 
LB AML=low-blast acute myelogenous leukemia, OS=overall survival, US=United States.
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Figure 13.b
Multiple Hierarchical Testing Procedure at IA2 and FA for the ex-US 
Submission
EFS=event-free survival, ex-US=all countries and regions excluding the United States, FA=final analysis, HR 
MDS=higher-risk myelodysplastic syndromes, IA2=second interim analysis, IA2/FA=IA2 and FA are performed as a 
single analysis, ITT=intent-to-treat, LB AML=low-blast acute myelogenous leukemia, OS=overall survival.
At IA2:

For the US submission, EFS in patients with HR MDS will be tested first, only at IA2, at a 
1-sided alpha of 0.025. The CHW weighted log-rank test statistics will be used. The weights 
are prespecified based on the observed number of EFS events in patients with HR MDS at IA1 
and the minimum number of EFS events in patients with HR MDS planned for IA2.
If the test of EFS in patients with HR MDS is statistically significant, OS in patients with 
HR MDS will be subsequently tested using the CHW weighted test statistic. If the test of OS in 
patients with HR MDS is statistically significant, then subsequent statistical testing using the 
CHW weighted test statistic will be performed in the following order: OS in patients with 
low-blast AML, and OS in patients with HR MDS/CMML.

For the ex-US submission, EFS in the ITT population will be tested first, at a 1-sided alpha of 
0.025. The CHW weighted test statistic will be used. The weights are prespecified based on the 
observed number of EFS events in patients with ITT at IA1 and the estimated number of EFS 
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events in the ITT population at IA2, which corresponds to the minimum number of EFS events 
in patients with HR MDS planned for IA2.
If the test of EFS in the ITT population is statistically significant, OS in the ITT population will 
be subsequently tested using the CHW weighted test statistic. If the test of OS in patients in the 
ITT population is statistically significant, then subsequent statistical testing using the CHW 
weighted test statistic will be performed, first for OS in patients with HR MDS and then for OS 
in patients with low-blast AML.
If EFS is not statistically significant in both patients with HR MDS and the ITT population at IA2, 
the study will stop for futility. If OS is statistically significant in both patients with HR MDS and 
the ITT population at IA2, the study will stop for efficacy. Otherwise, the study will continue to the 
FA.
At the FA:

For the US submission, if the test of OS in the HR MDS population fails to achieve statistical 
significance at IA2, OS in patients with HR MDS will be tested first using the CHW weighted 
test statistic. If statistical significance is achieved, subsequent statistical testing will be 
performed in the following order: OS in patients with low-blast AML, and OS in patients with 
HR MDS/CMML. The CHW weighted test statistic will be used for both tests.

For the ex-US submission, if the test of OS in the ITT population fails to achieve statistical 
significance at IA2, OS in the ITT population will be tested first using the CHW weighted test 
statistic. If statistical significance is achieved, subsequent statistical testing will be performed, 
first for OS in patients with HR MDS and then for OS in patients with low-blast AML. The 
CHW weighted test statistic will be used for both tests.
EFS in the HR MDS population (US submission) and in the ITT population (ex-US submission) 
will be tested first, only at IA2, using the 1-sided alpha of 0.025. All other tests specified in the 
multiple hierarchical testing procedures (Figure 13.a [US submission] and Figure 13.b [ex-US 
submission]) that will be performed at IA2 and FA, including OS in the HR MDS population (US 
submission), OS in the ITT population (ex-US submission), OS in the low-blast AML population, 
and OS in the HR MDS/CMML population, will use a 1-sided alpha of 0.0001 at IA2 and the 
remaining 1-sided alpha of 0.0249 at FA. The testing procedures for the US and ex-US 
submissions will be performed independently. Under the sequential procedure, the testing will be 
stopped once 1 test fails to achieve statistical significance. Naturally, no benefit will be claimed for
untested hypotheses.
When the EFS event size for the HR MDS population for IA2 is re-estimated at IA1, the numbers 
of OS and EFS events in other populations of interest for IA2 will be changed accordingly. The use 
of CHW weighted test statistics [8] can preserve a type-I error rate when the event sizes are 
changed. In addition, the multiple testing procedures (multiple hypotheses and multiple looks) that 
apply the sequential procedures, and the specified alpha spending approach, also maintain control 
of the familywise type I error rate, as discussed in Glimm et al [9].
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The analyses will also be performed for EFS in the HR CMML population at IA2 and for OS in the 
HR CMML population at IA2 and FA. They will not be included in the above multiple testing 
procedures and are for exploratory purposes only.
13.1.3.4
Analyses of Other Secondary Efficacy Endpoints
Other secondary efficacy parameters are: 6-month and 1-year survival rates; time to AML 
transformation; rate of CR (includes CR in patients with HR MDS or CMML, or low-blast AML), 
CR+CRi in patients with low-blast AML, CR+marrow CR in patients with HR MDS or CMML, 
CR+PR+HI in patients with HR MDS or CMML, CR+marrow CR+PR in patients with HR MDS 
or CMML, CR+marrow CR+PR+HI in patients with HR MDS or CMML, overall response, 
overall response by Cycle 6, and overall response 2; duration of CR, CR+CRi, overall response, 
and overall response 2; RBC and/or platelet transfusion independence; duration of RBC and/or 
platelet transfusion independence; time to first CR or PR or CRi; percent of patients who have at 
least 1 inpatient hospital admission(s) related to HR MDS or CMML, or low-blast AML; time to 
PD, relapse after CR (low-blast AML), relapse after CR or PR (HR MDS/CMML), or death; and 
ORR, EFS and OS in patients that have TP53 mutations, 17p deletions, and/or are determined to be 
in an adverse cytogenetic risk group in both treatment arms.
Disease response-related endpoints will be analyzed using IRC assessments.
6-month and 1-year Survival Rates
K-M estimates and the 95% CIs of 6-month and 1-year survival rates will be provided based on 
patients with HR MDS, the ITT population, and other disease subpopulations (patients with 
low-blast AML, patients with HR MDS/CMML, and patients with HR CMML) separately.
Time to AML Transformation
Time to AML transformation is defined as time from randomization to documented AML 
transformation. This definition only applies to HR MDS and CMML patients, so this analysis will 
be carried out only for patients with HR MDS, patients with HR CMML, and patients with HR
MDS/CMML. Patients who died before progression to AML will be censored. Stratified log-rank 
test will be used to compare time to AML transformation between the 2 arms. Hazard ratio and its 
95% CI will be calculated using the stratified Cox model. K-M survival curves and K-M medians 
(if estimable), together with the 95% CIs, will be calculated for each arm.
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Rate of CR (CR in patients with HR MDS or CMML, or low-blast AML), CR+CRi in 
patients with low-blast AML, CR+marrow CR (in patients with HR MDS or CMML), 
CR+PR+HI (in patients with HR MDS or CMML), CR+marrow CR+PR (in patients with 
HR MDS or CMML), CR+marrow CR+PR+HI (in patients with HR MDS or CMML), 
overall response (CR+PR in patients with HR MDS or CMML; CR+CRi+PR in patients 
with low-blast AML), overall response by Cycle 6 ([CR+PR in patients with HR MDS or 
CMML; CR+CRi+PR in patients with low-blast AML] by Cycle 6), and overall response 
2 (CR+PR+HI in patients with HR MDS or CMML; CR+CRi+PR in patients with low-blast 
AML)
Rate of CR (CR in patients with HR MDS or CMML, or low-blast AML), CR+CRi in patients with 
low-blast AML, CR+marrow CR (in patients with HR MDS or CMML), CR+PR+HI (in patients 
with HR MDS or CMML), CR+marrow CR+PR (in patients with HR MDS or CMML), CR+ 
marrow CR + PR + HI (in patients with HR MDS or CMML), overall response (CR+PR in patients 
with HR MDS or CMML; CR+CRi+PR in patients with low-blast AML), overall response by 
Cycle 6 ([CR+PR in patients with HR MDS or CMML; CR+CRi+PR in patient with low-blast 
AML] by Cycle 6), and overall response 2 (CR+PR+HI in patients with HR MDS or CMML; 
CR+CRi+PR in patients with low-blast AML) are disease response-related endpoints, which will 
be analyzed using IRC assessments for the Response-Evaluable population. Stratified CMH test 
will be used to compare the 2 treatment arms. The difference in rates and the associated 95% CIs 
will be presented.
Duration of CR, CR+CRi (in patients with low-blast AML), Overall Response, and Overall 
Response 2
Duration of CR, CR+CRi (in patients with low-blast AML), overall response, and overall response 
2 will be summarized descriptively using the K-M method.
Rate of RBCs and/or Platelet Transfusion Independence
Analysis of RBC and/or platelet transfusion independence will be based on patients with HR MDS, 
the ITT population, and other disease subpopulations (patients with low-blast AML, patients with 
HR MDS/CMML, and patients with HR CMML), separately.
A patient is defined as RBC and/or platelet-transfusion independent if he/she receives no RBC 
and/or platelet transfusions for a period of at least 8 weeks [16,45] during the time period from the 
first dose of study drug administration through 30 days after the last dose of any study drug. Rate 
of RBC and/or platelet-transfusion independence is defined as number of patients who become 
RBC and/or platelet transfusion independent divided by the number of patients who are RBC 
and/or platelet transfusion dependent at Baseline. Rate of RBC and/or platelet transfusion 
independence, will be summarized by treatment group. Stratified CMH test will be used to 
compare the 2 treatment arms. The difference in rates and the associated 95% CIs will be 
presented.
Duration of RBC and/or Platelet Transfusion Independence
Analysis of duration of RBC and/or platelet transfusion independence will be based on patients 
with HR MDS, the ITT population, and other disease subpopulations (patients with low-blast 
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AML, patients with HR MDS/CMML, and patients with HR CMML) who are RBC and/or platelet 
transfusion independent during the trial, separately.
Duration of transfusion independence is defined as the longest time between the last RBC and/or 
platelet transfusion before the start of the RBC and/or platelet transfusion-independent period and 
the first RBC and/or platelet transfusion after the start of the transfusion-independent period, 
which occurs ≥8 weeks later.
Time to First CR or PR or CRi (in patients with low-blast AML)
Analysis of time to first CR or PR or CRi (in patients with low-blast AML) will be based on the 
response-evaluable patients with HR MDS, the ITT population, and other disease subpopulations 
(patients with low-blast AML, patients with HR MDS/CMML, and patients with HR CMML), and 
the response-evaluable population for the overall patient population separately.
Time to first CR or PR or CRi is defined as time from randomization to first documented CR or PR 
or CRi, whichever occurs first. Time to first CR or PR or CRi will be analyzed similarly to time to 
AML transformation.
Rates of HI
Rates of HI will be analyzed using IRC assessments for the Response-Evaluable population of 
patients with HR MDS, patients with HR MDS/CMML, and patients with HR CMML. Stratified 
CMH test will be used to compare the 2 treatment arms. The difference in rates and the associated 
95% CIs will be presented.
Percent of Patients Who Have at Least One Inpatient Hospital Admission Related to HR 
MDS or CMML, or AML
Analysis of percent of patients who have at least one inpatient hospital admission related to 
HR MDS or CMML, or low-blast AML will be based on patients with HR MDS, the ITT 
population, and other disease subpopulations (patients with low-blast AML, patients with 
HR MDS/CMML, and patients with HR CMML) separately. Inpatient hospital admission data 
will be collected through transformation to AML (HR MDS or CMML patients) or until initiation 
of subsequent therapy (all patients), whichever occurs first.
The number and percentage of patients who have at least one inpatient hospital admission(s) 
related to HR MDS or CMML or AML will be summarized by treatment group. The rate 
difference and the associated 95% CIs will be provided. 
Time To PD, Relapse after CR (low-blast AML), Relapse after CR or PR 
(HR MDS/CMML), or Death
Analysis of time to PD, relapse after CR (low-blast AML), relapse after CR or PR 
(HR MDS/CMML), or death will be based on the ITT population and the disease subpopulations 
(patients with HR MDS/CMML, patients with HR MDS, patients with HR CMML, and patients 
with low-blast AML), separately.
Time to PD, relapse after CR (low-blast AML), relapse after CR or PR (HR MDS/CMML), or 
death is defined as the time from the date of randomization until the date of the first documentation 
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of disease progression, relapse after CR (low-blast AML), relapse after CR or PR (HR 
MDS/CMML), or death due to any cause, whichever occurs first. Time to PD, relapse after CR or 
PR, or death will be analyzed similarly as time to AML transformation.
ORR, EFS, and OS in Patients who Have TP53 Mutations, 17p deletions, and/or are 
Determined to be in Adverse Cytogenetic Risk Group 
ORR, EFS, and OS in patients who have TP53 mutations and/or 17p deletions, and are determined 
to be in an adverse cytogenetic risk group will be analyzed using the similar method as ORR, EFS, 
and OS in patients with HR MDS, the ITT population, and other disease subpopulations (patients 
with low-blast AML, patients with HR MDS/CMML, and patients with HR CMML) separately.
13.1.4
PK Analysis
Individual pevonedistat plasma concentration-time data collected in this study will be listed.
The PK data collected in this study are intended to contribute to future population PK analyses of 
pevonedistat. These analyses may additionally include data collected in other pevonedistat clinical 
studies. The analysis plan for population PK analysis will be defined separately and results of these 
analyses will be reported separately.
13.1.5
PRO Analyses
The PRO analysis will be performed based on subscale scores from EORTC QLQ-C30 and 
supplemental items. The actual value and change from baseline of the subscale scores for EORTC 
QLQ-C30 will be summarized using descriptive statistics by treatment group over time. The 
EORTC QLQ-C30 domain scores will also be analyzed using linear mixed models by 
incorporating the measurements across different time points. The percentage of missing EORTC 
QLQ-C30 questionnaires at each cycle will be described. Data from the EQ-5D-5L will be 
assessed using descriptive statistics by treatment group over time.
13.1.6
Safety Analysis
All available safety data will be included in data listings and tabulations. Data that are potentially 
spurious or erroneous will be examined according to standard data management operating 
procedures.
Safety population will be used for all safety analyses.
Safety will be evaluated by the incidence of AEs, severity and type of AEs, and by changes from 
baseline in the patient’s vital signs, weight, ECOG PS, ECG results, and clinical laboratory results 
using the safety population. Exposure to study drug and reasons for discontinuation will be 
tabulated.
TEAEs are AEs that occur after administration of the first dose of any study drug and through 
30 days after the last dose of any study drug. AEs will be tabulated according to the MedDRA by 
SOC, high-level term, and preferred term, and will include the following categories:

TEAEs.
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
Drug-related TEAEs.

Treatment-emergent drug-related Grade 3, 4, and 5 AEs (presented by grade and overall).

Treatment-emergent Grade 3, 4, and 5 AEs (presented by grade and overall).

TEAEs resulting in study drug discontinuation.

The most commonly reported TEAEs (ie, those events reported by ≥10% of all patients).

Treatment-emergent SAEs.

Nonserious TEAEs (≥5% in any arm).
Descriptive statistics for the actual values of clinical laboratory parameters (and/or change from 
Baseline in clinical laboratory parameters) will be presented for all scheduled measurements over 
time. Mean laboratory values over time will be plotted for key laboratory parameters.
Descriptive statistics for the actual values (and/or the changes from Baseline) of vital signs and 
weight over time will be tabulated by scheduled time point.
Shift tables for laboratory parameters will be generated based on changes in NCI CTCAE grade 
from Baseline to the worst postbaseline value. Graphical displays of key safety parameters, such as 
scatter plots of baseline versus worst postbaseline values, may be used to understand the safety 
profile of pevonedistat plus azacitidine.
Baseline and change from baseline ECOG PS will be summarized.
All concomitant medications collected from Screening through the study period will be classified 
to preferred terms according to the WHO Drug Dictionary. All blood (RBC, platelet) transfusions 
will also be reviewed to determine transfusion dependence or independence, as detailed in 
Section 9.4.14.
Thirty-/60-day mortality rate is defined as the proportion of patients who survive at most 
30/60 days from the first dose of study drug, which will be summarized by treatment arm based on 
the Safety population.
Additional safety analyses may be performed to most clearly enumerate rates of toxicities and to 
further define the safety profile of pevonedistat plus azacitidine.
13.1.7
EFS Events Re-estimation at IA1
The EFS event-size adaptation rule is a prespecified stepwise function to avoid the back 
calculation problem resulting from 1 event size corresponding to either barely promising or highly 
promising interim results. The event-size adaptation rule will be designed by the sponsor’s 
independent design statistician and approved by the sponsor’s head of biostatistics. Neither the 
independent design statistician nor the sponsor’s head of biostatistics are involved in the study 
conduct.
The adaptation rules will be outlined in a separate document and will not be accessible to the 
sponsor’s study team until completion of the study. The rules will be available only to the 
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sponsor’s independent design statistician, the sponsor’s head of biostatistics, the IDMC, and the 
statistics representative in the sponsor’s executive committee (if different from the sponsor’s head 
of biostatistics).
The conditional power for EFS will be calculated based on patients with HR MDS at IA1 to 
re-estimate the number of EFS events for patients with HR MDS for the EFS FA if EFS hazard 
ratio ≤1.0 in patients with HR MDS, in patients with HR MDS/CMML, or in the ITT population. 
The prespecified EFS event size re-estimation adaptation rule is a step function, which is 
calculated on the basis of Liu and Hu [82].
To ensure integrity in this open-label study, it will be designed with the following features:

The adaptation decision rule will be prespecified before the study starts and will be included in 
the IDMC charter appendix only—not described in the protocol or SAP. It will be accessed 
only by IDMC, head of biostatistics and sponsor design statistician, who are not involved in 
the study conduct. Therefore, the study team and the investigational site personnel will not 
have knowledge of the adaptation decision rule.

The IDMC will determine EFS event size in patients with HR MDS for IA2 at IA1. An IDMC 
charter will be developed to include details regarding all statistical evaluations and operational 
procedures for the IAs and EFS event size adaptation.

The EFS event size adaptation rule will be chosen such that the interim results cannot be 
derived from the increase in EFS events.

A separate statistical reporting organization will be selected to facilitate the activities of the 
IDMC. This organization will be responsible for handling the unblinded data and producing 
materials needed for the IDMC.

Sponsor employees and clinical research organization employees working on the conduct of 
this study will be blinded throughout the study to analysis results that are not publicly released 
and to the adaptation rule. 

Investigators from all investigational sites will not have access to any analysis results that are 
not publicly released or to the adaptation rule during study conduct.
13.2
Determination of Sample Size
There is 1 primary endpoint, of EFS, and 1 key secondary endpoint of OS. The total number of 
patients was calculated on the basis of maintaining 83% power to test the key secondary endpoint 
OS in patients with HR MDS at a 1-sided alpha level of 0.025, as well as sufficient representation 
of patients with low-blast AML. The study is also adequately powered to test the primary endpoint, 
EFS, in patients with HR MDS and in the ITT population for full approval in the US submission 
and the ex-US submission, respectively, as well as to test OS in the ITT population.
A total of approximately 450 patients, including at least 350 patients with HR MDS or CMML and 
at least 100 patients with low-blast AML, will be enrolled, with 320 patients with HR MDS 
required to obtain 202 OS events in patients with HR MDS. Patients will be randomized in a 
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1:1 ratio to the 2 treatment arms, stratified by low-blast AML, IPSS-R risk group of very high, 
high, or intermediate for MDS/CMML [1]. Assuming an enrollment rate that increases from an 
initial 1 patient per month to 22 patients per month after the first 10 months, with a dropout rate of 
approximately 10%, the study will take approximately 27 months for patient accrual and an 
additional approximately 38 months for follow-up from the enrollment of the last patient.
The minimal planned event size of 147 EFS events from patients with HR MDS is based on an 
optimistic assumption of a hazard ratio of 0.585 (median EFS of 17.09 months in the combination 
arm versus 10 months in the azacitidine alone arm) with approximately 90% power at a 1-sided 
alpha of 0.025. The maximal planned event size of 249 EFS events from patients with HR MDS is 
based on a relatively conservative assumption of a hazard ratio of 0.663 (median EFS of 15.08 
months in the combination arm versus 10 months in the azacitidine alone arm) with approximately 
90% power at a 1-sided alpha of 0.025. It is projected that the EFS event size from the ITT 
population ranges approximately from 158 (approximately 92% power, 1-sided alpha=0.025, 
hazard ratio=0.585, median EFS of 22.22 months in the combination arm versus 13 months in the 
azacitidine alone arm) to 305 (approximately 95% power, 1-sided alpha=0.025, hazard 
ratio=0.663, median EFS of 19.61 months in the combination arm versus 13 months in the 
azacitidine alone arm).
With the assumption of a hazard ratio of 0.663 for OS in patients in HR MDS (median OS of 36.95 
months in the combination arm versus 24.5 months in the azacitidine alone arm), 202 OS events 
provide approximately 83% power at a 1-sided alpha of 0.025. It is projected that approximately 
280 OS events will occur to the ITT population, providing approximately 93% power to test OS in 
the ITT population (1-sided alpha=0.025, hazard ratio=0.663, median OS of 36.95 months in the 
combination arm versus 24.5 months in the azacitidine alone arm). 
14.0
QUALITY CONTROL AND QUALITY ASSURANCE
14.1
Study-Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and institution guarantee access to source documents by the sponsor or its 
designee (CRO) and by the IRB or IEC.
All aspects of the study and its documentation will be subject to review by the sponsor or designee 
(as long as blinding is not jeopardized), including but not limited to the IB, study medication, 
subject medical records, informed consent documentation, documentation of subject authorization 
to use personal health information (if separate from the ICFs), and review of eCRFs and associated 
source documents. It is important that the investigator and other study personnel are available 
during the monitoring visits and that sufficient time is devoted to the process.
In the event a monitor cannot visit the site in a timely manner due to the COVID-19 pandemic, 
alternative monitoring approaches such as remote source data verification (SDV) may be used to 
ensure data quality and integrity and maintain patient safety. Alternative monitoring approaches 
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should be used only where allowed by the local Health Authority, privacy laws, and permitted by 
the IRB/IEC.
14.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will require 
deviation from protocol-specified procedures, the investigator should consult with the sponsor or 
designee (and IRB or IEC, as required) to determine the appropriate course of action. There will be 
no exemptions (a prospectively approved deviation) from the inclusion or exclusion criteria.
The site should document all protocol deviations in the subject’s source documents. In the event of 
a significant deviation, the site should notify the sponsor or its designee (and IRB or IEC, as 
required). Significant deviations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the subject, or confound interpretation of primary study 
assessment.
The sponsor will assess any protocol deviation; if it is likely to affect to a significant degree the 
safety and rights of a subject or the reliability and robustness of the data generated, it may be 
reported to regulatory authorities as a serious breach of GCP and the protocol.
The procedure below applies to Japanese sites only.
The investigator can deviate and change from the protocol for any medically unavoidable reason, 
for example, to eliminate an immediate hazard to study subjects, without a prior written agreement 
with the sponsor or a prior approval from IRB. In the event of a deviation or change, the principal 
investigator should notify the sponsor and the head of the site of the deviation or change as well as 
its reason in a written form, and then retain a copy of the written form. When necessary, the 
principal investigator may consult and agree with the sponsor on a protocol amendment. If the 
protocol amendment is appropriate, the amendment proposal should be submitted to the head of 
the site as soon as possible and an approval from IRB should be obtained.
The investigator should document all protocol deviations.
14.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, including 
those of foreign governments (eg, the US Food and Drug Administration [FDA], the United 
Kingdom Medicines and Healthcare products Regulatory Agency, the Pharmaceuticals and 
Medical Devices Agency of Japan). If the study site is contacted for an inspection by a regulatory 
body, the sponsor should be notified immediately. The investigator and institution guarantee 
access for quality assurance auditors to all study documents as described in Section 14.1.
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15.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of Helsinki, 
and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will conduct the study 
according to applicable local or regional regulatory requirements and align his or her conduct in 
accordance with the “Responsibilities of the Investigator” that are listed in Appendix D. The 
principles of Helsinki are addressed through the protocol and through appendices containing 
requirements for informed consent and investigator responsibilities.
15.1
IRB and/or IEC Approval
IRBs and IECs must be constituted according to the applicable (state and federal/local) 
requirements of each participating region. The sponsor or designee will require documentation 
noting all names and titles of members who make up the respective IRB or IEC. If any member of 
the IRB or IEC has direct participation in this study, written notification regarding his or her 
abstinence from voting must also be obtained. Those American sites unwilling to provide names 
and titles of all members because of privacy and conflict of interest concerns should instead 
provide a Federal Wide Assurance Number or comparable number assigned by the Department of 
Health and Human Services.
The sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the IB, a copy of the ICF, and, if 
applicable, subject recruitment materials and/or advertisements and other documents required by 
all applicable laws and regulations, must be submitted to a central or local IRB or IEC for approval. 
The IRB’s or IEC’s written approval of the protocol and subject informed consent must be 
obtained and submitted to the sponsor or designee before commencement of the study (ie, before 
shipment of the sponsor-supplied drug or study specific screening activity). The IRB or IEC 
approval must refer to the study by exact protocol title, number, and version date; identify versions 
of other documents (eg, ICF) reviewed; and state the approval date. The sponsor will notify the site 
of activation status once the sponsor has confirmed the adequacy of site regulatory documentation 
and, when applicable, the sponsor has received permission from competent authority to begin the 
trial. Until the site receives notification of activation status no protocol activities, including 
screening may occur.
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the ICF, recruitment 
materials intended for viewing by subjects, local safety reporting requirements, reports and 
updates regarding the ongoing review of the study at intervals specified by the respective IRB or 
IEC, and submission of the investigator’s final status report to IRB or IEC. All IRB and IEC 
approvals and relevant documentation for these items must be provided to the sponsor or its 
designee.
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and sponsor.
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15.2
Subject Information, Informed Consent, and Subject Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The ICF, subject authorization form (if applicable), and subject 
information sheet (if applicable) describe the planned and permitted uses, transfers, and 
disclosures of the subject’s personal and personal health information for purposes of conducting 
the study. The ICF and the subject information sheet (if applicable) further explain the nature of 
the study, its objectives, and potential risks and benefits, as well as the date informed consent is 
given. The ICF will detail the requirements of the participant and the fact that he or she is free to 
withdraw at any time without giving a reason and without prejudice to his or her further medical 
care.
The investigator is responsible for the preparation, content, and IRB or IEC approval of the ICF 
and if applicable, the subject authorization form. The ICF, subject authorization form (if 
applicable), and subject information sheet (if applicable) must be approved by both the IRB or IEC 
and the sponsor before use.
The ICF, subject authorization form (if applicable), and subject information sheet (if applicable) 
must be written in a language fully comprehensible to the prospective subject. It is the 
responsibility of the investigator to explain the detailed elements of the ICF, subject authorization 
form (if applicable), and subject information sheet (if applicable) to the subject. Information 
should be given in both oral and written form whenever possible and in the manner deemed 
appropriate by the IRB or IEC. If the subject is not capable of rendering adequate written informed 
consent, then the subject’s legally acceptable representative may provide such consent for the 
subject in accordance with applicable laws and regulations.
The subject, or the subject’s legally acceptable representative, must be given ample opportunity to: 
(1) inquire about details of the study and (2) decide whether or not to participate in the study. If the 
subject, or the subject’s legally acceptable representative, determines he or she will participate in 
the study, then the ICF and subject authorization form (if applicable) must be signed and dated by 
the subject, or the subject’s legally acceptable representative, at the time of consent and before the 
subject entering into the study. The subject or the subject’s legally acceptable representative 
should be instructed to sign using their legal names, not nicknames, using blue or black ballpoint 
ink. The investigator must also sign and date the ICF and subject authorization (if applicable) at 
the time of consent and before subject entering into the study; however, the sponsor may allow a 
designee of the investigator to sign to the extent permitted by applicable law.
Once signed, the original ICF, subject authorization form (if applicable), and subject information 
sheet (if applicable) will be stored in the investigator’s site file. The investigator must document 
the date the subject signs the informed consent in the subject’s medical record. Copies of the 
signed ICF, the signed subject authorization form (if applicable), and subject information sheet (if 
applicable) shall be given to the subject.
All revised ICFs must be reviewed and signed by relevant subjects or the relevant subject’s legally 
acceptable representative in the same manner as the original informed consent. The date the 
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revised consent was obtained should be recorded in the subject’s medical record, and the subject 
should receive a copy of the revised ICF.
15.3
Subject Confidentiality
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or date 
of birth, and subject initials may be used to verify the subject and accuracy of the subject’s unique 
identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the sponsor 
requires the investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (eg, FDA, Medicines and Healthcare products Regulatory Agency, 
Pharmaceuticals and Medical Devices Agency), the sponsor’s designated auditors, and the 
appropriate IRBs and IECs to review the subject’s original medical records (source data or 
documents), including, but not limited to, laboratory test result reports, ECG reports, admission 
and discharge summaries for hospital admissions occurring during a subject’s study participation, 
and autopsy reports. Access to a subject’s original medical records requires the specific 
authorization of the subject as part of the informed consent process (see Section 15.2).
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s eCRF).
15.4
Publication, Disclosure, and Clinical Trial Registration Policy
15.4.1
Publication 
The investigator is obliged to provide the sponsor with complete test results and all data derived by 
the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the sponsor.
The sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 
this section and the Clinical Study Site Agreement. In the event of any discrepancy between the 
protocol and the Clinical Study Site Agreement, the Clinical Study Site Agreement will prevail.
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15.4.2
Clinical Trial Registration
To ensure that information on clinical trials reaches the public in a timely manner and to comply 
with applicable laws, regulations and guidance, Takeda will, at a minimum register interventional 
clinical trials it sponsors anywhere in the world on ClinicalTrials.gov or other publicly accessible 
websites on or before start of study (ie, first patient randomized), as defined in Takeda 
Policy/Standard. Takeda contact information, along with investigator’s city, state (for Americas 
investigators), country, and recruiting status will be registered and available for public viewing. 
As needed Takeda and Investigator/site contact information may be made public to support 
participant access to trials via registries. In certain situations/registries, Takeda may assist 
participants or potential participants to find a clinical trial by helping them locate trial sites closest 
to their homes by providing the investigator name, address, and phone number via email/phone or 
other methods callers requesting trial information. Once subjects receive investigator contact 
information, they may call the site requesting enrollment into the trial. The investigative sites are 
encouraged to handle the trial inquiries according to their established subject screening process. If 
the caller asks additional questions beyond the topic of trial enrollment, they should be referred to 
the sponsor.
Any investigator who objects to Takeda providing this information to callers must provide Takeda 
with a written notice requesting that their information not be listed on the registry site. 
15.4.3
Clinical Trial Results Disclosure
Takeda will post the results of clinical trials on ClinicalTrials.gov or other publicly accessible 
websites (including the Takeda corporate site) and registries, as required by Takeda 
Policy/Standard, applicable laws and/or regulations. 
Data Sharing
The sponsor is committed to responsible sharing of clinical data with the goal of advancing 
medical science and improving patient care. Qualified independent researchers will be permitted 
to use data collected from patients during the study to conduct additional scientific research, which 
may be unrelated to the study drug or the patient’s disease. The data provided to external 
researchers will not include information that identifies patients personally.
15.5
Insurance and Compensation for Injury
Each subject in the study must be insured in accordance with the regulations applicable to the site 
where the subject is participating. If a local underwriter is required, then the sponsor or sponsor’s 
designee will obtain clinical study insurance against the risk of injury to clinical study subjects. 
Refer to the Clinical Study Site Agreement regarding the sponsor’s policy on subject 
compensation and treatment for injury. If the investigator has questions regarding this policy, he or 
she should contact the sponsor or sponsor’s designee.
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16.0
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alterations, monosomal karyotype, and dismal outcome. Blood 2012;119(9):2114-21.
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genome mapping reveals alterations of innate immunity signaling and overexpression of 
JMJD3 in human myelodysplastic syndrome CD34+ cells. Leukemia 2013;27(11):2177-86.
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76. Vidaza 25 mg/mL powder for suspension for injection [Summary of Product Characteristics]. 
Uxbridge, United Kingdom: Celgene Europe Ltd, 2014.
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effectiveness in acute myelogenous leukemia. Ann Intern Med 1976;85(2):237-45.
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Azacitidine prolongs overall survival compared with conventional care regimens in elderly 
patients with low bone marrow blast count acute myeloid leukemia. Journal of Clinical 
Oncology 2010;28(4):562-9.
79. Dombret H, Seymour JF, Butrym A, Wierzbowska A, Selleslag D, Jang JH, et al. Results of a 
phase 3, multicenter, randomized, open-label study of azacitidine (AZA) vs conventional care 
regimens (CCR) in older patients with newly diagnosed acute myeloid leukemia (AML). 
Haematologia 2014;99(s1):788-89.
80. Schanz J, Tuchler H, Sole F, Mallo M, Luno E, Cervera J, et al. New comprehensive 
cytogenetic scoring system for primary myelodysplastic syndromes (MDS) and oligoblastic 
acute myeloid leukemia after MDS derived from an international database merge. Journal of 
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81. Vardiman JW, Harris NL, Brunning RD. The World Health Organization (WHO) 
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Appendix A
Treatment-Related Mortality Rates
Source: Walter et al 2011[7].
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Appendix B
Study Diagrams
STUDY OVERVIEW DIAGRAM 1:
PATIENTS WITH HR MDS OR CMML
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Refer to Section 9.4.20 for response definitions (eg, CR, PR, transformation to AML, PD).
AE=adverse event, AML=acute myelogenous leukemia, CMML=chronic myelomonocytic leukemia, CR=complete 
remission, D/C=discontinuation (of study treatment), EFS=event-free survival, HMAs= hypomethylating agents, HR 
MDS=higher-risk myelodysplastic syndromes, OS=overall survival, PD=progressive disease, PR=partial remission, 
WBC=white blood cell.
(a) Patients who have started subsequent therapy will not be required to have monthly visits but will have a bone 
marrow aspirate and hematology tests (see Table 9.d) at the time of suspected transformation to AML. Bone marrow 
aspirate and hematology tests will be sent to the central laboratory.
(b) Subsequent therapy is defined as agent(s) with antileukemic/anti-MDS activity (eg, lenalidomide, cytarabine, 
anthracyclines, purine analogues, and HMAs other than azacitidine). Patients who discontinue study treatment to 
receive single-agent azacitidine off study would not be counted as receiving subsequent therapy.
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STUDY OVERVIEW DIAGRAM 2:
PATIENTS WITH LOW-BLAST AML
Refer to Section 9.4.20 for response definitions (eg, CR and PD).
AE=adverse event, CR=complete remission, D/C=discontinuation (of study treatment), EFS=event-free survival,
HMAs= hypomethylating agents, MDS= myelodysplastic syndromes, OS=overall survival, PD=progressive disease.
(a) Subsequent therapy is defined as agent(s) with antileukemic/anti-MDS activity (eg, lenalidomide, cytarabine, 
anthracyclines, purine analogues, and HMAs other than azacitidine). Patients who discontinue study treatment to 
receive single-agent azacitidine off study would not be counted as receiving subsequent therapy.
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Appendix C
Schedule of Events
Screening 
(a,b)
Treatment Cycle (28 Days) (c,d,e)
End of
Treatment
(f)
Follow-up (g)
Cycle 1
Cycle 2 and beyond
EFS
Response 
FU
OS
Days
1
2
3
5
8
15
21
1
3
5
22
Every 
month
Every 
month
Every 3 
months
Procedures
Window
±1 
day
±1 
day
±10 
days
+10 days
±1 
week
±1 week
±2 
weeks
Informed consent
X
Inclusion/exclusion (h)
X
Demographics
X
Complete medical history and 
IPSS-R risk categorization 
(patients with HR MDS or 
CMML)
X
Modified Charlson Comorbidity 
Index assessment (i)
X
Complete physical examination 
X
X
Symptom-directed physical 
examination
X
X
X
X
Height
X
Weight
X
X(j)
X(j)
X
ECOG performance status
X
X
X
Vital signs (k)
X
X
X
X
X
X
X
X
12-lead ECG (l)
X
X
Chest x-ray (m)
X
Pregnancy test (n)
X
X
X
X
Hematology (o)
X
X
X
X
X
X
X
X
X
X
X
Coagulation (p)
X
Complete chemistry panel (o,q)
X
X
X
X
X
X
Select chemistry panel (o,r)
X
X
X
X
X
X
X
Footnotes are on last table page.
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Appendix C
Schedule of Events (continued)
Screening 
(a,b)
Treatment Cycle (28 Days) (c,d,e)
End of
Treatment
(f)
Follow-up (g)
Cycle 1
Cycle 2 and beyond
EFS
Response 
FU
OS
Days
1
2
3
5
8
15
21
1
3
5
22
Every 
month
Every 
month
Every 3 
months
Procedures
Window
±1 
day
±1 
day
±10 
days
+10 days
±1 
week
±1 week
±2 
weeks
Blood phosphate (s)
X
X
Reticulocyte count and ferritin 
(t)
X
X
X
X
Urinalysis with microscopic 
analysis (u)
X
X
EORTC QLQ-C30 and EORTC 
supplemental items (v)
X
X
X
X
X
X
EQ-5D-5L (v)
X
X
X
X
X
X
Hospitalization assessment (v)
X
X
X
X
X
Plasma samples for pevonedistat 
PK
X (w)
X 
(w)
X 
(w)
X 
(x)
Whole blood sample for 
molecular analysis (y)
X
X
Buccal epithelial cells sample 
for DNA
X (z)
SAE collection (aa)
SAEs including serious pretreatment events will be reported from the time informed consent is signed 
through 30 days after the last dose of any study drug
AE collection 
X (bb)
Recorded from the first dose of any study drug through 30 days after the last dose of any 
study drug. TEAEs should be monitored until they are resolved or are clearly determined to 
be due to a patient’s stable or chronic condition or intercurrent illness(es).
Concomitant 
medications/therapy
Recorded from the first dose of any study drug through 30 days after the last dose of any 
study drug
RBC and platelet transfusion 
documentation
Recorded from 8 weeks before randomization through 30 days after the last dose of any study drug
Subsequent therapies (cc)
X
X
X
X
Survival follow-up contact
X
Footnotes are on last table page.
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Appendix C
Schedule of Events (continued)
Screening 
(a,b)
Treatment Cycle (28 Days) (c,d,e)
End of
Treatment
(f)
Follow-up (g)
Cycle 1
Cycle 2 and beyond
EFS
Response 
FU
OS
Days
1
2
3
5
8
15
21
1
3
5
22
Every 
month
Every 
month
Every 3 
months
Procedures
Window
±1 
day
±1 
day
±10 
days
+10 days
±1 
week
±1 week
±2 
weeks
Disease Assessment
Disease assessment based on 
hematology tests (o,dd)
X
X
X
X
Disease assessment based on 
bone marrow aspiration/biopsy 
See the Bone Marrow Collection and Assessment Schedule Table A
Study Drug Administration: Single-Agent Azacitidine or Combination Pevonedistat Plus Azacitidine (e,ee,ff)
Pevonedistat infusion
Days 1, 3, and 5 of each cycle
Azacitidine administration
Days 1-5 and 8 and 9 of each cycle
AE=adverse event, ALP=alkaline phosphatase, ALT=alanine aminotransferase, AML=acute myelogenous leukemia, aPTT=activated partial thromboplastin time, AST=aspartate 
aminotransferase, BSA=body surface area, BUN=blood urea nitrogen, CMML=chronic myelomonocytic leukemia, DME=drug metabolizing enzymes, ECG=electrocardiogram, 
ECOG=Eastern Cooperative Oncology Group, eCRF=electronic case report form, EFS=event-free survival, EOT=end of treatment, HMAs=hypomethylating agents, 
HRQOL=health-related quality of life, IEC=independent ethics committee, IPSS-R=Revised International Prognostic Scoring System, IRB=institutional review board, 
IV=intravenous(ly), LDH=lactate dehydrogenase, MDS=myelodysplastic syndromes, OS=overall survival, PK=pharmacokinetic, PT=prothrombin time, RBC=red blood cell, 
SAE=serious adverse event, SC=subcutaneous(ly), TEAE=treatment emergent adverse events, WBC=white blood cell.
Nonessential protocol visits that do not require on-site sample collection and assessment may be completed via telemedicine (video or phone conversation between the patient and the 
treating physician, if allowed per Health Authorities, privacy laws, and institutional and local guidelines) in situations where a site visit cannot be conducted, such as in a COVID-19 
pandemic. 
(a) Screening assessments will be performed within 28 days before randomization. Baseline assessments are defined as those performed at the closest time before the start of study 
drug administration.
(b) Except for hematology, procedures conducted during the Screening period that are performed within 24 hours of Cycle 1 Day 1 can also be used as the baseline evaluation and do 
not need to be repeated. If dosing falls on a Monday, the collection window may be extended to collect samples on the previous Friday.
(c) On dosing days, all procedures are to be performed before pevonedistat or azacitidine dosing unless specified otherwise. 
(d) For a new cycle of treatment with study drug(s) to begin, toxicities considered to be related to treatment with study drug(s) must have resolved to the level or grade defined in 
Section 8.3.1.
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(e) The first dose of study drug must be administered within 5 days of randomization on study. It is strongly recommended that dosing for both treatment arms occur on the days 
specified. However, dosing of either drug may be delayed for safety reasons or other unavoidable circumstances (eg, weather conditions affecting clinic accessibility). If pevonedistat 
dosing is delayed, a minimum of 1 full calendar day between any 2 doses should be maintained. In each cycle, a maximum of 3 doses of pevonedistat and 7 doses azacitidine (as 
applicable) should not be exceeded. For the combination arm, pevonedistat and azacitidine should always be administered on the same day (eg, instead of pevonedistat dosing on 
Days 1, 3, and 5, it would be acceptable to dose on Days 1, 5, and 8). If dosing is adjusted, study procedures should be performed on the actual day of dosing.
(f) The EOT visit will occur 30 days (+10 days) after the last dose of study drug(s) or before the start of subsequent antineoplastic therapy if that occurs sooner. After the EOT visit, 
patients with HR MDS or CMML will enter EFS follow-up if their disease has not transformed to AML. Patients with low-blast AML will enter response follow-up if their disease has 
not progressed (as defined in Section 9.4.20) and they have not started subsequent therapy.
(g) Patients with HR MDS or CMML will have EFS follow-up study visits every month if their disease has not transformed to AML and they have not started subsequent therapy. 
Patients who have started subsequent therapy will not be required to have monthly visits but will have a bone marrow aspirate and hematology tests (samples sent to central laboratory) 
at the time of suspected transformation to AML or PD (for patients who discontinue treatment without evidenced of PD). Patients with low-blast AML will have response follow-up 
study visits every month until they relapse from CR or meet the criteria for PD. All patients will enter OS follow-up (contacted every 3 months) when they have confirmed 
transformation to AML (for patients with HR MDS or CMML at enrollment) or experienced PD or relapse from CR (for patients with low-blast AML at study enrollment).
(h) Confirmation of patient eligibility by the sponsor’s project clinician (or designee) is required before randomization. A Patient Eligibility Checklist must be completed and 
submitted by the investigator for review and approval by the sponsor or designee before patient randomization.
(i) See Appendix L for the Modified Charlson Comorbidity Index. 
(j) Weight will be measured within 3 days before Day 1 dosing in each cycle, for calculating BSA. BSA will be calculated using a standard formula (see example in Appendix M) on 
Cycle 1 Day 1, and on Day 1 of subsequent cycles if the patient experiences a 5% change in body weight from the weight used for the most recent BSA calculation.
(k) Vital signs, including diastolic and systolic blood pressure, heart rate, and body temperature will be collected at Screening, predose on Days 1, 3, and 5 on each treatment arm of 
each treatment cycle, at EOT, and as clinically indicated. Diastolic and systolic blood pressure, and heart rate will be collected postdose on Days 1, 3, and 5 on each treatment arm of 
each treatment cycle. Vital sign measurements will be taken with the patient in the supine or sitting position.
(l) Additional ECGs may be performed as clinically indicated.
(m) If a chest x-ray or chest computed tomography scan was performed within 2 months before randomization, the chest x-ray does not need to be performed during Screening.
(n) A serum pregnancy test will be performed for women of childbearing potential at Screening. A pregnancy test must also be performed for women of childbearing potential at every 
cycle (typically performed on Day 1 of the cycle; however, if a serum pregnancy test is used, this may be performed up to 3 days before Day 1) with negative results available before 
the first dose is administered in that cycle. A pregnancy test will also be performed for women of childbearing potential at the EOT visit. Pregnancy tests may also be repeated during 
the study if requested by an IEC/IRB or if required by local regulations.
(o) Clinical laboratory evaluations will be performed by a central laboratory. The central laboratory results also should be used for determination of eligibility by the sponsor’s project 
clinician (or designee) before randomization. For dosing decisions and/or safety concerns, local hematology and chemistry results should be used; however, samples must still be sent 
to the central laboratory as well. Hematology and chemistry samples may be collected up to 3 days before Day 1 dosing and 24 hours before Days 3 and 5 dosing, when required. 
Local laboratory evaluations may be done more frequently at the investigator’s discretion.
(p) Coagulation panel includes PT and aPTT (to be performed by the central laboratory).
(q) The complete chemistry panel will include the following: BUN, creatinine, sodium, potassium, chloride, carbon dioxide, glucose, urate, total bilirubin, direct bilirubin, ALP, LDH, 
AST, ALT, albumin, magnesium, phosphate, and calcium.
(r) The select chemistry panel will include the following: BUN, creatinine, total bilirubin, ALP, AST, and ALT.
(s) Blood phosphate test to be performed on Day 5 of each treatment cycle or the day on which the third dose of pevonedistat is given if it is not Day 5 (to be performed by the central 
laboratory).
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(t) Reticulocyte counts and ferritin level testing will be performed by the central laboratory only. Reticulocyte count and ferritin samples may be collected up to 3 days before Day 1 
dosing. 
(u) Urinalysis will include assessments of turbidity and color, pH, specific gravity, protein, ketones, bilirubin, occult blood, nitrite, glucose, and leukocyte esterase. Urine microscopic 
analysis will include erythrocytes, leukocytes, bacteria, casts, and crystals. These samples will be analyzed by a central laboratory.
(v) Patient-reported outcomes (HRQOL) and hospitalization assessment (ie, details regarding any hospitalizations since the last assessment) should be completed before any other 
study procedures are performed or study drug regimen is administered. The EORTC QLQ-C30, EORTC supplemental items, and EQ-5D-5L will be completed for all patients.
(w) Combination Pevonedistat Plus Azacitidine Arm only: blood samples (approximately 3 mL each) for the determination of pevonedistat plasma concentrations will be collected 
during Cycle 1 at the following time points: predose (within 1 hour before azacitidine dosing), Day 1 at the end of the pevonedistat infusion (immediately before stopping the infusion), 
at 1.5 hours (30 minutes) and at 4 hours (45 minutes) after completion of the pevonedistat infusion; Day 3 predose (within 10 minutes before azacitidine dosing); and Day 5 
predose (within 10 minutes before azacitidine dosing), at the end of the pevonedistat infusion (immediately before stopping the infusion), and before the patient’s discharge from the 
clinic visit (or for patients who are hospitalized, after stopping the infusion following postdose vital sign assessments). The exact date and time of each sample collection and the 
actual start and stop times of the infusion should be recorded accurately, and particular care should be given to the recording of blood sampling times that occur close to the infusion. 
Details regarding the preparation, handling, and shipping of samples are provided in the Study Manual.
(x) Combination Pevonedistat Plus Azacitidine Arm only: blood samples (approximately 3 mL each) for the determination of pevonedistat plasma concentrations will be collected at 
Cycle 2 and Cycle 4 Day 1 (at the end of the pevonedistat infusion [immediately before stopping the infusion] and 3 hours [45 minutes] after completion of the pevonedistat 
infusion); an additional sample will be collected predose (within 10 minutes before azacitidine dosing) on Cycle 4 Day 3. The exact date and time of each sample collection and the 
actual start and stop times of the infusion should be recorded accurately, and particular care should be given to the recording of blood sampling times that occur close to the infusion. 
Details regarding the preparation, handling, and shipping of samples are provided in the Study Manual.
(y) Whole blood samples for molecular analysis will be obtained at Screening or anytime before the first administration of study drug, within ±10 days when marrow aspirate for 
molecular analysis is obtained on Cycle 2, Cycle 4, Cycle 6, Cycle 9, and relapse (see Table A). The 10-day window for collection of this sample allows for it to be obtained along 
with other blood collection procedures thereby reducing the number of venipunctures. The date and cycle of collection of the blood sample for molecular analysis should be noted on 
the eCRFs. Whole blood samples will be sent to a central laboratory for molecular analysis.
(z) Buccal epithelial cell samples will be collected for DNA analysis and for genotyping of DME and/or transporter polymorphisms; procedure is specified in the Study Manual.
(aa) SAEs will be entered on the eCRF (see Section 10.2). SAEs should be monitored until they are resolved or are clearly determined to be due to a patient’s stable or chronic 
condition or intercurrent illness(es). 
(bb) Nonserious pretreatment events related to study screening procedures will be reported from the time of the signing of the ICF up to first dose of study drug and recorded in the 
eCRFs. 
(cc) Subsequent therapy is defined as an agent(s) with antileukemic/anti-MDS activity (eg, cytarabine, anthracyclines, purine analogues, and HMAs other than azacitidine). Patients 
who discontinue study treatment to receive single-agent azacitidine off study would not be counted as receiving subsequent therapy.
(dd) Hematology tests will also be collected at relapse or PD, and as clinically indicated (see Section 9.4.20 for detailed examples). 
(ee) Combination Pevonedistat Plus Azacitidine Arm only: see Section 8.1.2 for pevonedistat dosing instructions. On Days 1, 3, and 5 when both study drugs are administered, 
azacitidine will be administered first followed by pevonedistat. Subsequent pevonedistat doses may be reduced because of toxicity in accordance with Section 8.3. 
(ff) All patients will receive azacitidine 75 mg/m2 IV or SC on Days 1 through 5 (inclusive), Day 8, and Day 9 of each cycle in accordance with Section 8.1.1. The azacitidine dose 
may be reduced because of toxicity in accordance with Section 8.3. 
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Table A
Bone Marrow Collection and Assessment Schedule
Assessment
Screening
Cycle 2 Day 22
(+6 Days)
Cycle 4 Day 
22 (+6 days)
Cycle 6 Day 
22 (+6 days)
Cycle 9 Day 
22 (+6 days), 
and Then 
Every 3 
Cycles 
Thereafter
Relapse(a)
EFS 
Follow-up
Response 
Follow-up
Bone marrow blast count
(Local analysis, and central 
analysis if required)(b)
X (c)
X (d)
X (d,e)
X (d,e)
X (d,e)
X
X (f)
X (g)
Fresh bone marrow aspirate 
sample for cytogenetics 
(Local and central 
analyses) (h)
X(i)
X
X (e)
X (e)
X (e)
X
Mutation analysis (j)
(Local analysis only)
X
Fresh bone marrow aspirate 
sample for molecular 
analysis (Central analysis 
only)
X (k)
X (k)
X (e,k)
X (e,k)
X (e,k)
X (l)
CR=complete remission, EFS=event-free survival, FISH=fluorescence in situ hybridization, PCR=polymerase chain reaction, PD=progressive disease.
(a) Relapse includes the following:
Relapse from CR or PR in patients with HR MDS or CMML.
Relapse from CR in patients with AML.
PD in patients with AML with a PR at end of treatment. 
(b) 1 aspirate smear from the local analysis should be submitted to the central laboratory at timepoints where blast counts samples are sent to central laboratory.
(c) A bone marrow biopsy (in addition to bone marrow aspirate) is required only at Screening to confirm the diagnosis but if a bone marrow biopsy is not collected 
routinely per country institutional guidelines, it is not required. Bone marrow aspirates will be collected at all other time points, at relapse or PD, and as clinically 
indicated (see Section 9.4.20 for detailed examples). A bone marrow biopsy may be collected with bone marrow aspirate in accordance with institutional guidelines. 
If a bone marrow aspirate and biopsy were performed within 28 days before randomization, these archival samples may be used to confirm diagnosis and patient 
eligibility and do not need to be repeated. However, a bone marrow aspirate for molecular analysis is still required at Screening (see footnote i). The bone marrow 
pathology report(s) will be submitted to the central laboratory. A bone marrow aspirate is required during Screening for bone marrow blast count and will serve as 
a baseline to assess response. The screening marrow aspirate also is required for central molecular analysis and for local as well as central cytogenetics. If local 
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cytogenetics was done during the 28 days before randomization and before the screening bone marrow aspirate, it need not be repeated during the screening bone 
marrow aspirate.
(d) A bone marrow aspirate for blast count (to inform disease burden assessment) will be performed on Day 22 (+6 days) of Cycle 2, Cycle 4, Cycle 6, Cycle 9 and 
every 3 cycles thereafter. Results must be available before dosing starts in the next cycle. 
(e) Following Cycle 4, bone marrow aspirates will be performed only as clinically indicated in patients who achieve CR. Patients who achieve a CR by Cycle 4 are 
encouraged, but not required to have a bone marrow aspirates on Cycles 6 and 9. Patients with AML who have a CRi are required to have bone marrow aspirates on 
Cycles 6 and 9. 
(f) Patients with HR MDS or CMML not in CR or PR will have bone marrow assessments performed for EFS follow-up at time of suspected PD and at the time of 
suspected transformation to AML. Additional bone marrow aspirates may be performed if warranted by changes in peripheral blood counts. Patients with HR MDS 
or CMML who discontinue treatment while in CR or PR will also have a bone marrow aspirate at the time of suspected relapse. Patients who transform to AML after 
EOT will proceed into OS follow-up. 
(g) Patients with low-blast AML who discontinue treatment without evidence of CR and without PD will have a bone marrow aspirate at the time of suspected PD 
during response follow-up. Patients who discontinue treatment while in CR will also have a bone marrow aspirate performed at the time of suspected relapse. 
Patients with PD after EOT will proceed into OS follow-up.
(h) Local and central cytogenetics will be performed at Screening. Central cytogenetics will be performed at all other time points noted. Local cytogenetics may also 
be done at other time points at the site’s discretion, but results will not be collected in the eCRF, and cytogenetics report(s) will not be submitted to the central 
laboratory outside of the requirement during Screening.
(i) Cytogenetics analysis for eligibility will be done locally at the clinical site and will be used to randomize the patient. A bone marrow aspirate sample taken within 
28 days of randomization will be tested according to institutional guidelines in a cytogenetics laboratory routinely used by the site. Analyses should be done by 
karyotype, and by FISH if possible. Results will be collected in the eCRF and the cytogenetics report(s) will be submitted to the central laboratory. Central 
cytogenetics also will be performed at Screening 
(j) Mutation analysis on Screening bone marrow aspirate samples to be performed locally at the clinical site according to institutional guidelines/standard practice 
(eg, genomic analysis or PCR analysis) and this information will be collected from sites. If mutation analysis is not performed routinely per country/institutional 
guidelines, it is not required. Results will be collected in the eCRF and the mutation analysis report(s) will be submitted to the central laboratory. Results of mutation 
analysis if performed within 28 days of randomization may be submitted to the central laboratory. 
(k) A fresh bone marrow aspirate obtained at Screening or anytime before the first administration of study drug, will be used for baseline molecular characterization. 
A bone marrow aspirate sample for molecular analysis will also be obtained when a bone marrow aspirate is done on Day 22 (+6 days) of Cycle 2, Cycle 4, Cycle 
6, Cycle 9 and relapse. Bone marrow aspirate samples will be sent to a central laboratory for molecular analysis.
(l) If relapse is suspected, the sample for molecular analysis will be collected at the time the bone marrow sample for disease assessment is collected and sent to the 
central laboratory (per instructions in the Laboratory Manual). Patients with HR MDS/CMML who relapse from CR or PR (HR MDS/CMML) or patients with 
low-blast AML who relapse from CR or progress from PR will have fresh bone marrow aspirate sample sent for molecular analysis (Central Analysis).
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Appendix D
Responsibilities of the Investigator
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. The responsibilities imposed on investigators by the FDA are 
summarized in the “Statement of Investigator” (Form FDA 1572), which must be completed and 
signed before the investigator may participate in this study.
The investigator agrees to assume the following responsibilities by signing a Form FDA 1572:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff who will assist in the protocol.
3. If the investigator/institution retains the services of any individual or party to perform 
trial-related duties and functions, the investigator/institution should ensure that this individual 
or party is qualified to perform those trial-related duties and functions and should implement 
procedures to ensure the integrity of the trial-related duties and functions performed and any 
data generated.
4. Ensure that study related procedures, including study specific (non routine/non standard panel) 
screening assessments are NOT performed on potential subjects, before the receipt of written 
approval from relevant governing bodies/authorities.
5. Ensure that all colleagues and employees assisting in the conduct of the study are informed of 
these obligations.
6. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform to 
21 CFR Part 56, ICH, and local regulatory requirements.
7. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and approval 
of the protocol. Promptly report to the IRB/IEC all changes in research activity and all 
anticipated risks to subjects. Make at least yearly reports on the progress of the study to the 
IRB/IEC, and issue a final report within 3 months of study completion.
8. Ensure that requirements for informed consent, as outlined in 21 CFR Part 56, ICH, and local 
regulations, are met.
9. Obtain valid informed consent from each subject who participates in the study, and document 
the date of consent in the subject’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each ICF should contain a subject authorization section that 
describes the uses and disclosures of a subject’s personal information (including personal 
health information) that will take place in connection with the study. If an ICF does not include 
such a subject authorization, then the investigator must obtain a separate subject authorization 
form from each subject or the subject’s legally acceptable representative.
10. Prepare and maintain adequate case histories of all persons entered into the study, including 
eCRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
2 years following notification by the sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
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contact and receive written approval from the sponsor before disposing of any such 
documents.
11. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
12. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor. *This responsibility lies on 
the appropriate individual, designated by the site in Japan. 
13. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours.
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Appendix E
Investigator Consent to Use of Personal Information
Takeda will collect and retain personal information of investigator, including his or her name, 
address, and other personally identifiable information. In addition, investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, US, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
Investigator’s personal information may be retained, processed, and transferred by Takeda and 
these other parties for research purposes including the following:

Assessment of the suitability of investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may contain 
the same chemical compound present in the study medication.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of study records.

Posting investigator site contact information, study details and results on publicly accessible 
clinical trial registries, databases, and websites.
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in investigator’s own 
country.
Investigator acknowledges and consents to the use of his or her personal information by Takeda 
and other parties for the purposes described above.
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Appendix F
ECOG Scale for Performance Status
Grade
Description
0
Normal activity. Fully active, able to carry on all predisease performance without restriction.
1
Symptoms but ambulatory. Restricted in physically strenuous activity, but ambulatory and able to 
carry out work of a light or sedentary nature (eg, light housework, office work).
2
In bed <50% of the time. Ambulatory and capable of all self-care, but unable to carry out any work 
activities. Up and about more than 50% of waking hours.
3
In bed >50% of the time. Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair.
5
Dead
Source: Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and response criteria 
of the Eastern Cooperative Oncology Group. American Journal of Clinical Oncology 1982;5(6):649-55.
ECOG=Eastern Cooperative Oncology Group.
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Appendix G
Definition of Postmenopausal
A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause. A high follicle-stimulating hormone (FSH) level in the postmenopausal range may be used 
to confirm a postmenopausal state in women not using hormonal contraception or hormonal 
replacement therapy. However in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. Please refer to the following source for additional information: 
European Heads of Medicines Agencies Clinical Trial Facilitation Group; see 
hma.eu/fileadmin/dateien/Human_Medicines/01-About_HMA/Working_Groups/CTFG/2014_09
_HMA_ CTFG_Contraception.pdf
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Appendix H
Methods of Contraception Considered to be Effective
Acceptable Methods Considered Highly Effective1
Birth control methods that can achieve a failure rate of less than 1% per year when used 
consistently and correctly are considered as highly effective. Such methods include:

combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation 2:
–
oral.
–
Intravaginal.
–
Transdermal.

progestogen-only hormonal contraception associated with inhibition of ovulation 1:
–
oral.
–
Injectable.
–
implantable 3.

intrauterine device (IUD) 3.

intrauterine hormone-releasing system (IUS) 3.

bilateral tubal occlusion 3.

vasectomised partner 3,4.

sexual abstinence 5.
Methods that are Considered Less Highly Effective
Acceptable birth control methods that result in a failure rate of more than 1% per year include:

progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mode of action.

male or female condom with or without spermicide 6.

cap, diaphragm or sponge with spermicide 6.
_________________________________________________________________________________________
Source: European Heads of Medicines Agencies Clinical Trial Facilitation Group; see 
hma.eu/fileadmin/dateien/Human_Medicines/01-About_HMA/Working_Groups/CTFG/2014_09_HMA_ 
CTFG_Contraception.pdf
1) If patients are taking oral contraceptives and experience adverse events, such as severe vomiting, that interfere with 
taking these oral medicines, one of the other highly effective methods of contraception should be used.
2) Hormonal contraception may be susceptible to interaction with the investigational medicinal product, which may 
reduce the efficacy of the contraception method.
3) Contraception methods that in the context of this guidance are considered to have low user dependency.
4) Vasectomised partner is a highly effective birth control method provided that partner is the sole sexual partner of the 
woman of childbearing potential participant of the study and that the vasectomised partner has received medical 
assessment of the surgical success.
5) In the context of this guidance sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred 
and usual lifestyle of the subject.
6) A combination of male condom with either cap, diaphragm or sponge with spermicide (double-barrier methods) are 
also considered acceptable, but not highly effective, birth control methods.
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Appendix I
Cockcroft-Gault Equation 
For male patient/subject: 
Creatinine Clearance=(140-age [years] weight [kg]) OR (140–age [years] weight [kg])
72 (serum creatinine [mg/dL])
0.81 (serum creatinine [mol/L])
For female patient/subject:
Creatinine Clearance=0.85 (140-age[years] weight [kg]) OR 0.85 (140–age[years] weight [kg])
72 (serum creatinine [mg/dL])
0.81 (serum creatinine[mol/L])
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Appendix J
New York Heart Association Classification of Cardiac Disease
The following table presents the New York Heart Association classification of cardiac disease 
[83].
Class
Functional Capacity
Objective Assessment
I
Patients with cardiac disease but without resulting limitations of physical 
activity. Ordinary physical activity does not cause undue fatigue, palpitation, 
dyspnea, or anginal pain.
No objective evidence of 
cardiovascular disease
II
Patients with cardiac disease resulting in slight limitation of physical activity. 
They are comfortable at rest. Ordinary physical activity results in fatigue, 
palpitation, dyspnea, or anginal pain.
Objective evidence of 
minimal cardiovascular 
disease
III
Patients with cardiac disease resulting in marked limitation of physical 
activity. They are comfortable at rest. Less than ordinary activity causes 
fatigue, palpitation, dyspnea, or anginal pain.
Objective evidence of 
moderately severe 
cardiovascular disease
IV
Patients with cardiac disease resulting in inability to carry on any physical 
activity without discomfort. Symptoms of heart failure or the anginal 
syndrome may be present even at rest. If any physical activity is undertaken, 
discomfort is increased.
Objective evidence of 
severe cardiovascular 
disease
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Appendix K
CYP3A Inducers
Treatment with any of the strong CYP3A inducers listed in the following table within 14 days 
before the first dose of pevonedistat was a criterion for exclusion from enrollment in this study. 
Based on findings from Study P1015, strong CYP3A inducers are not expected to have a clinically 
meaningful effect on pevonedistat systemic exposures, and as of Amendment 07, administration 
of these drugs is permitted while on study treatment. Note that HIV medications that are strong 
CYP3A inducers are not included in this list because HIV-positive patients are excluded from 
study participation.
In Vivo Inducers of CYP3A
Strong Inducers
(≥80% decrease in AUC)
Carbamazepine
Phenytoin
Phenobarbital
Primidone
Rifabutin
Rifampin
Rifapentine
St. John’s wort
AUC=area under the plasma concentration-time curve.
Please refer to the following sources for additional information: medicine.iupui.edu/clinpharm/ddis/main-table/ and 
fda.gov/drugs/developmentapprovalprocess/developmentresources/%20druginteractionslabeling/ucm093664.htm.
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Appendix L
Modified Charlson Comorbidity Index
Modified Charlson Comorbidity Index
Point
Comorbid Condition
1
Myocardial infarction
1
Congestive heart failure
1
Cerebrovascular disease
1
Ulcer
1
Hepatic disease (mild)
1
Diabetes (mild or moderate)
1
Pulmonary disease (moderate or severe)
1
Connective tissue disease
2
Diabetes (severe with end-organ damage)
2
Renal disease (moderate or severe)
2
Solid tumor (without metastases)
3
Hepatic disease (moderate or severe)
6
Solid tumor (with metastases)
Total score
Source: From Etienne et al, 2007 [84].
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Appendix M BSA Calculation
BSA should be calculated using a standard formula. An example formula follows:
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Appendix N
Formula for ANC Calculation
ANC=total leukocyte count×total percentage of neutrophils (segmented neutrophils+band 
neutrophils)
Example:
If total leukocyte count=4.3; segmented neutrophils=48%; band neutrophils=2% 
Then: 4300×(0.48+0.02)=4300×0.5=ANC of 2150
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Appendix O
Detailed Description of Amendments to Text 
The primary sections of the protocol affected by the changes in Amendment 14 is indicated. The 
corresponding text has been revised throughout the protocol.
Change 1: Updated the name of the legal entity to Takeda Development Center Americas, Inc., 
95 Hayden Avenue, Lexington, MA 02421.
The primary change occurs in Title Page:
Initial 
wording in 
Title page
Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda 
Pharmaceutical Company Limited
Please note: Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda 
Pharmaceutical Company Limited, may be referred to in this protocol as 
“Millennium,” “sponsor,” or “Takeda”.
Amended 
or new 
wording in
Title page
Takeda Development Center Americas, Inc. 
95 Hayden Avenue
Lexington, MA 02421
Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda Pharmaceutical 
Company Limited
Please note: Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda 
Pharmaceutical Company Limited, may be referred to in this protocol as “Millennium,” 
“sponsor,” or “Takeda”.
Rationale for Change: To update the name of the legal entity to Takeda Development Center 
Americas, Inc. and to update its address.
The following sections also contain this change:

Section 2.0 STUDY SUMMARY.

Section 3.4 Corporate Identification.
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