A Randomized, Open-label, Controlled, Phase 2 Study of Pevonedistat, Venetoclax, and Azacitidine Versus Venetoclax Plus Azacitidine in Adults With Newly Diagnosed Acute Myeloid Leukemia Who Are Unfit for Intensive Chemotherapy
Phase: PHASE2
Conditions: Acute Myeloid Leukemia (AML)
Sponsor: Takeda

For non-commercial use only

 
 
CONFIDENTIAL
PROTOCOL
A Randomized, Open-label, Controlled, Phase 2 Study of Pevonedistat, Venetoclax, and 
Azacitidine Versus Venetoclax Plus Azacitidine in Adults With Newly Diagnosed Acute 
Myeloid Leukemia Who Are Unfit for Intensive Chemotherapy
Triple Combination of Pevonedistat and Venetoclax Plus Azacitidine in Adults
With Acute Myeloid Leukemia Who Are Unfit for Intensive Chemotherapy
Sponsor:
Takeda Development Center Americas, Inc.
95 Hayden Avenue
Lexington, Massachusetts 02421, USA
Telephone: +1 (617) 761-6939
Study Number:
Pevonedistat-2002
EudraCT Number:
2019-003117-33
Compound:
Pevonedistat (TAK-924/MLN4924)
Date:
21 January 2022
Version/Amendment 
Number
4
Amendment History:
Date
Amendment No.
Amendment Type
Region
21 January 2022
4
Substantial
Global
08 July 2021
3
Substantial (not implemented)
Global
28 July 2020
2
Substantial
Global
10 July 2020
1
Substantial
Global
21 November 2019
Initial Protocol
Not applicable
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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Protocol Incorporating Amendment No. 4
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CONFIDENTIAL
1.0
ADMINISTRATIVE INFORMATION
1.1
Contacts 
A separate contact information list will be provided to each site.
Serious adverse event (SAE) and pregnancy reporting information is presented in Section 10.0, as 
is information on reporting product complaints. 
Takeda sponsored investigators per individual country requirements will be provided with 
emergency medical contact information cards to be carried by each patient.
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.
The names and contact information for the Medical Monitor and Responsible Medical Officer are 
in the Study Manual. For SAE and pregnancy reporting, see Section 10.0.
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CONFIDENTIAL
INVESTIGATOR AGREEMENT
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, 
prescribing information, 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 patients in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Council for Harmonisation, E6 GCP: Consolidated Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting SAEs defined in Section 10.0 of this protocol.

Terms outlined in the clinical study site agreement.

Responsibilities of the investigator (Appendix C).
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix D 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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Protocol Incorporating Amendment No. 4
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1.3
Protocol Amendment 4 Summary of Changes
Protocol Amendment 4 Summary and Rationale:
This section describes the changes in reference to the protocol incorporating Amendment 4.
The primary reasons for this amendment are to modify the statistical design and schedule of 
assessments/procedures, given emerging data from the pevonedistat program.
Results of the registration-enabling Study Pevonedistat-3001 (PANTHER), 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, 
became available in September 2021. The primary endpoint of event-free survival (EFS) was not 
met and no statistically significant benefits were observed with pevonedistat treatment. As such, 
Takeda will not pursue further development of pevonedistat in any indication.
On the basis of these results, the Pevonedistat-2002 Protocol Amendment 4 contains the following 
key design changes:

Remove the interim analysis (IA) to evaluate EFS for futility and event size re-estimation.

Update the timing for the final analysis (FA).

Provide guidance for modification of the study procedures and assessments for patients who 
remain on study treatment.

Update several secondary objectives and endpoints.

Remove the Independent Review Committee (IRC) assessment of disease evaluation data.

Remove Independent Data Monitoring Committee (IDMC) evaluations of the safety and 
efficacy data.
Protocol Amendment 3 (dated 08 July 2021), which converted the phase 2 study to a 
registration-enabling phase 3 study and included a change in the primary endpoint, expansion of 
sample size, and increase in number of sites, will not be implemented. Thus, the changes described 
below for the current Protocol Amendment 4 are relative to Protocol Amendment 2 (dated 
28 July 2020) rather than Protocol Amendment 3.
In this amendment, minor grammatical, editorial, formatting, and administrative changes not 
affecting the conduct of the study are included for clarification and administrative purposes only.
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CONFIDENTIAL
Protocol Amendment 4
Summary of Changes Since the Last Version of the Approved Protocol Amendment 2
Change 
Number
Sections Affected by Change
Description of Each Change and Rationale
Location
Description
Rationale
1.
Section 2.0 Study Summary
Section 13.1.3.4 Multiplicity 
Control (deleted)
Section 13.2 IA and Event Size 
Re-estimation
Section 13.3 Determination of 
Sample Size
Modified the statistical analysis 
for primary and secondary 
endpoints by removing the 
interim analysis (IA) and 
event-size re-estimation.
Changes made to align the 
statistical analysis with the
current expected data.
2.
Appendix A Modified Schedule of 
Events and throughout the 
document where it is referenced.
Appendix L Schedule of 
EventsSchedule of Events
and throughout the document 
where it is referenced.
Provided a modified SOE for 
patients continuing treatment 
after implementation of 
Protocol Amendment 4.
Moved the original (Protocol 
Amendment 2) SOE from 
Appendix A to Appendix L for 
reference purposes.
Changes made to reduce data 
collection and lessen patient 
burden and to more closely 
align with clinical practice.
3.
Section 2.0 Study Summary
Section 5.1.2.2 Other Secondary 
Objectives
Section 5.2.2.2 Other Secondary 
Endpoints
Section 6.1 Overview of Study 
Design
Table 6.a Primary and Secondary 
Endpoints for Disclosures
Section 9.4.23 Patient Reported 
Outcomes (deleted)
Section 9.4.24 Hospitalization 
Assessment (deleted)
Section 9.10 Posttreatment 
Follow-up Assessments (EFS, 
Response, and OS)
Section 13.1.3.3 Analyses of Other 
Secondary Efficacy Endpoints
Section 13.1.6 Patient-Reported 
Outcomes (deleted)
Removed the secondary 
objectives and endpoints 
relating to:

6-month, 1-year, and 
2-year survival rates.

Duration of composite 
complete remission (CCR), 
complete remission + 
partial recovery of blood 
cells (CR + CRh), and 
overall response rate 
(ORR).

Determination of time to 
relapse from CR/complete 
remission with incomplete 
blood count recovery 
(CRi), or death, whichever 
occurs first.

Failure to achieve CR or 
CRi at completion of 
6 treatment cycles, relapse 
from CR/CRi or death from 
any cause, whichever 
occurs first.

Health-related quality of 
life (HRQOL) assessments.

Red blood cell (RBC) and 
platelet transfusion 
Relevant data for analysis are 
not expected due to 
discontinuation of the study. 
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Protocol Incorporating Amendment No. 4
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CONFIDENTIAL
Protocol Amendment 4
Summary of Changes Since the Last Version of the Approved Protocol Amendment 2
Change 
Number
Sections Affected by Change
Description of Each Change and Rationale
Location
Description
Rationale
independence rates and 
duration for each treatment 
arm.

Comparison of 
hospitalization rates for 
patients in each treatment 
arm.
4.
Section 2.0 Study Summary
Table 6.a Primary and Secondary 
Endpoints for Disclosures
Section 6.3 Duration of Study
Section 6.3.2 End of Study/Study 
Completion Definition and Planned 
Reporting
Section 6.3.4 Total Study Duration
Section 6.3.5 Early 
Discontinuation of the Study
Updated the period of 
evaluation up to approximately 
3 years.
Added sponsor’s decision as a 
reason for early discontinuation 
of the study.
Change made to reflect the 
current expected timeframe for 
study completion
5.
Section 2.0 Study Summary
Section 6.1 Overview of Study 
Design
Table 6.a Primary and Secondary 
Endpoints for Disclosures
Section 8.8 Blinding and 
Unblinding
Section 11.1 IRC (deleted)
Section 13.1.3.1 Analyses for 
Primary Efficacy Endpoint
Section 13.1.3.3 Analyses of Other 
Secondary Efficacy Endpoints
Revised text to indicate the 
evaluation of disease for 
primary and secondary 
endpoints will be based on 
investigator assessment; 
independent review committee 
(IRC) assessment will no longer 
be required.
Since the study is being 
terminated by the sponsor, 
investigator assessment of 
efficacy is sufficient.
6.
Section 8.8 Blinding and 
Unblinding
Section 13.1.1 Analysis Sets (Per 
Protocol Population) 
Section 14.1 Study-Site 
Monitoring Visits
Removed the requirement that 
the sponsor and sponsor’s staff 
are to be blinded to treatment 
assignment.
Removed blinding to increase 
efficiency of statistical data 
analysis 
7.
Section 11.2 Independent Data 
Monitoring Committee (deleted)
Removed independent data 
monitoring committee (IDMC) 
evaluations.
A separate evaluation by the 
IDMC is no longer necessary 
because the sponsor will be 
unblinded,.
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Protocol Amendment 4
Summary of Changes Since the Last Version of the Approved Protocol Amendment 2
Change 
Number
Sections Affected by Change
Description of Each Change and Rationale
Location
Description
Rationale
8.
Section 2.0 Study Summary
Section 9.6 Completion of Study 
(for Individual Patients)
Section 9.8 Withdrawal of Patients 
From Study
Section 9.11 Posttrial Access
Section 9.12 Duration of PTA
Updated and clarified text on 
the posttrial access (PTA)
program and its duration.
Change made to reflect the 
current approach to be taken by 
the sponsor.
9.
Section 2.0 Study Summary
Section 6.1 Overview of Study 
Design
Section 9.4.18 Clinical Laboratory 
Evaluations
Section 9.4.18.1 Clinical 
Chemistry, Hematology, and 
Urinalysis
Section 9.4.19 Disease Assessment
Revised to indicate that local 
laboratories will be used 
following implementation of 
Protocol Amendment 4.
Change made as central 
laboratory evaluations are no 
longer required.
10.
Section 9.6 Completion of Study 
(for Individual Patients)
Section 9.8 Withdrawal of Patients 
From Study
Added study termination by the 
sponsor as a reason for study 
completion.
Change made to provide 
guidance and clarify reasons for 
study completion.
11.
Section 13.1.3.1 Analyses for 
Primary Efficacy Endpoint
Removed language regarding 
data censorship and planned 
subgroup and sensitivity 
analyses for event-free survival 
(EFS).
These EFS analyses are no 
longer applicable since the IRC 
assessment has been removed.
12.
Section 14.1 Study-Site 
Monitoring Visits
Provided alternative monitoring 
visit approaches such as remote 
source data verification (SDV).
Change made to provide 
general guidance for SDV to be 
performed remotely during the 
coronavirus disease 2019
(COVID-19) pandemic.
13.
Section 8.3.1.3 Venetoclax Dosing 
With CYP3A4 Inducers and 
Inhibitors
Removed isavuconazole from 
the list of cytochrome P450 
(CYP)3A inhibitor.
Isavuconazole is not a CYP3A 
inhibitor and was included in 
error.
14.
Section 8.10 Preparation, 
Reconstitution, and Dispensing
Added normal saline (0.9% 
sodium chloride) solution as a 
diluent for pevonedistat.
Change made to add an 
additional diluent for 
pevonedistat dose preparation.
15.
Section 8.2 Reference/Control 
Therapy: Venetoclax Plus 
Azacitidine
Clarified that body surface area 
(BSA) should be measured in 
both treatment arms.
Provided missing information 
for the reference/control 
therapy.
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CONFIDENTIAL
Protocol Amendment 4
Summary of Changes Since the Last Version of the Approved Protocol Amendment 2
Change 
Number
Sections Affected by Change
Description of Each Change and Rationale
Location
Description
Rationale
16.
Section 9.4.20 Biomarker, 
Pharmacodynamic, and PK 
Samples
Section 9.4.21 PK Measurements
Updated the location of 
instructions for 
pharmacokinetic (PK) sample 
collection.
Change made to clarify location 
of instructions.
17.
Section 9.4.2 Reconsent of Patients
Updated text to include a 
subsection for patient reconsent 
following implementation of 
Protocol Amendment 4.
Added to ensure that patients 
continuing on study after 
implementation of Protocol 
Amendment 4 will be 
reconsented.
18.
Section 13.1.5 Pharmacodynamic 
Analysis
Updated text to add flexibility 
to data analyses.
Change made to include the 
sponsor’s revised data analysis 
approach.
19.
Section 6.3.6 Posttrial Access 
(section deleted)
Deleted redundant text.
PTA information is also in 
Section 9.11; thus, duplicate 
information in Section 6.3.6 has 
been deleted.
20.
Section 8.3.4 Criteria for 
Discontinuation of Study Drug 
(section deleted)
Deleted redundant text.
Discontinuation criteria are also 
included in Section 9.7; thus, 
duplicate information in 
Section 8.3.4 has been deleted.
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TABLE OF CONTENTS
1.0
ADMINISTRATIVE INFORMATION ...........................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
1.3
Protocol Amendment 4 Summary of Changes............................................................5
2.0
STUDY SUMMARY ....................................................................................................16
3.0
STUDY REFERENCE INFORMATION ......................................................................22
3.1
Study-Related Responsibilities.................................................................................22
3.2
Principal Investigator/Coordinating Investigator ......................................................22
3.3
List of Abbreviations ...............................................................................................23
3.4
Corporate Identification...........................................................................................26
4.0
INTRODUCTION.........................................................................................................27
4.1
Background .............................................................................................................27
4.1.1
Scientific Background......................................................................................27
4.2
Nonclinical Experience............................................................................................28
4.3
Clinical Experience..................................................................................................29
4.4
PK ...........................................................................................................................31
4.5
Pharmacodynamics..................................................................................................32
4.6
Rationale for the Proposed Study.............................................................................33
4.6.1
Rationale for the Study Population...................................................................34
4.6.2
Rationale for the Combination of Pevonedistat Plus Venetoclax in Patients 
With AML.......................................................................................................34
4.6.3
Therapeutic Rationale for the Combination of Pevonedistat, Venetoclax and 
Azacitidine in Patients With AML...................................................................35
4.6.4
Rationale for Dose and Schedule of Study Drugs.............................................36
4.7
Potential Risks and Benefits.....................................................................................36
4.7.1
Pevonedistat ....................................................................................................36
4.7.2
Venetoclax.......................................................................................................40
4.7.3
Azacitidine ......................................................................................................44
4.7.4
Summary of Risks and Benefits .......................................................................46
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................47
5.1
Objectives................................................................................................................47
5.1.1
Primary Objective............................................................................................47
5.1.2
Secondary Objectives ......................................................................................47
5.1.3
Safety Objectives.............................................................................................47
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5.1.4
Exploratory Objectives ....................................................................................48
5.2
Endpoints.................................................................................................................48
5.2.1
Primary Endpoint.............................................................................................48
5.2.2
Secondary Endpoints .......................................................................................49
5.2.3
Safety Endpoints..............................................................................................49
5.2.4
Exploratory Endpoints .....................................................................................49
6.0
STUDY DESIGN..........................................................................................................50
6.1
Overview of Study Design.......................................................................................50
6.2
Number of Patients ..................................................................................................53
6.3
Duration of Study ....................................................................................................53
6.3.1
Duration of an Individual Patient’s Study Participation....................................53
6.3.2
End of Study/Study Completion Definition and Planned Reporting..................53
6.3.3
Timeframes for Primary and Secondary Endpoints to Support Disclosures ......54
6.3.4
Total Study Duration .......................................................................................54
6.3.5
Early Discontinuation of the Study ..................................................................54
7.0
STUDY POPULATION................................................................................................55
7.1
Inclusion Criteria .....................................................................................................55
7.2
Exclusion Criteria ....................................................................................................56
8.0
STUDY DRUG .............................................................................................................58
8.1
Study Drug Administration: Pevonedistat With Venetoclax and Azacitidine ............58
8.2
Reference/Control Therapy: Venetoclax Plus Azacitidine ........................................59
8.3
Dose Modification Guidelines..................................................................................60
8.3.1
Criteria for Retreatment and Dose Delays ........................................................60
8.3.2
Dose Modification for Hematologic Toxicities.................................................62
8.3.3
Dose Modification for Nonhematologic Toxicities...........................................64
8.4
Excluded Concomitant Medications and Procedures ................................................65
8.5
Permitted Concomitant Medications and Procedures................................................66
8.6
Precautions and Restrictions ....................................................................................67
8.7
Management of Clinical Events ...............................................................................68
8.7.1
Azacitidine ......................................................................................................68
8.7.2
Pevonedistat in Combination With Azacitidine ................................................68
8.7.3
Venetoclax.......................................................................................................69
8.7.4
Guidance for Clinical Assessment and Management of Hemodynamic 
Compromise ....................................................................................................69
8.7.5
Management of Cytopenia and Infection..........................................................70
8.7.6
Guidance Management of Leukostasis.............................................................71
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8.7.7
Guidance for Management of Extravasation.....................................................71
8.8
Blinding and Unblinding..........................................................................................71
8.9
Description of Investigational Agents ......................................................................71
8.9.1
Pevonedistat ....................................................................................................71
8.9.2
Venetoclax.......................................................................................................72
8.9.3
Azacitidine ......................................................................................................72
8.10
Preparation, Reconstitution, and Dispensing ............................................................72
8.11
Packaging and Labeling...........................................................................................73
8.12
Storage, Handling, and Accountability.....................................................................73
8.13
Other Protocol-Specified Materials ..........................................................................73
9.0
STUDY CONDUCT......................................................................................................73
9.1
Study Personnel and Organizations..........................................................................73
9.2
Arrangements for Recruitment of Patients................................................................74
9.3
Treatment Group Assignments.................................................................................74
9.4
Study Procedures.....................................................................................................74
9.4.1
Informed Consent ............................................................................................74
9.4.2
Reconsent of Patients.......................................................................................74
9.4.3
Patient Demographics......................................................................................75
9.4.4
Inclusion/Exclusion Confirmation....................................................................75
9.4.5
Medical History...............................................................................................75
9.4.6
Physical Examination ......................................................................................75
9.4.7
Patient Height..................................................................................................76
9.4.8
Patient Weight .................................................................................................76
9.4.9
Modified Charlson Comorbidity Index Assessment .........................................76
9.4.10
ECOG Performance Status...............................................................................76
9.4.11
Vital Signs.......................................................................................................76
9.4.12
ECG ................................................................................................................76
9.4.13
Chest X-Ray....................................................................................................76
9.4.14
Pregnancy Test ................................................................................................76
9.4.15
Concomitant Medications and Procedures........................................................77
9.4.16
AEs .................................................................................................................77
9.4.17
Enrollment.......................................................................................................77
9.4.18
Clinical Laboratory Evaluations.......................................................................77
9.4.19
Disease Assessment.........................................................................................79
9.4.20
Biomarker, Pharmacodynamic, and PK Samples..............................................81
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9.4.21
PK Measurements............................................................................................84
9.4.22
Pharmacodynamic Measurements....................................................................84
9.5
Completion of Study Treatment (for Individual Patients) .........................................85
9.6
Completion of Study (for Individual Patients)..........................................................86
9.7
Discontinuation of Treatment With Study Drug and Patient Replacement................86
9.8
Withdrawal of Patients From Study .........................................................................87
9.9
Study Compliance....................................................................................................87
9.10
Posttreatment Follow-up Assessments (EFS, Response, and OS) .............................88
9.11
Posttrial Access .......................................................................................................88
9.12
Duration of PTA......................................................................................................88
10.0
ADVERSE EVENTS ....................................................................................................88
10.1
Definitions...............................................................................................................88
10.1.1
PTE Definition ................................................................................................88
10.1.2
AE Definition ..................................................................................................88
10.1.3
SAE Definition................................................................................................89
10.2
Procedures for Recording and Reporting AEs and SAEs..........................................90
10.3
Monitoring of AEs and Period of Observation .........................................................91
10.4
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events.........91
10.5
Procedures for Reporting Product Complaints or Medication Errors (Including 
Overdose) ................................................................................................................91
10.6
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities...........92
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................92
11.1
Takeda Safety Monitoring........................................................................................92
12.0
DATA HANDLING AND RECORDKEEPING............................................................92
12.1
eCRFs......................................................................................................................92
12.2
Record Retention .....................................................................................................93
13.0
STATISTICAL METHODS..........................................................................................94
13.1
Statistical and Analytical Plans ................................................................................94
13.1.1
Analysis Sets ...................................................................................................94
13.1.2
Analysis of Demographics and Other Baseline Characteristics.........................94
13.1.3
Efficacy Analysis.............................................................................................95
13.1.4
PK Analysis.....................................................................................................96
13.1.5
Pharmacodynamic Analysis.............................................................................97
13.1.6
Safety Analysis................................................................................................97
13.2
IA and Event Size Re-estimation..............................................................................98
13.3
Determination of Sample Size..................................................................................98
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14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................98
14.1
Study-Site Monitoring Visits ...................................................................................98
14.2
Protocol Deviations..................................................................................................99
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................99
15.0
ETHICAL ASPECTS OF THE STUDY......................................................................100
15.1
IRB and/or IEC Approval ......................................................................................100
15.2
Patient Information, Informed Consent, and Patient Authorization.........................101
15.3
Patient Confidentiality ...........................................................................................102
15.4
Publication, Disclosure, and Clinical Trial Registration Policy...............................102
15.4.1
Publication.....................................................................................................102
15.4.2
Clinical Trial Registration..............................................................................103
15.4.3
Clinical Trial Results Disclosure....................................................................103
15.5
Insurance and Compensation for Injury..................................................................103
16.0
REFERENCES............................................................................................................104
LIST OF IN-TEXT TABLES
Table 6.a
Primary and Secondary Endpoints for Disclosures .............................................54
Table 8.a
Dose Adjustments for Venetoclax ......................................................................63
Table 8.b
Dose Reductions for Azacitidine ........................................................................63
Table 8.c
Excluded Concomitant Medications and Procedures...........................................65
Table 8.d
Management of Potential Venetoclax Interactions With CYP3A and P-gp 
Inhibitors for Patients With AML.......................................................................66
Table 8.e
Concomitant Medications and Procedures Permitted During the Study...............67
Table 9.a
Hematology Tests ..............................................................................................78
Table 9.b
Complete Serum Chemistry and Tumor Lysis Syndrome Panels ........................78
Table 9.c
Select Serum Chemistry Panel ...........................................................................78
Table 9.d
Urinalysis With Microscopic Analysis ...............................................................79
Table 9.e
Response Criteria...............................................................................................80
Table 9.f
Specimen Name in the Schedule of Procedures ..................................................82
LIST OF APPENDICES
Appendix A
Modified Schedule of Events ...........................................................................107
Appendix B
Study Diagram.................................................................................................109
Appendix C
Responsibilities of the Investigator...................................................................110
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Appendix D
Investigator Consent to Use of Personal Information........................................112
Appendix E
ECOG Scale for Performance Status ................................................................113
Appendix F
Body Surface Area...........................................................................................114
Appendix G
Excluded Moderate and Strong CYP3A Inducers.............................................115
Appendix H
New York Heart Association Classification of Cardiac Disease........................116
Appendix I
Modified Charlson Comorbidity Index.............................................................117
Appendix J
Formula for ANC Calculation ..........................................................................118
Appendix K
Modification of Diet in Renal Disease Study Equation.....................................119
Appendix L
Schedule of Events...........................................................................................120
Appendix M
Protocol History...............................................................................................127
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2.0
STUDY SUMMARY
Name of Sponsor(s): Takeda Development Center 
Americas, Inc. (TDCA)
Compound: Pevonedistat
(TAK-924; MLN4924)
Title of Protocol: A Randomized, Open-label, Controlled, 
Phase 2 Study of Pevonedistat, Venetoclax, and Azacitidine 
Versus Venetoclax Plus Azacitidine in Adults With Newly 
Diagnosed Acute Myeloid Leukemia Who Are Unfit for 
Intensive Chemotherapy
EudraCT No.: 2019-003117-33
Study Number: Pevonedistat-2002
Phase: 2
Study Design:
General eligibility may be assessed before the formal screening period if it is part of standard clinical practice. 
However, per the Schedule of Events, 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 150 patients with newly diagnosed acute myeloid leukemia (AML) will be enrolled 
in this study. At enrollment, patients will be randomized at a 1:1 ratio to receive (either pevonedistat + venetoclax + 
azacitidine [Arm A] or venetoclax + azacitidine [Arm B]) in 28-day treatment cycles. Patients will be stratified by age 
(18 to <75 years; ≥75 years) and AML subtype (de novo AML; secondary AML). Secondary AML (sAML) is defined 
as AML after myelodysplastic syndromes (MDS) or myeloproliferative neoplasms (MPN), or therapy-related AML 
(t-AML) following cytotoxic therapy, and/or radiotherapy for a malignant or nonmalignant disease.
Patients, including those who achieve complete remission (CR) or complete remission with incomplete blood count 
recovery (CRi), may receive study treatment until they experience unacceptable toxicity, relapse, or progressive 
disease (PD) as defined in this study. Patients 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 the patient is still 
receiving clinical benefit from the treatment, based on the clinical judgment of the investigator, and the continuation is 
endorsed by the sponsor’s project clinician (or designee). Patients who continue in the study under these conditions 
must be reconsented before continuing to receive study treatment. Patients may choose to discontinue treatment at any 
time.
Patients will attend the end-of-treatment visit 30 days (+10 days) after the last dose of study drug or before the start of 
subsequent antineoplastic therapy if that occurs sooner. Patients who discontinue study treatment without evidence of 
PD will enter event-free survival (EFS) follow-up and have study visits every month for assessments inclusive of 
physical examination, clinical blood tests, and upon relapse from CR or CRi, and bone marrow aspirate (BMA) 
sampling. Patients will enter overall survival (OS) follow-up (contacted every 3 months to document subsequent 
therapies and survival status) when they have relapsed from CR or CRi, failed to achieve CR or CRi, or started 
subsequent therapy. The Modified Schedule of Events (Appendix A) will be followed upon implementation of 
Protocol Amendment 4. Long-term follow up visits (EFS/response and OS) will no longer be required; patients will 
complete an End of Treatment visit 30 (+10) days after the last dose of study drug(s) or before the start of 
antineoplastic therapy if that occurs sooner.
Disease response assessments will be based on the Revised Recommendations of the International Working Group for 
Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic 
Trials in Acute Myeloid Leukemia [1]. Formal disease assessments for study endpoints will be determined based on 
local BMA blast counts and transfusions, and central laboratory data. Disease response assessments will be carried out 
by the investigator. BMA samples will be collected at screening, during treatment, and during follow-up for blast 
count evaluation (to inform disease burden assessment). BMAs also will be used to analyze tumor cytogenetics, to 
analyze baseline somatic mutations and other molecular characteristics, to assess impact of therapy on depth and 
durability of response at predetermined time points using molecular techniques, and to identify treatment emergent 
mutations. Samples will be collected and analyzed from patients in both treatment arms. After implementation of 
Protocol Amendment 4, there will be no follow-up period and collection of BMA samples will not be required, except 
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as indicated per standard of care.
Sparse sampling for the determination of pevonedistat plasma concentrations will be collected from each patient in the 
investigational arm pevonedistat + venetoclax + azacitidine (Arm A) to contribute to a population pharmacokinetics 
(PK) analysis of pevonedistat co-administered with venetoclax and azacitidine.
Adverse events and Eastern Cooperative Oncology Group (ECOG) performance status will be assessed; 
electrocardiograms, clinical laboratory values, and vital signs measurements 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 5.0, effective 27 November 2017 [2].
Primary Objective:
The primary objective of the study is to determine whether the combination of pevonedistat + venetoclax + azacitidine 
improves EFS compared with venetoclax + azacitidine in patients with newly diagnosed AML who are unfit for 
intensive chemotherapy. EFS is defined as the time from study randomization to the date of failure to achieve CR/CRi 
(ie, discontinuing treatment without achieving CR/CRi), relapse from CR or CRi, or death from any cause, whichever 
occurs first [3].
Secondary Objectives:
Key Secondary Objective: To determine whether the combination of pevonedistat + venetoclax + azacitidine 
improves OS when compared with venetoclax + azacitidine in patients with newly diagnosed AML who are unfit for 
intensive chemotherapy.
Other Secondary Objectives:

To assess 30- and 60-day mortality rates in both treatment arms.

To determine whether the combination of pevonedistat + venetoclax + azacitidine improves the rate of CR, 
composite complete remission (CCR [CR + CRi]), overall response rate (ORR [CR + CRi + partial remission 
(PR)]), CR + partial recovery of blood cells (CRh); and leukemia response rate (CR + CRi + PR + morphological 
leukemia-free state [MLFS, marrow CR (mCR)]), compared with venetoclax + azacitidine.

To determine whether the combination of pevonedistat + venetoclax + azacitidine improves duration of CR and 
CRi compared with venetoclax + azacitidine.

To determine whether the combination of pevonedistat + venetoclax + azacitidine shortens time to first CR, CRi, 
or PR when compared with venetoclax + azacitidine.

To collect plasma concentration-time data for pevonedistat in combination with venetoclax + azacitidine to 
contribute to the future population PK and exposure response (safety/efficacy) analyses of pevonedistat.
Patient Population: Adults with newly diagnosed AML who are unfit for treatment with intensive chemotherapy.
Number of Patients:
Approximately 150 patients will be randomized in a 1:1 
ratio to receive either the investigational combination of 
pevonedistat + venetoclax + azacitidine (Arm A) or the 
control arm of venetoclax + azacitidine (Arm B).
Number of Sites: 
Approximately 85 sites globally.
Dose Level(s):
The treatment cycle for both arms in the study is 28 days.
Investigational Arm (Arm A):

Pevonedistat (20 mg/m2, IV infusion) on Days 1, 3, and 
5
PLUS

Venetoclax (400 mg) on Days 1 through 28 in Cycle 1.
Ramp-up (Cycle 1 only): venetoclax will be 
Route of Administration:
Pevonedistat: intravenous (IV) infusion.
Venetoclax: oral administration.
Azacitidine: IV or subcutaneous (SC), per 
investigator’s choice.
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administered at a dose of 100 mg on Day 1; 200 mg on 
Day 2; thereafter, at 400 mg on Days 3 through 28.
Venetoclax (400 mg) on Days 1 through 28 of a 28-day 
cycle at Cycle 2 and beyond. If remission is confirmed 
in Cycle 1 or thereafter, Venetoclax (400 mg) can be 
administered on Days 1 through 21 of a 28-day cycle in 
subsequent cycles, to prevent potential prolonged 
myelosuppression and treatment delays. If, in the 
opinion of the investigator, venetoclax (400 mg) 
administered on Days 1 through 21 (of a 28-day cycle) 
is well tolerated, venetoclax (400 mg) may be 
administered at full dosing frequency (400 mg given on 
Days 1 through 28 of 28-day cycle) in subsequent 
cycles.
PLUS

Azacitidine (75 mg/m2, IV or SC) on Days 1 through 7 
or Days 1 through 5, 8, and 9.
Control Arm (Arm B):

Venetoclax (400 mg) on Days 1 through 28 in Cycle 1.
Ramp-up (Cycle 1 only): venetoclax will be 
administered at a dose of 100 mg on Day 1; 200 mg on 
Day 2; thereafter, at 400 mg on Days 3 through 28.
Venetoclax (400 mg) on Days 1 through 28 of a 28-day 
cycle at Cycle 2 and beyond. If remission is confirmed 
in Cycle 1 or thereafter, Venetoclax (400 mg) can be 
administered on Days 1 through 21 of a 28-day cycle in 
subsequent cycles, to prevent potential prolonged 
myelosuppression and treatment delays. If, in the 
opinion of the investigator, venetoclax (400 mg) 
administered on Days 1 through 21 (of a 28-day cycle) 
is well tolerated, venetoclax (400 mg) may be 
administered at full dosing frequency (400 mg given on 
Days 1 through 28 of 28-day cycle) in subsequent 
cycles.
PLUS

Azacitidine (75 mg/m2, IV or SC) on Days 1 through 7 
or Days 1 through 5, 8, and 9.
Duration of Treatment: Patients, including those who 
achieve CR, may receive study treatment until they 
experience unacceptable toxicity, relapse, or experience PD 
as defined in this study. Patients 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 the patient is still receiving clinical 
benefit from the treatment, based on the clinical judgment 
of the investigator, and the continuation is endorsed by the 
sponsor’s project clinician (or designee). Patients may
choose to discontinue treatment at any time.
Period of Evaluation:
Up to approximately 3 years.
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Posttrial Access: Where permitted by local regulations, 
and if the responsible investigator and the sponsor agree 
that the patient would derive benefit from or would be 
harmed without continued access to the assigned treatment 
regimen, patients may continue to receive access to the 
assigned treatment regimen after the study is completed. If a 
posttrial access (PTA) program should become an option 
for a patient, then pevonedistat + venetoclax + azacitidine 
or venetoclax + azacitidine, depending on treatment arm 
assignment, may be provided through the PTA program.
Main Criteria for Inclusion:

Male or female patients aged ≥18 years with newly diagnosed AML, morphologically confirmed (World Health 
Organization [WHO] criteria 2008). Patients may have newly diagnosed primary de novo AML or secondary 
AML (sAML) defined as AML after myelodysplastic syndromes (MDS) or myeloproliferative neoplasms (MPN), 
or therapy-related AML (t-AML) following cytotoxic therapy, and/or radiotherapy for a malignant or 
nonmalignant disease.

To qualify for this study, a patient must be considered to be unfit for treatment with a standard Ara-C and 
anthracycline induction regimen due to age or co-morbidities defined by 1 of the following:
≥75 years of age
OR
≥18 to <75 years of age with at least one of the following:

ECOG performance status of 2 or 3.

Severe cardiac disorder (eg, congestive heart failure requiring treatment, ejection fraction ≤50%, or chronic 
stable angina).

Severe pulmonary disorder (eg, carbon monoxide lung diffusion capacity ≤65% or forced expiratory volume 
in 1 second ≤65%).

Creatinine clearance <45 mL/min (but ≥30 mL/min as part of general eligibility criteria).

Hepatic disorder with total bilirubin >1.5 times the upper limit of the normal range (ULN).

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):

Total bilirubin ≤1.5 times ULN except in patients with Gilbert’s syndrome. Patients with Gilbert’s syndrome 
may enroll with direct bilirubin ≤3 times the ULN of the direct bilirubin. Elevated indirect bilirubin due to 
posttransfusion hemolysis is allowed.

Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3.0 times the ULN.

Creatinine clearance ≥30 mL/minute (calculated by the Modification of Diet in Renal Disease Study 
equation).

Albumin >2.7 g/dL.

White blood cell count (WBC) <25 × 109/L. Patients who are cytoreduced with leukapheresis or with hydroxyurea 
may be enrolled if they meet the eligibility criteria before starting therapy.
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Main Criteria for Exclusion:

History of myeloproliferative neoplasm with BCR-ABL1 translocation or AML with BCR-ABL1 translocation.

Genetic diagnosis of acute promyelocytic leukemia.

Extramedullary AML without evidence of bone marrow involvement.

Prior treatment with hypomethylating agents for AML (treatment with hypomethylating agents for prior 
myelodysplastic syndromes [MDS] is not exclusionary).

Eligible for intensive chemotherapy and/or allogeneic stem cell transplantation.

Patients with either clinical evidence of or history of central nervous system involvement by AML.

Diagnosed or treated for another malignancy (except for adequately-treated carcinoma in situ of any organ or 
nonmelanoma skin cancer) within 1 year before randomization or previously diagnosed with another malignancy 
and have any evidence of residual disease that may compromise the administration of pevonedistat, venetoclax or 
azacitidine. Prior MDS is also allowed, but the patient cannot have received treatment for MDS within 14 days 
before first dose of any study drug.

Patient has a WBC count ≥25 × 109/L.

Patient with known hypersensitivity to pevonedistat, venetoclax, or azacitidine, and/or their excipients.

Uncontrolled HIV infection.

Patient is known to be positive for hepatitis B or C infection, with the exception of those with an undetectable viral 
load within 3 months.

Known hepatic cirrhosis.

Treatment with strong cytochrome P450 (CYP)3A4 inducers within 14 days before the first dose of the study drug.

Patients with the following will be excluded: uncontrolled intercurrent illness including, but not limited to known 
cardiopulmonary disease defined as unstable angina, clinically significant arrhythmia, congestive heart failure 
(New York Heart Association Class III or IV), and/or ST elevation myocardial infarction within 6 months before 
first dose, or severe symptomatic pulmonary hypertension requiring pharmacologic therapy, severe uncontrolled 
ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system 
abnormalities.

Patient who has chronic respiratory disease that requires continuous oxygen, or significant history of renal, 
neurologic, psychiatric, endocrinologic, metabolic, immunologic, hepatic, or cardiovascular disease that, in the 
medical judgement of the investigator, may compromise the delivery of pevonedistat, venetoclax, and/or 
azacitidine.

Patients with uncontrolled coagulopathy or bleeding disorder.
Main Criteria for Evaluation and Analyses:
Primary Endpoint: The primary endpoint of the study is EFS. EFS is defined as the time from study randomization to 
the date of failure to achieve CR/CRi (ie, discontinuing treatment without achieving CR/CRi), relapse from CR or 
CRi, or death from any cause, whichever occurs first [3].
Key Secondary Endpoint: The key secondary endpoint is OS.
Other Secondary Endpoints:

30- and 60-day mortality rates.

Disease response rates: CR; CCR (CR + CRi); ORR (CR + CRi + PR); CR + CRh (CRh is defined as <5% of blasts 
in the bone marrow, no evidence of disease, and partial recovery of peripheral blood counts [platelets >50,000/µL 
and absolute neutrophil count >500/µL]); and leukemia response rate (CR + CRi + PR + MLFS [mCR]).

Duration of CR and CRi.

Time to first CR, CRi, and PR.

Pevonedistat plasma concentration-time data.
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Statistical Considerations:
The study was originally designed to have approximately 85 EFS events to provide 80% power to detect a hazard ratio 
(HR) of 0.58 (median EFS of 19 months in the investigational pevonedistat + venetoclax + azacitidine arm [Arm A] 
versus 11 months in the venetoclax + azacitidine control arm [Arm B], assuming exponential distribution of EFS), 
using stratified log-rank test at one-sided 5% significance level. One interim analysis (IA) was planned in the original 
design. Following decisions and changes made within the pevonedistat program after read-out from Study 
Pevonedistat-3001, the IA was removed. Instead, final analysis (FA) will be conducted after Pevonsdistat-2002 
Protocol Amendment 4 is implemented. Study enrollment was complete with 164 patients randomized.
Sample Size: 
Approximately 150 patients will be randomized in a 1:1 ratio to receive either the combination of pevonedistat + 
venetoclax + azacitidine or venetoclax + azacitidine.
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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 supplier list in the study manual. The identified vendors will perform specific 
study-related activities either in full or in partnership with the sponsor.
3.2
Principal Investigator/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, and study participation. The signatory coordinating investigator will be required to 
review and sign the clinical study report (CSR) and by doing so agrees that it accurately describes 
the results of the study.
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3.3
List of Abbreviations
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AML
acute myeloid leukemia
ANC
absolute neutrophil count
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AUC
area under the plasma concentration-time curve
BCRP
breast cancer resistance protein
BH3
BCL-2 homology
BMA
bone marrow aspirate
BSA
body surface area
BUN
blood urea nitrogen
CCR
composite complete remission
CDL
cullin-dependent ubiquitin E3 ligases
CFR
Code of Federal Regulations
CL
clearance
CLL
chronic lymphocytic leukemia
Cmax
maximum observed plasma concentration
CMML
chronic myelomonocytic leukemia
COVID-19
coronavirus disease 2019
CR
complete response; complete remission
CrCl
creatinine clearance
CRh
complete remission + partial recovery of blood cells
(CRh is defined as <5% of blasts in the bone marrow, no evidence of disease, and partial recovery 
of peripheral blood counts [platelets >50,000/µL and absolute neutrophil count >500/µL])
CRi
complete remission with incomplete blood count recovery
CRL
cullin-RING ligase
CRO
contract research organization
CSR
clinical study report
CYP
cytochrome P450
DDI
drug-drug interaction
DLT
dose-limiting toxicity
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
EFS
event-free survival
EMA
European Medicines Agency
EORTC
European Organisation for Research and Treatment of Cancer
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EORTC-QLQ
European Organisation for Research and Treatment of Cancer-Quality of Life Questionnaire
EOT
end-of-treatment
EQ 5D-5L
EuroQoL 5 dimensions 5 levels (a standardized instrument for measuring generic health status)
EU
European Union
FA
final analysis
FDA
Food and Drug Administration
GCP
Good Clinical Practice
G-CSF
granulocyte-colony stimulating factor
GI
gastrointestinal
GLP
Good Laboratory Practices
HNSTD
highest nonseverely toxic dose
HR
hazard ratio
HR MDS
higher-risk MDS
HRQOL
health-related quality of life
HSCT
hematopoietic stem cell transplant
IA
interim analysis
IB
Investigator’s Brochure
IC
intensive chemotherapy
IC50
half maximal inhibitory concentration
ICF
informed consent form
ICH
International Council for Harmonisation
IDH2
isocitrate dehydrogenase 2
IDMC
independent data monitoring committee
IEC
independent ethics committee
INR
international normalized ratio
IRB
institutional review board
IRC
independent review committee
ITT
intent-to-treat
IV
intravenous(ly)
IWG
International Working Group
IWRS
interactive web response system
K-M
Kaplan-Meier
LDH
lactate dehydrogenase
LFT
liver function test
mCR
marrow complete remission
MDRD
Modification of Diet in Renal Disease
MDS
myelodysplastic syndromes
MedDRA
Medical Dictionary for Regulatory Activities
MHRA
Healthcare products Regulatory Agency
MLFS
morphological leukemia-free state
MOA
mechanism of action
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MPN
myeloproliferative neoplasm
MRD
minimal residual disease
MRP2
multidrug resistance-associated protein 2
MTD
maximum tolerated dose
MUGA
multigated acquisition
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
NOXA
BH3-only protein involved in regulating cell death decisions
OATP
organic anion-transporting protein
ORR
overall response rate
OS
overall survival
PD
progressive disease
P-gp
P-glycoprotein
PK
pharmacokinetics
PMDA
Pharmaceuticals and Medical Devices Agency of Japan
PP
Per-protocol
PR
partial response, partial remission
PRO
patient-reported outcome
PT
Preferred Term
PTA
posttrial access
PTE
pretreatment event
Q
intercompartmental distributional clearance
QTc
corrected QT interval
RBC
red blood cell
RFS
relapse-free survival
SAE
serious adverse event
sAML
secondary acute myeloid leukemia
SAP
statistical analysis plan
SC
subcutaneous(ly)
SmPC
Summary of Product Characteristics
SOE
schedule of events
SUSAR
suspected unexpected serious adverse reaction
t-AML
therapy-related AML
TEAE
treatment-emergent adverse event
TLS
tumor lysis syndrome
UK
United Kingdom
ULN
upper limit of the normal range
UPS
ubiquitin-proteasome system
US
United States
USPI
US prescribing information
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Vc
central volume
Vp
peripheral volume
WBC
white blood cell
WHO
World Health Organization
3.4
Corporate Identification
TDCA
Takeda Development Center Americas, Inc
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4.0
INTRODUCTION
4.1
Background
4.1.1
Scientific Background
4.1.1.1
Disease Under Treatment
Acute myeloid leukemia (AML) is an aggressive hematologic malignancy characterized by the 
infiltration of the bone marrow, blood, and, occasionally, other organs by clonal and often highly 
proliferative, abnormally/poorly differentiated hematopoietic cells termed myeloblasts [6]. There 
is enormous cytogenetic and molecular heterogeneity within AML, which greatly impacts 
prognosis [6]. AML is curable in approximately 40% of younger adults (<60 years of age) but only 
in about 10% of patients 60 years of age or older, whose median survival has historically been less 
than a year [6] but appears to be improving with the advent of combination regimens involving 
newer, targeted therapies [7-10]. Increasing age is associated with factors predictive of early death, 
for example, poor performance status or various comorbidities, and of treatment resistance, for 
example, adverse cytogenetics, secondary AML, or the multidrug-resistant phenotype [3]. AML 
has conventionally been treated with intensive chemotherapy (IC), including an anthracycline and 
cytarabine; however, IC often cannot be safely administered to older patients. With the use of IC, 
complete remission (CR) rates range from 60% to 80% among younger adults [3]. In fit, older 
patients able to receive IC, CR rates are around 50%. Unfortunately, relapse of AML is common, 
except in certain genetically defined subsets, and the 5-year overall survival (OS) of patients with 
relapsed AML is exceedingly poor (no more than approximately 10%). Recent therapeutic 
advances, eg, the isocitrate dehydrogenase 2 (IDH2) inhibitor enasidenib (Idhifa), may have 
improved the outlook for a minority of patients [11].
4.1.1.2
Study Drug: Pevonedistat
Pevonedistat (also known as TAK 924 and MLN4924; hereinafter referred to as pevonedistat) is a 
first-in-class, small molecule inhibitor of neural precursor cell expressed, developmentally 
down-regulated 8 (NEDD8)-activating enzyme (NAE) under development for the treatment of 
malignancies. The NEDD8 conjugation (neddylation) pathway is responsible for much of the 
regulated protein turnover in the cell, which is similar to the ubiquitin-proteasome system (UPS). 
However, UPS is known to regulate myriad processes in eukaryotic cells, whereas only a limited 
number of neddylation substrates have been described to date. Bortezomib for injection, a drug 
that acts by inhibiting the 26S proteasome, has proven utility in the treatment of multiple myeloma 
and mantle cell lymphoma. Therefore, it is anticipated that other compounds directed against 
different components of the UPS and/or the NEDD8 conjugation pathway may prove useful in the 
treatment of malignancies. NAE, E1 ligase, is an essential component of the NEDD8 conjugation 
pathway, which initiates the neddylation to protein substrates. Specifically, NEDD8 conjugation 
to cullin-dependent ubiquitin E3 ligases (CDLs) is necessary for their activity. The ligases in the 
NEDD8 conjugation pathway control the timely neddylation of many substrate proteins with 
important roles in cell cycle progression and signal transduction. The ubiquitination/neddylation 
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of proteins targets them for proteasomal degradation. These cellular processes are relevant to 
tumor cell growth, proliferation, and survival; as such, inhibitors of NAE activity may be of 
therapeutic value in the treatment of various cancers by inhibiting the degradation of a subset of 
proteins that are regulated by the proteasome. In nonclinical studies, treatment of cells with 
pevonedistat results in the accumulation of CDL substrates, followed by a DNA damage response 
and cell death. Pevonedistat treatment results in tumor growth inhibition in mouse tumor xenograft 
models of solid tumors, lymphoma, and AML.
4.2
Nonclinical Experience
The pharmacologic profile of pevonedistat has been thoroughly characterized in vitro and in vivo. 
These studies demonstrate that pevonedistat is a potent, reversible, and selective mechanism-based 
inhibitor of NAE activity. Pevonedistat inhibited viability of a wide variety of tumor cell lines and 
showed antitumor activity when administered as a single-agent and in combination with other 
treatments in immunocompromised xenograft-bearing mice.
Pevonedistat has an acceptable nonclinical absorption, distribution, metabolism, and excretion 
profile. Plasma clearance varied in nonclinical species, and plasma half-life varied from 1 hr in rats 
to 15 hours in monkeys. Pevonedistat was highly bound in whole blood and plasma of mice, rats, 
dogs, monkeys, and humans. No metabolite unique to humans was observed in vitro. In vitro, 
pevonedistat is predominantly metabolized by the cytochrome P450 (CYP)3A4. However, a 
clinical drug-drug interaction (DDI) study (C15011) conducted for pevonedistat in combination 
with a strong CYP3A4/P-glycoprotein (P-gp) inhibitor, itraconazole, did not show any clinically 
meaningful change in the pevonedistat exposure. Pevonedistat is neither an inhibitor of CYP1A2, 
2C9, 2C19, 2D6, or 3A4/5 (IC50 >100 µM and Ki >50 µM) nor an inducer of CYP1A2, 2B6, or 
3A4/5 (at up to 30 µM) but is a weak inhibitor of CYP2B6 and 2C8 (IC50 = 97.6 and 23.1 µM, 
respectively). The major elimination pathway of pevonedistat in animals is through the hepatic 
route. Pevonedistat is a substrate of P-gp, breast cancer resistance protein (BCRP), and multidrug 
resistance-associated protein 2 (MRP2) in Caco-2 cells. Pevonedistat is also a weak inhibitor of 
P-gp (IC50 = 41.2 to 56.0 µM) and BCRP (IC50 = 6.3 µM) but not of MRP2 (IC50 >200 µM). 
Additionally, pevonedistat is not a substrate for organic anion-transporting proteins (OATPs).
Findings in the GLP-compliant, definitive toxicity studies in Sprague-Dawley rats and beagle dogs 
generally were comparable and predominantly related to the pharmacologic effects (or sequelae 
thereof) of pevonedistat. The primary dose-limiting toxicities (DLTs) in both species were 
considered to be gastrointestinal (GI) injury with electrolyte and hydration perturbations and 
complications linked with bone marrow and lymphoid tissue depletion. Additionally, an acute 
phase-like response was observed in both species and consisted of alterations in body temperature, 
increased serum fibrinogen, decreased serum albumin, alterations in circulating neutrophils, and in 
dogs, increased neutrophil infiltration in multiple tissues. Cardiovascular effects in the dog and rat
were also noted and consisted of decreased blood pressure (mean and systolic), increased heart rate, 
and shortened partial response (PR) and QT intervals followed by an increased diastolic blood 
pressure. In rats, increased blood pressure was noted 24 hours postdose. The highest nonseverely 
toxic dose (HNSTD) (administered cyclically) was 15 mg/kg (300 mg/m2) in dogs and 60 mg/kg 
(360 mg/m2) in rats. At the HNSTD, the most sensitive indicators of pevonedistat-related effects in 
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both species included GI tract functional perturbations (emesis [dogs only] and abnormal excreta), 
hematologic alterations, and acute phase response (increased fibrinogen and decreased albumin). 
The primary pevonedistat-related effects are considered to be monitorable and reversible. Toxicity 
(cardiopulmonary effects, renal changes, and hepatic injury) noted at higher doses in rats (≥120 
mg/kg) appeared to be correlated with sepsis.
Pevonedistat was not mutagenic in the bacterial reverse mutation assay (Ames assay). In a 
combined micronucleus test and comet assay study in Sprague-Dawley rats, pevonedistat induced 
chromosome damage in immature erythrocytes in the bone marrow micronucleus test and showed 
evidence of DNA damage in the liver in the comet assay. Based on the mechanism of action of 
pevonedistat (DNA re-replication) and following biological effects on the cell cycle, these 
findings are not unexpected.
Microscopic changes were observed in male and female reproductive organs in repeat-dose 
toxicology studies (including vacuolation, degeneration, and necrosis of the seminiferous tubules 
of the testes and luminal cellular debris in the epididymides of both rats and dogs, incomplete 
corpora lutea in rats, and neutrophilic infiltrates in the ovary in dogs); therefore, pevonedistat 
likely represents a reproductive hazard. In a non-GLP compliant embryo-fetal development study 
in Sprague-Dawley rats (daily subcutaneous [SC] doses of 0, 5, 15, 30, and 45 mg/kg on gestation 
days 6 to 17), pevonedistat at ≥15 mg/kg resulted in maternal and/or fetal toxicity (including 
maternal decreased food consumption, postimplantation loss, decreased fetal body weights, 
external and skeletal fetal malformations); no maternal or fetal toxicity was observed at 5 mg/kg.
Detailed information regarding the nonclinical pharmacology and toxicology of pevonedistat is 
provided in the current Investigator’s Brochure (IB).
4.3
Clinical Experience
The clinical development program of pevonedistat began with 4 phase 1 studies of the 
monotherapy pevonedistat at doses ranging from 25 to 278 mg/m2:

Study C15001 in patients with solid tumors.

Study C15002 in patients with lymphoma or multiple myeloma.

Study C15003 in patients with AML, high-grade myelodysplastic syndromes (MDS), or acute 
lymphoblastic leukemia.

Study C15005 in patients with melanoma.
In these studies, toxicity involving multi organ failure on Cycle 1 Day 1, including SAEs of renal, 
hepatic, and cardiac failure, some with a fatal outcome, was identified at doses equal to or above 
110 mg/m2. On the basis of a comprehensive review of the available phase 1 clinical safety data at 
the time, a revised risk mitigation strategy, including limiting the dose to no higher than 100 
mg/m2 for single-agent administration, was implemented across the pevonedistat program in 
October 2012. The current understanding of the renal toxicity observed with pevonedistat suggests 
that it is not a primary event but is likely secondary to hemodynamic changes occurring in the 
setting of a type of acute phase response.
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Beyond the first four phase 1 studies, an approximate 436 additional patients have been treated 
with pevonedistat in single-agent and combination studies, and no Cycle 1 Day 1 SAEs as 
previously described have been observed. These patients received pevonedistat at a dose of 50 to 
100 mg/m2 as a single-agent, a dose of 15 to 30 mg/m2 in combination with different standard of 
care therapies, or a dose of 8 mg/m2 to 20 mg/m2 in combination with a CYP3A inhibitor.
As of 22 January 2019, a total of 647 patients are estimated to have received at least 1 dose of 
pevonedistat in the overall clinical development program. Fourteen clinical studies include the 
previously mentioned 4 monotherapy studies. Current development is focused on pevonedistat in 
combination with standard clinically available therapies in hematologic malignancies and solid 
tumors. These studies in patients with advanced malignancies are as follows:

Combination therapy of pevonedistat + standard of care in patients with solid tumors:
–
C15010 (phase 1b) is complete: evaluated the maximum tolerated dose (MTD) of 
pevonedistat plus docetaxel, gemcitabine, or the combination of carboplatin and paclitaxel.
–
C15011 (phase 1) is complete: evaluated the effects of fluconazole and itraconazole 
CYP3A-mediated inhibition (DDI) on the pharmacokinetics (PK), safety, and tolerability 
of pevonedistat.
–
Pevonedistat-1013 (phase 1) is complete: Part A assessed the mass balance, PK, and 
metabolism of [14C]-pevonedistat, and Part B evaluated the efficacy of pevonedistat in 
combination with docetaxel or the combination of carboplatin and paclitaxel.
–
Pevonedistat-1014 (phase 1) is ongoing: Part A (enrollment is complete) is evaluating the 
effects of pevonedistat on the corrected QT (QTc) interval. Part B is evaluating the efficacy 
of pevonedistat in combination with docetaxel or the combination of carboplatin and 
paclitaxel.
–
Pevonedistat-1015 (phase 1) is ongoing: Part A (enrollment is complete) is evaluating the 
effects of rifampin (DDI) on PK of pevonedistat. Part B is evaluating the efficacy of 
pevonedistat in combination with docetaxel or the combination of carboplatin and 
paclitaxel.

Combination therapy of pevonedistat + azacitidine in patients with hematologic malignances:
–
C15009 (phase 1b) is complete: The study established the MTD of pevonedistat in 
combination with azacitidine and assessed the safety and tolerability of the combination in 
treatment-naïve patients with AML ≥60 years.
For patients treated with pevonedistat 20 mg/m2 and azacitidine 75 mg/m2 (total: N = 61), 
most common treatment-emergent adverse events (TEAEs) in Study C15009 were 
constipation (48%), followed by fatigue and nausea (both 42%), anemia (41%), febrile 
neutropenia and thrombocytopenia (both 31%), decreased appetite (30%), pyrexia (27%), 
and neutropenia, diarrhea, and vomiting (25% each). Three patients received pevonedistat 
30 mg/m2 and azacitidine 75 mg/m2; 2 patients each event had an adverse event (AE) of 
thrombocytopenia, pneumonia, alanine aminotransferase (ALT) increased, blood 
creatinine increased, aspartate aminotransferase (AST) increased, and blood alkaline 
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phosphatase (ALP) increased. All other AEs in this treatment group were experienced by 1 
patient for each event.
Overall, responses of CR, complete remission with incomplete blood count recovery (CRi), 
and PR were observed in 31 out of 61 (51%) of patients treated at the MTD (20 mg/m2) of 
the safety population and 31 out of 52 patients (60%) of patients in the MTD 
response-evaluable population.
–
Pevonedistat-1012 (phase 1/1b) is complete: evaluated the safety and tolerability of the 
pevonedistat monotherapy and the combination of pevonedistat + azacitidine in adult East 
Asian population with AML or MDS; determined the recommended phase 2/3 doses of the 
combination; and characterized the PK of the monotherapy and the combination.
In the single-agent pevonedistat arm (N = 10), the most common TEAEs were pneumonia 
(7 patients [70%]), febrile neutropenia (6 patients [60%]), and constipation, nausea, 
stomatitis, insomnia (all 4 patients [40%] each). In the combination arm (N = 13), the most 
common TEAEs were constipation (9 patients [69%]), vomiting (7 patients [54%]), back 
pain (6 patients [46%]), and nausea and anemia (5 patients [38%] each).
Overall, 6 (31.6%) of 19 patients in the response-evaluable population of the study 
(pevonedistat single-agent or in combination with azacitidine) achieved a response (CR, 
CRi, or PR for patients with AML; CR, PR, hematologic improvement, or marrow 
complete remission [mCR] for patients with higher-risk [HR] MDS).
–
Pevonedistat-1016 (phase 1/1b) is ongoing: The study is enrolling patients with HR MDS, 
chronic myelomonocytic leukemia (CMML), and AML who have severe renal or mild 
hepatic impairment. The objectives of the study are to determine the PK (of pevonedistat), 
disease response, safety, and MTD (of the combination therapy) for this population.
–
Pevonedistat-2001 (phase 2) is ongoing (enrollment is complete): The primary objective of 
the study is to assess whether the combination of pevonedistat + azacitidine versus the 
azacitidine monotherapy improves event-free survival (EFS) in a patient population with 
HR MDS, CMML, and AML.
–
Pevonedistat-3001 (phase 3) is ongoing: The study is being conducted to assess efficacy 
and safety of pevonedistat + azacitidine, versus the monotherapy azacitidine, as a first-line 
treatment for patients with HR MDS, CMML, and AML. The primary endpoint is overall 
response rate (ORR) by Cycle 6 and the key secondary endpoint is EFS.
4.4
PK
Population PK analysis was conducted using data from pevonedistat single-agent studies (C15001, 
C15002, C15003, and C15005) and pevonedistat in combination with standard of care 
chemotherapy (C15009 and C15010) in patients with solid tumor or hematologic malignancies. 
The database contained 335 patients contributing 3768 PK observations. Pevonedistat plasma 
concentration-time profiles were well described by a 2-compartment model with linear elimination. 
Body surface area (BSA) was an important predictor of clearance (CL), intercompartmental 
distributional clearance (Q), and both central and peripheral volumes (Vc and Vp, respectively). 
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For a typical patient with a BSA of 1.73 m2, an alpha half-life of 1.27 hours and a beta (elimination) 
half-life of 7.85 hours are estimated. Concurrent administration of carboplatin and paclitaxel 
decreased the CL of pevonedistat by approximately 44%, translating to an approximately 80% 
higher pevonedistat exposure area under the plasma concentration-time curve (AUC) during 
co-administration with carboplatin and paclitaxel, consistent with pevonedistat concentration data 
observed in Study C15010. Co-administration with azacitidine, gemcitabine, or docetaxel did not 
appear to affect pevonedistat exposures. Race, sex, age, tumor type (hematologic vs solid), mild or 
moderate renal impairment (creatinine clearance [CrCl] ≥30 mL/min), and mildly impaired liver 
function (ie, total bilirubin ≤ upper limit of the normal range [ULN] and ALT/AST ≤2.5 times the 
ULN), had no impact on pevonedistat PK.
An open-label DDI Study C15011 evaluated the CYP3A-mediated inhibitory effects of 
fluconazole and itraconazole on pevonedistat PK in patients with advanced solid tumors. The 
results indicated that itraconazole, a strong CYP3A/P-gp inhibitor, and fluconazole, a moderate 
CYP3A inhibitor, had no clinically meaningful effects on pevonedistat PK.
For detailed information please consult the current IB.
4.5
Pharmacodynamics
As detailed in Section 4.2, nonclinical studies have identified specific pathways that are modulated 
by NAE inhibition in cultured cells and animal models. Several specific pharmacodynamic assays 
have been developed to track the biological consequences of NAE inhibition in patient tumor, skin, 
and blood, such as immunohistochemistry analysis of CDT1 and NRF2 levels as well as 
upregulation of NRF2 dependent transcripts. A total of 8 NRF2 dependent genes were identified in 
preclinical studies as induced by pevonedistat-mediated NAE inhibition: ATF3, GCLM, GSR, 
MAG1, NQO1, SLC7A11, SRXN1, and TXNRD1. Increases in these 8 genes have been 
demonstrated following ex vivo dosing of human whole blood with pevonedistat and following 
treatment of cell lines with pevonedistat and, therefore, represent a pharmacodynamic marker 
downstream of NAE inhibition. Analysis of patient samples from pevonedistat clinical studies 
provide evidence of pathway inhibition downstream of NAE and biological activity of 
pevonedistat in whole blood, skin, and tumor tissue (solid tumor or AML bone marrow–derived 
blasts) at all doses tested in pharmacodynamic assays. These doses range from 15 to 261 mg/m2
across various single-agent, phase 1 pevonedistat trials, including the monotherapy studies 
(C15001, C15002, C15003, C15005) and study C15011 (DDI study). Analysis of postdose tumor 
and skin samples demonstrated an increase in expression of CDT1 and/or NRF2 consistent with 
stabilization of these proteins following decreased CDL activity consequent to NAE inhibition by 
pevonedistat. However, substantial heterogeneity was observed between patients in the degree of 
CDT1 and NRF2 induction in both tumor and skin tissues, with no apparent correlation between 
pevonedistat dose and observed fold change. Across studies (C15001, C15002, C15003, C15005, 
and C15011), gene expression analysis done on peripheral blood mononuclear cells identified 
NQO1 and SLC7A11 as the genes with the largest and most consistent increases among all 8 
NAE-regulated transcriptional targets analyzed. These data support the use of these 2 genes as 
appropriate pharmacodynamic markers of pevonedistat activity going forward.
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Inhibition by venetoclax efficiently disrupts Bcl-2 signaling in cells and rapidly induces multiple 
hallmarks of apoptotic cell death in Bcl-2-dependent human tumor cell lines (NDA 208573: 
Pharmacology Review, 26 March 2016). This include induction of cytochrome C release and cl. 
caspase activation. In addition, venetoclax had no effect on the viability of BAX-/-BAK-/-MEFs 
cells, indicating that these Bcl-2 family effectors are required for the cell killing activity of this 
Bcl-2–selective inhibitor. In this study, pharmacodynamic assessment will be performed to 
determine changes in the relative expression levels of BCL2, BCLXL, MCL1, BAX, BAK, and 
apoptosis-related proteins between pre- and posttreatment bone marrow aspirate (BMA) or 
peripheral blood samples in both bulk leukemia and leukemic stem/progenitor cells. As mentioned 
in Section 4.6.2, myeloid leukemia cell differentiation protein (MCL-1, a pro-survival Bcl-2 
family member) upregulation is thought to be a primary mode of resistance to venetoclax. 
Preclinical studies suggest that pevonedistat may work to prevent venetoclax resistance through 
degradation of MCL-1. In addition, pevonedistat inhibits NEDD8-activating enzyme, thereby 
preventing ubiquitination of c-Myc (and other proteins). Elevated c-Myc causes transactivation of 
proapoptotic factors like BCL-2 homology 3 (BH3)-only protein involved in regulating cell death 
decisions (NOXA). NOXA neutralizes prosurvival proteins like MCL-1 and subsequently leads to 
activation of the pro-apoptotic proteins BAX and BAK, leading to a lowered threshold to apoptosis 
and thereby maintaining sensitivity to venetoclax and navitoclax. Importantly, NOXA knockdown 
provides substantial protection from pevonedistat-induced apoptosis in AML lines [12]. Therefore 
MCL-1, c-Myc, NOXA, BAX and BAK may represent pharmacodynamic biomarkers in the 
combination of pevonedistat and venetoclax.
For detailed information please consult the current IB.
4.6
Rationale for the Proposed Study
Venetoclax is a potent, selective and orally bioavailable small molecule inhibitor of BCL-2 and 
has shown promising anti-leukemia activity in patients with relapsed or refractory chronic 
lymphocytic leukemia (CLL) as monotherapy and modest single-agent activity in select subtypes 
of AML [13-15]. Venetoclax is currently United States (US) Food and Drug Administration (FDA) 
approved for the treatment of patients with CLL with del(17)(p13.1) and for patients with AML, in 
combination with either low-dose cytarabine or hypomethylating agents (eg, azacitidine or 
decitabine) [4,16].
The combination of venetoclax + hypomethylating agents is emerging as a new standard of care 
for older patients with newly diagnosed AML who are unfit for standard intensive chemotherapy 
[4]. Venetoclax, in combination with either decitabine or azacitidine, is being studied in an 
ongoing clinical trial to evaluate the safety and efficacy of the respective combinations [17] in 
patients with untreated AML who are ≥65 years of age and unfit for chemotherapy. Beginning 
with a short ramp-up phase of venetoclax to the target dose, patients received venetoclax at a dose 
of 400 mg, 800 mg, or 1200 mg daily, along with standard dosing of decitabine intravenous (IV) 
(20 mg/m2 × 5 days) or azacitidine IV/SC (75 mg/m2 × 7 days). To date, 145 patients with a 
median age of 74 years (range, 65 to 86 years) have been treated. For 49% of patients, cytogenetics 
were a poor risk, and 25% of patients had secondary AML (sAML) (either after 
MDS/myeloproliferative neoplasm [MPN] or with prior chemotherapy). Nausea (43%), 
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thrombocytopenia (38%), neutropenia (34%), and decreased white blood cell (WBC) count (26%) 
were the most common AEs related to the venetoclax treatment. The CR/CRi rate for the entire 
cohort was 66% with a median duration of CR/CRi of 11.0 months. In the subgroup of patients 
with secondary AML, the CR/CRi rate was 65%. The 30-day and 60-day mortality rates were 3% 
and 8%, respectively. The median OS for the entire cohort was 17.5 months (95% CI, 12.3 months 
to upper limit not reached). For older, unfit patients with newly diagnosed AML these results 
represent the best survival data reported to date. Emerging clinical and exposure response data 
suggest that the 400 mg dose of venetoclax has the best benefit-risk profile. A phase 3 study of 
venetoclax at a treatment dose of 400 mg plus azacitidine is ongoing.
4.6.1
Rationale for the Study Population
AML is the most common form of acute leukemia in adults. Despite advances in the management 
of hematologic malignancies, the development of novel targeted and immune therapies, and 
improvements in supportive care, the overall outcome for patients with AML remains poor. This 
prognosis can be attributed to several factors, which include increased frequency in an older 
population, poor response to chemotherapy, high relapse rates, and limited effective therapy 
options for patients who have relapsed. Many patients with AML are not candidates for standard 
induction therapy; therefore, strategies to increase duration of response or reduce relapse in this 
patient population are needed. Development of new therapies for patients with AML, who are unfit 
for induction therapy, remains an important unmet clinical need.
A phase 1/2 study (University of Texas MD Anderson Cancer Center) of pevonedistat in 
combination with azacitidine plus venetoclax in patients with secondary AML (sAML) is ongoing.
4.6.2
Rationale for the Combination of Pevonedistat Plus Venetoclax in Patients With 
AML
Hematologic malignancies are highly dependent upon the antiapoptotic protein BCL-2 for survival. 
Overexpression of BCL-2 is associated with tumor initiation, disease progression, and drug 
resistance and is thus a compelling target for antitumor therapy. BCL-2 family proteins mediate an 
intrinsic, mitochondrial apoptosis pathway. BCL-2, BCL-XL, and MCL-1 are antiapoptotic 
BCL-2 family proteins that keep the cell alive, while BH3 proteins BIM, BID, BAD, NOXA, 
PUMA, and HRK are pro-apoptotic BCL-2 family proteins that trigger cell death.
Venetoclax is a potent, selective and orally bioavailable small molecule inhibitor of BCL-2 that 
binds with >1000-fold higher affinity for BCL-2 than for BCL-XL or MCL-1 [18]. Venetoclax has 
shown promising antileukemia activity in patients with previously untreated as well as relapsed or 
refractory CLL as monotherapy and modest single-agent activity in select subtypes of AML 
[13,18,19]; venetoclax is currently approved by the FDA for the treatment of patients with CLL 
with or without del(17)(p13.1).
There is notable preclinical rationale for the combination of venetoclax with pevonedistat in the 
treatment of AML. In one study, pevonedistat was shown to exert synergistic cytotoxic effect 
when combined with Bcl-2 inhibitors such as venetoclax or navitoclax [12,20]. This was likely 
mediated indirectly by pevonedistat-induced accumulation of the cullin-RING ligase (CRL) 
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substrate c-MYC. c-MYC activates the PMAIP1 gene that encodes for NOXA, leading to 
increased NOXA protein, subsequent BAX and BAK activation, and apoptosis. Because NOXA 
neutralizes Mcl-1, which is an established resistance mechanism for patients treated with 
venetoclax-based regimens [21,22], the combination of venetoclax with pevonedistat may help to 
prevent resistance to venetoclax and therefore prolong duration of response.
The combination of venetoclax with either low-dose cytarabine [4,16] or hypomethylating agents 
(eg, azacitidine or decitabine) [9,14] was recently approved by the FDA under accelerated 
approval and is emerging as a new standard of care for older patients with newly diagnosed AML 
who are unfit for standard intensive chemotherapy.
4.6.3
Therapeutic Rationale for the Combination of Pevonedistat, Venetoclax and 
Azacitidine in Patients With AML
Pevonedistat is a first-in-class, small molecule inhibitor of NAE, which catalyzes the rate-limiting 
step in the process of attachment of NEDD8 to CRLs, an important class of E3 ubiquitin ligases 
[23]. Inhibiting protein neddylation is a more selective way of inhibiting protein degradation than 
global proteasome inhibition [24]. In AML cell lines and primary specimens, pevonedistat 
treatment stabilized key NAE targets, inhibited nuclear factor kappa B activity, and induced DNA 
damage and reactive oxygen species generation [25]. In a comprehensive protein profiling study 
using a FLT3-ITD + AML cell line, 47 proteins were significantly up-regulated following 
pevonedistat treatment, mostly established cullin-dependent substrates [26]. Only 36% (17/47) of 
these proteins were also pharmacodynamically increased by pevonedistat treatment of melanoma 
cells, suggesting that protein modulation by pevonedistat may be tumor type-dependent. 
Azacitidine antagonizes ribonucleotide reductase, which is induced by pevonedistat, and the 
combination was found to synergize in induction of apoptosis of a variety of AML cell lines via 
this mechanism [26]. These findings were recapitulated in a FLT3-ITD + AML xenograft model. 
In a phase 1 clinical trial of pevonedistat monotherapy in patients with relapsed/refractory AML or 
MDS (n = 72), single-agent activity was observed, with achievement of CR in 2 patients and PR in 
2 patients receiving pevonedistat IV on Days 1, 3 and 5 of a 21-day cycle, and PR in 2 patients 
receiving the drug on Days 1, 4, 8, and 11 of a 21-day cycle [27].
Following this signal, a phase 1 study of pevonedistat in combination with azacitidine was 
conducted in 61 patients ≥60 years of age with previously untreated AML [19]. Patients were 
required to have at least 1 feature that made them poor candidates for IC; these included age 
≥75 years, history of an antecedent hematologic disorder, adverse karyotype or an Eastern 
Cooperative Oncology Group (ECOG) performance status of 2. The combination was 
well-tolerated, and the recommended phase 2 dose was established at 20 mg/m2/day of 
pevonedistat, administered on Days 1, 3 and 5, in combination with 75 mg/m2/day of azacitidine, 
administered on Days 1 through 5, 8, and 9, of a 28-day cycle. The ORR was 60% among 
52 evaluable patients, of whom 26 (43%) patients had secondary AML. There were no meaningful 
differences between the response rates (ORR, CR, Cri, and PR rates) between patients with de 
novo AML and secondary AML; however, there was a trend towards improved OS among the 
patients with secondary AML (median, 11.2 months vs 5.6 months for de novo AML, 7 months for 
the whole cohort). The median duration of remission was 8.3 months. 61% of the responses 
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occurred by Cycle 2, and 90% by Cycle 4. Interestingly, 6 of 9 patients with TP53 mutations 
responded (3 CR/CRi, 3 PR) with a median duration of 8.46 months; 4 of the 9 patients remained 
on study for >10 cycles. Concurrent administration of azacitidine did not affect the PK of 
pevonedistat.
On the basis of the clinical benefit observed with pevonedistat + azacitidine [19], improved 
efficacy of venetoclax in AML when combined with azacitidine [4], and preclinical evidence of 
synergy between venetoclax and pevonedistat [12,20], it is thought that combination therapy with 
pevonedistat + venetoclax + azacitidine may result in improved outcomes compared with either 
combination alone in patients with newly diagnosed AML who are unfit for standard intensive 
chemotherapy.
4.6.4
Rationale for Dose and Schedule of Study Drugs
The selection of pevonedistat doses 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 azacitidine 
75 mg/m2 given on Days 1 through 5, 8, and 9, in 28-day treatment cycles. In this study, 
azacitidine will be administered on 75 mg/m2 on Days 1 through 7, or Days 1 through 5, 8, and 9, 
the dose regimen of azacitidine in an ongoing phase 1/2 study (University of Texas MD Anderson 
Cancer Center) of pevonedistat in combination with azacitidine plus venetoclax. The 
recommended dose in the ongoing study is pevonedistat 20 mg/m2 on Days 1, 3, and 5 in 
combination with azacitidine at 75 mg/m2 for 7 days plus venetoclax 400 mg daily in 28-day 
treatment cycles. If remission is confirmed in Cycle 1 or thereafter, Venetoclax (400 mg) can be 
administered on Days 1 through 21 of a 28-day cycle in subsequent cycles, to prevent potential 
prolonged myelosuppression and treatment delays. If, in the opinion of the investigator, 
venetoclax (400 mg) administered on Days 1 through 21 (of a 28-day cycle) is well tolerated, 
venetoclax (400 mg) may be administered at full dosing frequency (400 mg given on Days 1 
through 28 of 28-day cycle) in subsequent cycles.
4.7
Potential Risks and Benefits
4.7.1
Pevonedistat
There are potential risks in the pevonedistat program that require monitoring. While these 
toxicities may be severe or life-threatening, it is anticipated that they can be managed by clinical 
monitoring and intervention. Patients will be monitored for these potential toxicities and for 
unanticipated toxicities when they receive pevonedistat during the study and for at least 30 days 
after their last dose.
4.7.1.1
Potential Risks From Phase 1 Studies
Events have been reported in completed phase 1 studies primarily at doses and schedules 
substantially higher than doses administered in current pevonedistat clinical studies. These events 
are being considered potential risks for the doses and schedules in the current studies, as follows:

Multi-organ failure that could result in death in the setting of an acute phase response.
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
Renal failure.

The events of multi-organ failure (hepatic, renal, and cardiac) with a fatal outcome, and 
renal failure alone, have been reported at doses of pevonedistat ranging from 110 to 
278 mg/m2.

Cardiac arrhythmias.

All events were supraventricular arrhythmias; all except 1 were unrelated. The events of 
supraventricular arrhythmias were all considered as unrelated to pevonedistat except for 
1 event of atrial fibrillation that occurred in a patient with a history of risk factors for 
cardiac disease.

Myelosuppression with increased susceptibility to infection, bleeding, and anemia.

GI toxicity including or resulting in dehydration and/or electrolyte imbalance.

Hypophosphatemia.
4.7.1.2
Potential Risks Confounded by Underlying Disease or Malignancy
Events have been reported from clinical trials that are confounded by the patient’s underlying 
medical condition, including malignancy. These events are noted in the absence of randomized, 
controlled data:

Fatigue.

Chills.

Decreased appetite.

Neutropenia.

Anemia.

Thrombocytopenia.

Febrile neutropenia.

GI bleeding.

All events were assessed by the investigator as unrelated; the majority occurred in the 
setting of thrombocytopenia.

Multi-organ failure in the setting of infection.
4.7.1.3
Potential Risks Primarily Based on Findings From Animal Studies
Potential risks that are derived from findings in animal studies in rats and dogs include:

Myocardial degeneration and thrombosis.

Pulmonary hypertension.
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
Cardiovascular changes that could result in tachycardia, decreased or increased systolic blood 
pressure, and increased diastolic blood pressure.

Enteropathy (including dehydration and electrolyte loss) with secondary sepsis.

Effects on the testes and ovaries that represent a reproductive hazard including sterility.

Increased developmental risk to the 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 doses.

Prolongation of the activated partial thromboplastin time (aPTT).

Local tissue injury when administered SC.
It is possible that pevonedistat will have toxicities that were not observed in or predicted from the 
studies completed in rats and dogs, or have not yet been identified in patients, which may be severe 
or fatal.
For detailed information, please consult the current IB.
4.7.1.4
Additional Safety Considerations
Cycle 1 Day 1 Toxicity/Multi-Organ Failure
A comprehensive review of the clinical trial safety data has shown that Cycle 1 Day 1 toxicity 
involving multi-organ failure, including SAEs of renal, hepatic, and cardiac failure, some with a 
fatal outcome, has been observed in phase 1, single-agent pevonedistat studies at doses equal to or 
above 110 mg/m2.
The sponsor’s current understanding of the renal toxicity observed with pevonedistat suggests that 
it is not a primary event but is likely secondary to hemodynamic changes occurring in the setting of 
a type of acute phase response.
Nonclinical investigative activities were undertaken to better understand the potential physiology 
behind the Cycle 1 Day 1 events observed with pevonedistat dosing. A model in which a 
minimally toxic, single dose of pevonedistat was administered with tumor necrosis factor alpha 
had several hallmarks associated with septic and/or cytokine-induced shock. The overall time 
course and target organs affected in this nonclinical model also appeared to closely mimic those 
observed in clinical Cycle 1 Day 1 events at single-agent doses ranging from 110 to 278 mg/m2.
In October 2012, a revised risk mitigation strategy limiting the dose to no higher than 50 mg/m2 for 
dosing on Days 1, 3, and 5 and no higher than 100 mg/m2 for dosing on Days 1, 4, 8, and 11 or 1, 8, 
and 15 for all studies for single-agent administration was implemented across the pevonedistat 
program. As of January 2019, approximately 436 additional patients have been treated with 
pevonedistat in single-agent and combination studies, and no Cycle 1 Day 1 SAEs as described 
above have been observed. These patients received pevonedistat at a dose of 50 to 100 mg/m2 as a 
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single-agent, a dose of 15 to 30 mg/m2 in combination with different standard of care therapies, or 
a dose of 8 to 20 mg/m2 in combination with a CYP3A inhibitor.
The schedule for pevonedistat infusion of Days 1, 3, and 5 was chosen for further studies.
Increases in Serum Creatinine
At doses equal to or below 50 mg/m2 on a Days 1, 3, and 5 schedule or below 100 mg/m2 on a Days 
1, 4, 8, and 11 schedule, there have been reports of changes in serum creatinine from baseline 
levels of Grade 0 to Grade 1, and from baseline levels of Grade 1 to Grade 2.
Increases in Liver Enzymes and Biochemical Tests
Grade 1 to Grade 4 increases in AE related to liver function analyses (such as for liver 
transaminases [up to Grade 4], bilirubin [up to Grade 3], and ALP [up to Grade 3]), have been 
noted following administration of pevonedistat in patients with advanced malignancies receiving 
pevonedistat as a single-agent and in combination with standard of care cytotoxic therapies. 
Among the single-agent studies, a Grade 4 AE occurred that was related to liver function (ALT 
increased). In Study C15009, in patients with AML treated with pevonedistat in combination with 
azacitidine, Grade 4 increases for AEs related to liver function analyses occurred as DLTs (ALT 
increased, AST increased), except for 1 event that was not assessed as a DLT (AST increased). In 
Study C15010 in patients with solid tumors treated with pevonedistat in combination with 
docetaxel, gemcitabine, or carboplatin plus paclitaxel, and also in Study C15011, a DDI study, 
AEs related to liver function analyses up to Grade 3 were observed.
Drug Interactions and Other Forms of Interactions
The risk of DDIs between pevonedistat and concomitantly administered drugs is currently 
informed by available nonclinical and clinical data.
In vitro, pevonedistat is metabolized via hydroxylation and oxidation, predominantly by CYP3A4 
with a small contribution from CYP2D6 (approximately 3%). An open-label DDI study, C15011, 
evaluated the CYP3A-mediated inhibitory effects of fluconazole and itraconazole on pevonedistat 
PK in patients with advanced solid tumors. The results indicated that itraconazole, a strong 
CYP3A/P-gp inhibitor, and fluconazole, a moderate CYP3A inhibitor, had no clinically 
meaningful effects on pevonedistat PK. On the basis of these findings, use of CYP3A/P-gp 
inhibitors in patients receiving pevonedistat is permitted. Strong CYP3A inducers are prohibited 
for patients receiving pevonedistat. For individual studies in the pevonedistat clinical program, 
reference should be made to the respective protocols for specific information relating to excluded 
and permitted medications.
In vitro, pevonedistat does not inhibit the activities of CYP1A2, 2C9, 2C19, 2D6, and 3A4/5, but 
weakly and reversibly inhibits both CYP2B6 and 2C8; it does not induce CYP1A2, 2B6, and 
3A4/5. Thus, pevonedistat is not expected to affect the PK of drugs that are metabolized by these 
CYP enzymes.
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Pevonedistat is also a substrate for the drug efflux transporters, P-gp and BCRP, and a weak 
inhibitor of P-gp and BCRP-mediated transport. Known BCRP inhibitor (ie, cyclosporine) is 
currently excluded, but limited use is permitted only if clinically necessary and no suitable 
alternative exists in clinical studies of pevonedistat. Additional in vitro transport studies showed 
that pevonedistat is not a substrate of the hepatic OATP, but it can inhibit OATP-mediated uptake 
of E3S and simvastatin and lovastatin from some donors. On the basis of these data and the 
recommended clinical dose range, pevonedistat is unlikely to affect the PK of other drugs that are 
known P-gp, BCRP, or OATP substrates, while the potential exists, albeit low, for drug 
interactions with BCRP inhibitors.
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.
4.7.2
Venetoclax
An ongoing study is evaluating the safety and efficacy of venetoclax in combination with either 
decitabine or azacitidine [17]. Enrolled patients are ≥65 years of age with previously untreated 
AML and who are ineligible for chemotherapy. After a short ramp-up phase of venetoclax to the 
target dose, patients received venetoclax at a dose of 400 mg, 800 mg, or 1200 mg daily, along 
with standard dosing of decitabine IV (20 mg/m2 × 5 days) or azacitidine IV/SC 
(75 mg/m2 × 7 days). At the most recent update, 145 patients have been treated with a median age 
of 74 years (range, 65 to 86 years). Cytogenetics were a poor risk in 49% of patients, and 25% of 
patients have secondary AML (either after MDS/MPN or with prior chemotherapy). The most 
common AEs related to venetoclax were nausea (43%), thrombocytopenia (38%), neutropenia 
(34%), and decreased WBC count (26%). The 30-day and 60-day mortality rates were 3% and 8%, 
respectively. The CR/CRi rate for the entire cohort was 66% with a median duration of CR/CRi of 
11.0 months. In the subgroup of patients with secondary AML, the CR/CRi rate was 65%. The 
median OS for the entire cohort was 17.5 months (95% CI, 12.3 months to upper limit not reached). 
These results represent the best survival data for older, unfit patients with newly diagnosed AML 
yet reported. Emerging clinical and exposure response data have suggested that the 400 mg dose of 
venetoclax has the best benefit-risk profile, and a phase 3 study of venetoclax 400 mg with 
azacitidine is ongoing.
Most Commonly Occurring Adverse Reactions (>10%): Neutropenia, anemia, 
thrombocytopenia, diarrhea, nausea, vomiting, constipation, fatigue, pyrexia, peripheral edema, 
hypokalemia, headache and cough.
Most Commonly Occurring Laboratory Abnormalities (>10%): Hyperkalemia and 
hyperphosphatemia.
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4.7.2.1
Warnings and Precautions
Tumor Lysis Syndrome
Tumor lysis syndrome (TLS), including fatal events and renal failure requiring dialysis, has 
occurred in previously treated CLL patients with high tumor burden when treated with venetoclax. 
Venetoclax can cause rapid reduction in tumor and thus poses a risk for TLS. Changes in blood 
chemistries consistent with TLS that require prompt management can occur as early as 6 to 8 hours 
following the first dose of venetoclax. The risk of TLS is a continuum based on multiple factors, 
including tumor burden and comorbidities. Reduced renal function (CrCl <80 mL/min) further 
increases the risk. Patients should be assessed for risk and should receive appropriate prophylaxis 
for TLS, including hydration and antihyperuricemics. Monitor blood chemistries and manage 
abnormalities promptly. Interrupt dosing if needed. Employ more intensive measures (IV 
hydration, frequent monitoring, hospitalization) as overall risk increases.
Concomitant use of venetoclax with strong or moderate CYP3A inhibitors and P-gp inhibitors 
increases venetoclax exposure, may increase the risk of TLS at initiation and during ramp-up 
phase and may require venetoclax dose adjustment.
Neutropenia
Grade 3 or 4 neutropenia occurred in 41% (98 out of 240) of patients treated with venetoclax. 
Monitor complete blood counts throughout the treatment period. Interrupt dosing or reduce dose 
for severe neutropenia. Consider supportive measures including anitmicrobials for signs of 
infection and use of growth factors (eg, granulocyte-colony stimulating factor [G-CSF]).
Immunization
Do not administer live attenuated vaccines before, during, or after treatment with venetoclax until 
B cell recovery occurs. The safety and efficacy of immunization with live attenuated vaccines 
during or following venetoclax therapy have not been studied. Advise patients that vaccinations 
may be less effective.
Embryo-Fetal toxicity
Given its mechanism of action and findings in animals, venetoclax may cause embryo-fetal harm 
when administered to a pregnant woman. In an embryo-fetal study conducted in mice, 
administration of venetoclax to pregnant animals at exposures equivalent to that observed in 
patients at the recommended dose of 400 mg daily resulted in postimplantation loss and decreased 
fetal weight. There are no adequate and well-controlled studies in pregnant women using 
venetoclax. Advise females of reproductive potential to avoid pregnancy during treatment. If 
venetoclax is used during pregnancy or if the patient becomes pregnant while taking venetoclax, 
the patient should be apprised of the potential hazard to the fetus.
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4.7.2.2
Use in Specific Populations
Renal Impairment
Patients with reduced renal function (CrCl <80 mL/min) are at increased risk of TLS. These 
patients may require more intensive prophylaxis and monitoring to reduce the risk of TLS when 
initiating treatment with venetoclax.
No specific clinical trials have been conducted in patients with renal impairment. Less than 0.1% 
of radioactive venetoclax was detected in urine. No dose adjustment is needed for patients with 
mild-moderate renal impairment (CrCl >30 mL/min) based on the results of population PK 
analysis. A recommended dose has not been determined for patients with severe renal impairment 
(CrCl <30 mL/min) or patients on dialysis.
Hepatic Impairment
No specific clinical trials have been conducted in patients with hepatic impairment; however, 
human mass balance study showed that venetoclax undergoes hepatic elimination. Although no 
dose adjustment is recommended in patients with mild or moderate hepatic impairment based on 
results of a population PK analysis, a trend for increased AEs was observed in patients with 
moderate hepatic impairment; monitor these patients more closely for signs of toxicity during the 
initiation and dose ramp-up phase. A recommended dose has not been determined for patients with 
severe hepatic impairment.
4.7.2.3
Drug Interactions
Venetoclax is predominantly metabolized by CYP3A4/5.
Strong CYP3A Inhibitors
Concomitant use of venetoclax with strong CYP3A inhibitors (eg, ketoconazole, conivaptan, 
clarithromycin, indinavir, itraconazole, lopinavir, ritonavir, telaprevir, posaconazole and 
voriconazole) at initiation and during the ramp-up phase is contraindicated. However, CYP3A4 
inhibitors may be used to manage antifungal prophylaxis with “azole” therapy in neutropenic 
patients (refer to Section 8.3.1.3 and Table 8.d for further details).For patients who have 
completed the ramp-up phase and are on a steady daily dose of venetoclax, reduce the venetoclax 
dose by at least 75% when used concomitantly with strong CYP3A inhibitors (refer to Section 
8.3.1.3 for further details). Resume the venetoclax dose that was used before initiating the CYP3A 
inhibitor 2 to 3 days after discontinuation of the inhibitor.
Co-administration of ketoconazole increased venetoclax maximum observed plasma 
concentration (Cmax) by 2.3-fold and AUC by 6.4-fold.
Moderate CYP3A Inhibitors and P-gp Inhibitors
Avoid concomitant use of moderate CYP3A inhibitors (eg, erythromycin, ciprofloxacin, diltiazem, 
dronedarone, fluconazole, verapamil) or P-gp inhibitors (eg, amiodarone, azithromycin, captopril, 
carvedilol, cyclosporine, felodipine, quercetin, quinidine, ranolazine, ticagrelor) with venetoclax. 
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Consider alternative treatments. If a moderated CYP3A inhibitor or a P-gp inhibitor must be used, 
reduce the venetoclax dose by at least 50% (refer to Section 8.3.1.3 for further details). Monitor 
patients more closely for signs of venetoclax toxicities.
Resume the venetoclax dose that was used before initiating the CYP3A inhibitor or P-gp inhibitor 
2 to 3 days after discontinuation of the inhibitor.
Avoid grapefruit products, Seville oranges, and starfruit during treatment with venetoclax as they 
contain inhibitors of CYP3A.
Co-administration of a single dose of rifampin, a P-gp inhibitor, increased venetoclax Cmax by 106% 
and AUC by 78%.
CYP3A Inducers
Avoid concomitant use of venetoclax with strong CYP3A inducers (eg, carbamazepine, phenytoin, 
rifampin, St. John’s wort) or moderate CYP3A inducers (eg, bosentan, efavirenz, modafinil, 
nafcillin). Consider alternative treatments with less CYP3A induction.
Co-administration of multiple doses of rifampin, a strong CYP3A inducer, decreased venetoclax 
Cmax by 42% and AUC by 71%.
Effects of Venetoclax on Other Drugs
Warfarin: An 18% to 28% increase in warfarin Cmax and AUC of R and S-warfarin is noted after 
single doses of venetoclax and warfarin. International normalized ratio (INR) needs to be 
monitored closely.
P-gp Substrates: In vitro data suggest venetoclax has inhibition potential on P-gp substrates at 
therapeutic dose levels in the gut. Therefore, co-administration of narrow therapeutic index P-gp 
substrates (eg, digoxin, everolimus, and sirolimus) with venetoclax should be avoided. If one must 
be used, administer at least 6 hours before dosing with venetoclax.
4.7.2.4
PK
Following multiple oral doses under fed conditions, the maximum plasma concentration of 
venetoclax was reached 5 to 8 hours after dosing. AUC increased dose proportionally over the 
dose range of 150 to 800 mg.
When given with a low-fat meal, venetoclax exposure increased by approximately 3.4-fold and 
with a high-fat meal, increased by 5.1- to 5.3-fold compared with fasting conditions. Venetoclax 
should be administered with a meal.
Venetoclax is highly protein bound. The mean blood-to-plasma ratio was 0.57. Volume of 
distribution ranged from 256 to 321 L in patients.
The terminal elimination half-life is approximately 26 hours.
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After a single oral administration of 200 mg radiolabeled (14C)-venetoclax dose, >99.9% is 
recovered in the feces with <0.1% in the urine within 9 days. Hepatic elimination is the primary 
route of clearance.
Based on population PK analyses, age, race, sex, and weight do not have a clinically meaningful 
effect on venetoclax clearance.
4.7.3
Azacitidine
Most Commonly Occurring Adverse Reactions (SC or IV Route): Nausea, anemia, 
thrombocytopenia, vomiting, pyrexia, leukopenia, diarrhea, injection site erythema, constipation, 
neutropenia, ecchymosis. The most common adverse reactions by IV route also included petechiae, 
rigors, weakness and hypokalemia.
Adverse Reactions Most Frequently (>2%) Resulting in Clinical Intervention (SC or IV 
Route): Patient discontinuation because of leukopenia, thrombocytopenia, or neutropenia; dose 
held for leukopenia, neutropenia, thrombocytopenia, pyrexia, pneumonia, or febrile neutropenia; 
dose reduced for leukopenia, neutropenia, or thrombocytopenia.
In clinical studies, adverse reactions to azacitidine were qualitatively similar between the IV and 
SC routes of administration. In clinical studies with SC administration of azacitidine, adverse 
reactions of neutropenia, thrombocytopenia, anemia, nausea, vomiting, diarrhea, constipation, and 
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.
4.7.3.1
Warnings and Precautions
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.
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. Azacitidine is contraindicated in patients with advanced malignant hepatic 
tumors.
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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. 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 chronic myelogenous leukemia treated 
with azacitidine and etoposide. Because elderly patients are more likely to have decreased renal 
function, select the dose carefully and monitor renal function.
In patients with cancer, the PK of azacitidine in 6 patients with normal renal function 
(CrCl >80 mL/min) and 6 patients with severe renal impairment (CrCl <30 mL/min) were 
compared following daily SC dosing (Days 1 through 5) at 75 mg/m2/day. Severe renal 
impairment increased azacitidine exposure by approximately 70% after single and 41% after 
multiple SC administrations. This increase in exposure was not correlated with an increase in AEs. 
The exposure was similar to exposure in patients with normal renal function receiving 100 mg/m2. 
Therefore, a Cycle 1 dose modification is not recommended.
However, if unexplained reductions in serum bicarbonate levels to <20 mEq/L occur, reduce the 
dosage by 50% for the next course. Similarly, if unexplained elevations of blood urea nitrogen 
(BUN) or serum creatinine occur, delay the next cycle until values return to normal or baseline and 
reduce the dose by 50% for the next course.
TLS
Azacitidine may cause fatal or serious TLS. TLS may occur despite concomitant use of allopurinol. 
Assess baseline risk, monitor, and treat as appropriate.
Embryo-Fetal Risk
Based on the mechanism of action and findings in animals, azacitidine can cause fetal harm when 
administered to a pregnant woman. Azacitidine administered to pregnant rats via a single 
intraperitoneal dose approximating 8% of the recommended human daily dose caused fetal death 
and anomalies.
DDIs
No formal clinical drug interaction studies with azacitidine have been conducted. An in vitro study 
of azacitidine incubation in human liver fractions indicated that azacitidine may be metabolized by 
the liver. Whether azacitidine metabolism may be affected by known microsomal enzyme 
inhibitors or inducers has not been studied. An in vitro study with cultured human hepatocytes 
indicated that azacitidine at concentrations up to 100 µM (IV Cmax = 10.6 µM) does not cause any 
inhibition of CYP2B6 and CYP2C8. The potential of azacitidine to inhibit other CYP enzymes is 
not known. In vitro studies with human cultured hepatocytes indicate that azacitidine at 
concentrations of 1.0 µM to 100 µM does not induce CYP 1A2, 2C19, or 3A4/5.
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PK
The PK of azacitidine were studied in 6 patients with MDS following a single 75 mg/m2 SC dose 
and a single 75 mg/m2 IV dose. Azacitidine is rapidly absorbed after SC administration; the peak 
plasma azacitidine concentration of 750 ± 403 ng/mL occurred in 0.5 hour. The bioavailability of 
SC azacitidine relative to IV azacitidine is approximately 89%, based on area under the curve. 
Mean volume of distribution following IV dosing is 76 ± 26 L. Mean apparent SC clearance is 167 
± 49 L/hour and mean half-life after SC administration is 41 ± 8 minutes. The AUC and Cmax of SC 
administration of azacitidine in 21 patients with cancer were approximately dose proportional 
within the 25 to 100 mg/m2 dose range. Multiple dosing at the recommended dose-regimen does 
not result in drug accumulation. Published studies indicate that urinary excretion is the primary 
route of elimination of azacitidine and its metabolites. Following IV administration of radioactive 
azacitidine to 5 cancer patients, the cumulative urinary excretion was 85% of the radioactive dose. 
Fecal excretion accounted for <1% of administered radioactivity over 3 days. Mean excretion of 
radioactivity in urine following SC administration of 14C-azacitidine was 50%. The mean 
elimination half-lives of total radioactivity (azacitidine and its metabolites) were similar after IV 
and SC administrations, about 4 hours. The effects of hepatic impairment, gender, age, or race on 
the pharmacokinetics of azacitidine have not been studied.
4.7.4
Summary of Risks and Benefits
While there is notable preclinical rationale for the combination of venetoclax with pevonedistat in 
the treatment of AML as noted in Section 4.6.2, this is the first controlled, comparative study by 
the sponsor in which there will be exposure to humans with the triple combination of pevonedistat, 
venetoclax, and azacitidine. Pevonedistat has been studied with Bcl-2 inhibitors, such as 
venetoclax or navitoclax [12], showing synergistic cytotoxic effects. The combination of 
pevonedistat with azacitidine has been shown to be tolerated in previous studies (ie, C15009 and 
Pevonedistat-1012). The addition of venetoclax may result in additional adverse effects, which are 
either different from those typically seen with pevonedistat and azacitidine regimens or occurring 
at a higher frequency, eg, neutropenia, diarrhea, nausea, upper respiratory tract infections, fatigue, 
musculoskeletal pain, edema, and cough.
The ORR of pevonedistat in combination with azacitidine has been shown in a phase 1 study 
(C15009) in patients with untreated AML not suitable for induction therapy to be 60% of the 
52 evaluable patients (51% in intent-to-treat [ITT] population) [19]. It is postulated that the 
addition of venetoclax to a regimen of pevonedistat plus azacitidine will improve OS and/or 
increase the rate and duration of CR and/or shorten the time to response in patients with AML. 
Combining pevonedistat with venetoclax may help to prevent resistance to venetoclax and 
therefore prolong the duration of response in this population with an unmet medical need.
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5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objective
The primary objective of the study is to determine whether the combination of pevonedistat + 
venetoclax + azacitidine improves EFS compared with venetoclax + azacitidine in patients with 
newly diagnosed AML who are unfit for intensive chemotherapy. EFS is defined as the time from 
study randomization to the date of failure to achieve CR/CRi (ie, discontinuing treatment without 
achieving CR/CRi), relapse from CR or CRi, or death from any cause, whichever occurs first [3].
5.1.2
Secondary Objectives
5.1.2.1
Key Secondary Objective
The key secondary objective is to determine whether the combination of pevonedistat + venetoclax 
+ azacitidine improves OS when compared with venetoclax + azacitidine in an unfit population of 
patients with AML.
5.1.2.2
Other Secondary Objectives
Other secondary objectives are:

To assess 30- and 60-day mortality rates in both treatment arms.

To determine whether the combination of pevonedistat + venetoclax + azacitidine improves 
the rate of CR, composite complete remission (CCR [CR + CRi]), ORR (CR + CRi + PR), 
CR + partial recovery of blood cells ([CRh], and leukemia response rate (CR + CRi + PR + 
morphological leukemia-free state [MLFS, mCR]), compared with venetoclax + azacitidine.

To determine whether the combination of pevonedistat + venetoclax + azacitidine improves 
duration of CR and CRi, compared with venetoclax + azacitidine.

To determine whether the combination of pevonedistat + venetoclax + azacitidine shortens 
time to first CR, CRi, or PR when compared with venetoclax + azacitidine.

To collect plasma concentration-time data for pevonedistat in combination with 
venetoclax + azacitidine to contribute to the future population PK and exposure response 
(safety/efficacy) analyses of pevonedistat.
5.1.3
Safety Objectives
The safety objective is to evaluate the safety of the combination of 
pevonedistat + venetoclax + azacitidine when compared with venetoclax + azacitidine in patients 
with AML who are unfit for induction therapy.
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5.1.4
Exploratory Objectives
Exploratory objectives may be tested in a subset of patients and/or samples. The exploratory 
objectives may include but are not limited to the following:

To evaluate the potential relationship between molecular characteristics of the tumor in terms 
of mutations, gene expression, protein abundance and protein/pathway activation status of 
apoptosis-related and Bcl-2 family-related effector genes/ proteins (eg, BCL2, NOXA 
BCL-XL, MCL1, BAX, BAK, and BH3) at baseline and efficacy and/or safety of the 
combination of pevonedistat +venetoclax + azacitidine versus venetoclax + azacitidine.

To evaluate the impact of treatment on apoptosis and survival mechanisms at the RNA/protein 
levels within both bulk leukemia and leukemic stem/progenitor cells isolated from BMA or 
peripheral blood pre- and posttreatment in both treatment arms.

To determine correlation of cytogenetic abnormalities/risk categories and molecular markers 
associated with poor prognosis in AML, such as FLT3 ITD, RUNX-1, IDH1, EZH2, ASXL1, 
TP53 with response and other clinical endpoints of interest in both treatment arms.

To determine impact of therapy on elimination of leukemic stem cells in pevonedistat + 
venetoclax + azacitidine versus venetoclax + azacitidine.

Identification of new somatic mutations posttreatment initiation and changes in activity of key 
signaling pathways in tumors from patients who initially respond to pevonedistat + venetoclax 
+ azacitidine or venetoclax + azacitidine therapy and then exhibit progressive disease (PD).

Confirm pevonedistat target transcriptional modulation of CRL protein substrates (NQO1, 
SLC7A11) in peripheral blood in pevonedistat + venetoclax + azacitidine arm.

To compare minimal residual disease (MRD) negativity rates and depth with response, EFS, 
relapse-free survival (RFS), OS kinetics and duration of response between study arms.

To compare MRD negativity rates and depths in patients who achieve CR or CRi in both 
treatment arms.

Exploratory endpoints such as evaluating circulating serum proteins and miRNA signatures 
associated with response or resistance to pevonedistat + venetoclax + azacitidine treatment 
will be executed as warranted based on response, to support new emerging hypothesis or 
strategic need.
5.2
Endpoints
5.2.1
Primary Endpoint
The primary endpoint of the study is EFS. EFS is defined as the time from study randomization to 
the date of failure to achieve CR/CRi (ie, discontinuing treatment without achieving CR/CRi), 
relapse from CR or CRi, or death from any cause, whichever occurs first [3].
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5.2.2
Secondary Endpoints
5.2.2.1
Key Secondary Endpoint
The key secondary endpoint of the study is OS.
5.2.2.2
Other Secondary Endpoints
Other secondary endpoints are:

30- and 60-day mortality rates.

Disease response rates:
–
CR rate.
–
CCR (CR + CRi) rate.
–
ORR (CR + CRi + PR) rate.
–
CR + CRh (CRh is defined as <5% of blasts in the bone marrow, no evidence of disease, 
and partial recovery of peripheral blood counts [platelets >50,000/µL and absolute 
neutrophil count (ANC) >500/µL]) rate.
–
Leukemia response rate (CR + CRi + PR + MLFS [marrow CR]).

Duration of CR and CRi.

Time to first CR, CRi, and PR.

Pevonedistat plasma concentration-time data.
5.2.3
Safety Endpoints
The safety endpoints are:

AEs, including SAEs.

Clinical laboratory values.

Electrocardiograms (ECGs).

ECOG performance status.

Vital signs.
5.2.4
Exploratory Endpoints
Exploratory endpoints may be tested in a subset of patients and/or samples. The exploratory 
endpoints may include but not limited to:

Relative gene and protein expression levels of apoptosis-related and Bcl-2 family-related 
effectors such as BCL2, BCLXL, MCL1, BAX, and BAK in pre- and posttreatment samples of 
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both bulk leukemia and leukemic stem/progenitor cells isolated from BMA or peripheral blood 
in pevonedistat + venetoclax + azacitidine versus venetoclax + azacitidine arms.

Screening cytogenetic abnormalities/risk categories and molecular markers associated with 
poor prognosis in AML such as FLT3 ITD, RUNX-1, IDH1, EZH2, ASXL1, TP53, K-RAS 
and correlation with clinical efficacy in both treatment arms.

Clearance of leukemic stem cells in pevonedistat + venetoclax + azacitidine versus venetoclax 
+ azacitidine.

Evaluate potential mechanisms of treatment-emergent resistance, such as identification of new 
somatic mutations posttreatment initiation and changes in activity of key signaling pathways in 
tumors from patients who initially respond to pevonedistat + venetoclax + azacitidine or 
venetoclax + azacitidine therapy and then exhibit PD.

Pevonedistat target transcriptional modulation of CRL protein substrates (NQO1, SLC7A11) 
in peripheral blood in pevonedistat + venetoclax + azacitidine arm.

MRD negativity rates and depth in relation to response, EFS, RFS, OS kinetics and duration of 
response in both treatment arms.

MRD negativity rates and depths in patients who achieve CR or CRi in both treatment arms.
6.0
STUDY DESIGN
6.1
Overview of Study Design
On the basis of the results from the phase 3 Study Pevonedistat-3001, the overall pevonedistat drug 
development program has been modified. These modifications also affect Study 
Pevonedistat-2002 and are captured in the current Protocol Amendment 4; these changes will 
become effective once Protocol Amendment 4 is implemented.
This study is a multicenter, randomized, open-label, controlled phase 2 study of the triple 
combination with pevonedistat, venetoclax, and azacitidine (investigational arm, Arm A) versus 
venetoclax plus azacitidine (control arm, Arm B) in adult patients with AML who are unfit for 
intensive chemotherapy.
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 L), 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. 
Following implementation of Protocol Amendment 4, the frequency of study assessments and 
clinic visits will be reduced as shown in the Modified SOE (Appendix A).
It is expected that approximately 150 patients will be enrolled in this study. At enrollment, patients 
will be randomized at a 1:1 ratio to receive (either pevonedistat + venetoclax + azacitidine [Arm A] 
or venetoclax + azacitidine [Arm B]) in 28-day treatment cycles. Patients will be stratified by age 
(18 to <75 years, ≥75 years) and AML subtype (de novo AML; secondary AML). Secondary AML 
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(sAML) is defined as AML after MDS or MPN, or therapy-related AML (t-AML) following 
cytotoxic therapy, and/or radiotherapy for a malignant or nonmalignant disease.
Investigational Arm (Arm A):
Triple Combination (Pevonedistat + Venetoclax + Azacitidine)

Pevonedistat 20 mg/m2 (IV via 60-minute infusion) on Days 1, 3, and 5.

Venetoclax (400 mg) on Days 1 through 28 in Cycle 1.
Ramp-up (Cycle 1 only): venetoclax will be administered at a dose of 100 mg on Day 1; 
200 mg on Day 2; thereafter, at 400 mg on Days 3 through 28.
Venetoclax (400 mg) on Days 1 through 28 of a 28-day cycle at Cycle 2 and beyond. If 
remission is confirmed in Cycle 1 or thereafter, Venetoclax (400 mg) can be administered on 
Days 1 through 21 of a 28-day cycle in subsequent cycles, to prevent potential prolonged 
myelosuppression and treatment delays. If, in the opinion of the investigator, venetoclax (400 
mg) administered on Days 1 through 21 (of a 28-day cycle) is well tolerated, venetoclax (400 
mg) may be administered at full dosing frequency (400 mg given on Days 1 through 28 of 
28-day cycle) in subsequent cycles.

Azacitidine 75 mg/m2 (IV or SC) dosing on Days 1 through 7 or Days 1 through 5, 8, and 9.
Control Arm (Arm B):
Combination (Venetoclax + Azacitidine)

Venetoclax (400 mg) on Days 1 through 28 in Cycle 1.
Ramp-up (Cycle 1 only): venetoclax will be administered at a dose of 100 mg on Day 1; 
200 mg on Day 2; thereafter, at 400 mg on Days 3 through 28.
Venetoclax (400 mg) on Days 1 through 28 of a 28-day cycle at Cycle 2 and beyond. If 
remission is confirmed in Cycle 1 or thereafter, Venetoclax (400 mg) can be administered on 
Days 1 through 21 of a 28-day cycle in subsequent cycles, to prevent potential prolonged 
myelosuppression and treatment delays. If, in the opinion of the investigator, venetoclax (400 
mg) administered on Days 1 through 21 (of a 28-day cycle) is well tolerated, venetoclax (400 
mg) may be administered at full dosing frequency (400 mg given on Days 1 through 28 of 
28-day cycle) in subsequent cycles.

Azacitidine 75 mg/m2 (IV or SC) dosing on Days 1 through 7 or Days 1 through 5, 8, and 9.
Dose reductions with the study drugs, delays, or changes in the schedule may be allowed if related 
to safety or other unavoidable circumstances as detailed in Section 8.3.
Patients, including those who achieve CR, may receive study treatment until they experience 
unacceptable toxicity, relapse, or PD as defined in this study (see Section 9.4.19 and Table 9.e). 
Patients 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 the patient is still 
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receiving clinical benefit from the treatment. The continuation of treatment will be based on the 
clinical judgment of the investigator and endorsed by the sponsor’s project clinician (or designee). 
If the PD is a true progression of disease after CR/CRi, this would be scored as an event, despite 
the patient remaining on treatment. Patients who continue on study under these conditions must be 
reconsented before continuing study treatment. Patients may choose to discontinue treatment 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. Patients will 
enter EFS follow-up (study visits every month to include physical examination, clinical blood tests, 
BMA sampling to be conducted every 3 months, or upon suspected relapse from CR or CRi). 
Patients will enter OS follow-up (contacted every 3 months to document subsequent therapies and 
survival status).
Disease response assessments will be based on the Revised Recommendations of the International 
Working Group (IWG) for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, 
and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia [1]. Formal disease 
assessments for study endpoints will be determined based on local BMA blast counts and 
transfusions, and central laboratory data. Disease response assessments will be carried out by the 
investigator.
Bone marrow samples (aspirate and biopsy [in accordance with institutional guidelines], see 
Appendix L, Table 1) will be collected at screening, during treatment, and during follow-up for 
blast count evaluation (to inform disease burden assessment). Bone marrow aspirates also will be 
used to analyze tumor cytogenetics, to analyze baseline somatic mutations and other molecular 
characteristics, to assess impact of therapy on depth and durability of response at predetermined 
time points using molecular techniques, and to identify treatment emergent mutations. Samples 
will be collected and analyzed from patients in both treatment arms. After implementation of 
Protocol Amendment 4, there will be no follow-up period and the collection of BMA samples will 
not be required, except as indicated per standard of care.
Sparse sampling for the determination of pevonedistat plasma concentrations will be collected 
from each patient in the investigational arm receiving pevonedistat + venetoclax + azacitidine 
(Arm A) to contribute to a population PK analysis of pevonedistat co-administered with 
venetoclax and azacitidine.
AEs and ECOG performance status will be assessed; ECGs, clinical laboratory values, and vital 
signs measurements 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 5.0, effective 27 November 2017 [2]. Dose 
modification guidelines are presented in Section 8.3.
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6.2
Number of Patients
Approximately 150 patients with AML will be enrolled in this study from approximately 85 study 
sites globally. Enrollment is defined as randomization of a patient into 1 of the study treatment 
arms, following the signing of the informed consent form (ICF).
6.3
Duration of Study
Patient enrollment into this study is complete. After implementation of Protocol Amendment 4, 
patients who remain on treatment will be assessed as indicated in the Modified SOE (Appendix A) 
until discontinuing treatment or they are transitioned off the study (see Section 9.11 for 
information on posttrial access). The total duration of the study is expected to be up to 
approximately 3 years.
Study treatments may continue as long as the patient derives clinical benefit or until 1 or more of 
the following criteria applies:
1. PD. Patients 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 the 
patient is still receiving clinical benefit from the treatment, based on the clinical judgment of 
the investigator, and the continuation is endorsed by the sponsor’s project clinician (or 
designee).
2. Intercurrent illness that precludes further administration of study treatments.
3. Patient withdrawal of consent.
4. General or specific changes in patient condition that render the patient unable to receive further 
study treatments in the judgment of the investigator.
5. Unacceptable toxicity that in the opinion of the investigator makes it unsafe to continue study 
treatments.
6.3.1
Duration of an Individual Patient’s Study Participation
Patients, including those who achieve CR, may receive study treatment until they experience 
unacceptable toxicity, relapse, or PD as defined in this study. Patients 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 the patient is still receiving clinical benefit from the 
treatment, based on the clinical judgment of the investigator, 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. Patients may choose to 
discontinue treatment at any time.
6.3.2
End of Study/Study Completion Definition and Planned Reporting
The study will be considered complete after the FA for EFS has been completed or the study has 
been terminated by the sponsor. The estimated time frame for study completion is approximately 
up to 3 years after the first patient is enrolled. Patients who are still receiving study treatment and 
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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
Primary: EFS
Failure to achieve CR/CRi, relapse from 
CR/CRi, or death
Up to 3 years
Key Secondary: OS
The time from randomization to death from 
any cause
Up to 3 years
Other Secondary:

30- and 60-day mortality rates
The proportion of patients who survive at 
most 30/60 days from the first dose of study 
drug(s).

Disease response rates:
–
CR rate
–
CCR (CR + CRi) rate
–
ORR (CR + CRi + PR) rate
–
CR + CRh rate
–
Leukemia response rate (CR + 
CRi + PR + MLFS [marrow 
CR])
As evaluated by the investigator

Duration of CR and CRi
CR and CRi, time to first documentation of 
PD.

Time to first CR, CRi, and PR
The time from randomization until the first 
CR, CRi, and PR.

Pevonedistat plasma concentration 
data
Pevonedistat concentration at prespecified 
collection time.
AML: acute myeloid leukemia; CR: complete remission; CRh: <5% of blasts in the bone marrow, no evidence of disease, and 
partial recovery of peripheral blood counts (platelets >50,000/µL and absolute neutrophil count >500/µL); CRi: complete remission 
with incomplete blood count recovery; CCR: CR + CRi; EFS: event-free survival; MLFS: morphological leukemia-free state; 
ORR: overall response rate (CR + CRi + PR); OS: overall survival; PD: progressive disease; PR: partial remission.
6.3.4
Total Study Duration
It is anticipated that this study will last for up to approximately 3 years, after the first patient is 
enrolled.
6.3.5
Early Discontinuation of the Study
The study may be discontinued for reasons including medical or ethical reasons affecting the 
continued performance of the study, difficulties in the recruitment of patients, or due to sponsor 
decision.
Results of the registration-enabling Study Pevonedistat-3001 (PANTHER), 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 
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Syndromes, Chronic Myelomonocytic Leukemia, or Low-Blast Acute Myelogenous Leukemia, 
became available in September 2021. The primary endpoint of EFS was not met and no 
statistically significant benefits were observed with pevonedistat treatment. As such, Takeda will 
not pursue further development of pevonedistat in any indication.
Takeda is committed to continuing to provide study treatment to patients who are deriving benefit 
in Study Pevonedistat-2002 until they can be transitioned onto a PTA program (see Section 9.11) 
or discontinue for other protocol-specified reasons. Protocol Amendment 4 clarifies the overall 
study conduct and simplifies the assessments being performed, given the current state of the 
program and goal of decreasing the burden on patients.
7.0
STUDY POPULATION
7.1
Inclusion Criteria
Each patient must meet all the following inclusion criteria to be randomized to treatment:
1. Male or female patients aged ≥18 years.
2. Morphologically confirmed diagnosis of AML (World Health Organization [WHO] criteria
2008). Patients may have newly diagnosed primary de novo AML or sAML, defined as AML 
after MDS or MPN, or t-AML following cytotoxic therapy, and/or radiotherapy for a 
malignant or nonmalignant disease.
3. To qualify for this study, a patient must be considered to be unfit for treatment with a standard 
Ara-C and anthracycline induction regimen due to age or co-morbidities defined by 1 of the 
following:

≥75 years of age.
OR

≥18 to <75 years of age with at least one of the following:

ECOG performance status of 2 or 3.

Severe cardiac disorder (eg, congestive heart failure requiring treatment, ejection 
fraction ≤50%, or chronic stable angina).

Severe pulmonary disorder (eg, carbon monoxide lung diffusion capacity ≤65% or 
forced expiratory volume in 1 second ≤65%).

CrCl <45 mL/min (but ≥30 mL/min as part of general eligibility criteria, see 
Inclusion # 4, Section 7.1).

Hepatic disorder with total bilirubin >1.5 times the ULN.
4. 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):
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
Total bilirubin ≤1.5 times the ULN except in patients with Gilbert’s syndrome. Patients 
with Gilbert’s syndrome may enroll with direct bilirubin ≤3 times the ULN of the direct 
bilirubin. Elevated indirect bilirubin due to posttransfusion hemolysis is allowed.

ALT and AST ≤3.0 times the ULN.

CrCl ≥30 mL/min (calculated by the Modification of Diet in Renal Disease [MDRD] Study 
equation).

Albumin >2.7 g/dL.
5. WBC count <25 × 109/L. Patients who are cytoreduced with leukapheresis or with 
hydroxyurea may be enrolled if they meet the eligibility criteria before starting therapy.
6. Female patients who:

Are postmenopausal for at least 1 year before the screening visit, OR

Are surgically sterile, OR

If they are of childbearing potential, agree to practice 1 highly effective method of 
contraception and 1 additional effective (barrier) method at the same time, from the time of 
signing the informed consent through 6 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 patient. (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. Male patients, even if surgically sterilized (ie, status postvasectomy), who:

Agree to practice effective barrier contraception during the entire study treatment period 
and 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 patient. (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.)
8. Patient must voluntarily sign and date an informed consent, approved by an Independent 
Ethics Committee (IEC)/Institutional Review Board (IRB), prior to the initiation of any 
screening or study specific procedures, 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. History of MPN with BCR-ABL1 translocation or AML with BCR-ABL1 translocation.
2. Genetic diagnosis of acute promyelocytic leukemia.
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3. Eligible for intensive chemotherapy and/or allogeneic stem cell transplantation.
4. Extramedullary AML without evidence of bone marrow involvement.
5. Prior treatment with hypomethylating agents for AML (hypomethylating agent treatment for 
prior MDS is not exclusionary).
6. Patients with either clinical evidence of or history of central nervous system involvement by 
AML.
7. Diagnosed or treated for another malignancy (except for adequately treated carcinoma in situ 
of any organ or nonmelanoma skin cancer) within 1 year before randomization or previously 
diagnosed with another malignancy and have any evidence of residual disease that may 
compromise the administration of pevonedistat, venetoclax or azacitidine. Prior MDS is also 
allowed, but the patient cannot have received treatment for MDS within 14 days before first 
dose of any study drug.
8. Psychological, social, or geographic factors that otherwise preclude the patient from giving 
informed consent, following the protocol, or potentially hamper compliance with study 
treatment and follow-up.
9. Patient has a WBC count ≥25 × 109/L.
10. Known hypersensitivity to pevonedistat, venetoclax, or azacitidine, and/or their respective 
excipients.
11. Female patients who intend to donate eggs (ova) during the course of this study or for 6 months 
after receiving their last dose of study drug(s).
12. Female patients who are both 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.
13. Male patients who intend to donate sperm or father a child during the course of this study or for 
4 months after receiving their last dose of study drug(s).
14. Uncontrolled HIV infection.
Note: Known HIV positive patients who meet the following criteria will be considered 
eligible:

CD4 count >350 cells/mm3.

Undetectable viral load.

Maintained on modern therapeutic regimens utilizing non–CYP-interactive agents.

No history of AIDS-defining opportunistic infections.
15. Patient is known to be positive for hepatitis B or C infection, with the exception of those with 
an undetectable viral load within 3 months (hepatitis B or C testing is not required for 
eligibility assessment).
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16. Known hepatic cirrhosis.
17. Treatment with strong CYP3A4 inducers within 14 days before the first dose of the study drug. 
Strong CYP3A4 inducers are not permitted during this study (see Appendix G).
18. Patients with the following will be excluded: uncontrolled intercurrent illness including, but 
not limited to known cardiopulmonary disease defined as unstable angina, congestive heart 
failure (New York Heart Association Class III or IV [Appendix H]), and/or ST elevation 
myocardial infarction within 6 months before first dose; severe symptomatic pulmonary 
hypertension requiring pharmacologic therapy; severe uncontrolled ventricular arrhythmias, or 
electrocardiographic evidence of acute ischemia or active conduction system abnormalities; 
clinically significant arrhythmia (eg, well-controlled atrial fibrillation would not be an 
exclusion whereas uncontrolled atrial fibrillation would be an exclusion). Patients with 
medical comorbidities that will preclude safety evaluation of the investigational arm 
(pevonedistat + venetoclax + azacitidine [Arm A]) should not be enrolled.
19. Patient who has chronic respiratory disease that requires continuous oxygen, or significant 
history of renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, hepatic, or 
cardiovascular disease that, in the medical judgement of the investigator, may compromise the 
delivery of pevonedistat, venetoclax, and/or azacitidine.
20. Patients with uncontrolled coagulopathy or bleeding disorder.
21. High blood pressure which cannot be controlled by standard treatments.
22. Prolonged rate QTc interval ≥500 msec, calculated according to institutional guidelines.
23. Left ventricular ejection fraction <40%, based on echocardiogram or multigated acquisition 
(MUGA) scan at screening (data to be available within last 3 months of screening).
24. As infection is a common feature of AML, patients with active infection are permitted to enroll 
provided that the infection is under control and no signs of systemic inflammatory response 
beyond low grade fever that makes patient clinically unstable in the opinion of the investigator. 
Patients with uncontrolled infection shall not be enrolled until infection is treated and brought 
under control.
25. Patients who have received an investigational agent (for any indication) within 5 half-lives of 
the agent and until toxicity from this has resolved to Grade 1 or less; if the half-life of the agent 
is unknown, patients must wait 4 weeks before receiving the first dose of study treatment.
8.0
STUDY DRUG
8.1
Study Drug Administration: Pevonedistat With Venetoclax and Azacitidine
All protocol-specific criteria for administration of all 3 study drugs 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).
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The treatment cycle for the investigational triple combination (Arm A) is 28 days. The first dose of 
study drug must be administered within 5 days of randomization on study. The dosing and days 
specified for the triple treatment will occur as follows:

Pevonedistat 20 mg/m2 (via 60-minute IV infusion) on Days 1, 3, and 5.

Venetoclax (400 mg) on Days 1 through 28 in Cycle 1.
Ramp-up (Cycle 1 only): venetoclax will be administered at a dose of 100 mg on Day 1; 
200 mg on Day 2; thereafter, at 400 mg on Days 3 through 28.
Venetoclax (400 mg) will be administered on Days 1 through 28 of a 28-day cycle. If 
remission is confirmed in Cycle 1 or thereafter, venetoclax (400 mg) can be administered on 
Days 1 through 21 of a 28-day cycle in subsequent cycles, to prevent potential prolonged 
myelosuppression and treatment delays.
If, in the opinion of the investigator, venetoclax (400 mg) administered on Days 1 through 21 
(of a 28-day cycle) is well tolerated, venetoclax (400 mg) may be administered at full dosing 
frequency (400 mg given on Days 1 through 28 of 28-day cycle) in subsequent cycles.

Azacitidine (75 mg/m2, IV or SC) on Days 1 through 7 or Days 1 through 5, 8, and 9.
Dosing of the drugs 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 of azacitidine should not be exceeded. If pevonedistat dosing is delayed, 
any remaining doses may only be administered on days when azacitidine is also given. If dosing is 
adjusted, study procedures should be performed on the actual day of dosing. In the investigational 
arm, azacitidine will be administered first followed by pevonedistat. Actual start and stop times of 
the study drug administration, should be recorded accurately. 
The amount of study drug (pevonedistat and/or azacitidine) to be administered will be based on 
BSA. BSA will be calculated using a standard formula (see example in Appendix F) 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.
8.2
Reference/Control Therapy: Venetoclax Plus Azacitidine
Venetoclax is a BCL-2 inhibitor that is used in combination with azacitidine for the treatment of 
newly diagnosed AML in adults who are age 75 years or older, or who have comorbidities that 
preclude use of intensive induction chemotherapy. Details regarding venetoclax, approved for 
patients with AML, are contained in the USPI [16]. The Summary of Product Characteristics 
(SmPC) for venetoclax in Europe is for CLL only [28]; all safety information for AML should be 
referenced to the USPI.
The treatment cycle for the combination control arm (Arm B) is also 28 days. During the ramp-up 
(Cycle 1 only), venetoclax will be administered at a dose of 100 mg on Day 1; 200 mg on Day 2, 
and at 400 mg on Days 3 through 28. Venetoclax (400 mg) will be administered on Days 1 through 
28 (of a 28-day cycle) at Cycle 2 and beyond. If remission is confirmed in Cycle 1 or thereafter, 
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Venetoclax (400 mg) can be administered on Days 1 through 21 of a 28-day cycle in subsequent 
cycles, to prevent potential prolonged myelosuppression and treatment delays. If, in the opinion of 
the investigator, venetoclax (400 mg) administered on Days 1 through 21 (of a 28-day cycle) is 
well tolerated, venetoclax (400 mg) may be administered at full dosing frequency (400 mg given 
on Days 1 through 28 of 28-day cycle) in subsequent cycles. The tablets should be taken with a 
meal and water; they should not be chewed, crushed, or broken.
Azacitidine is a chemical analogue of cytidine that is widely used for the treatment of patients with 
AML and has been administered with pevonedistat in several clinical studies.
In a nonrandomized, open-label clinical study (NCT02203773 [16], 67 patients received the 
combination of venetoclax 400 mg (final dose after ramp-up) plus azacitidine 75 mg/m2. At the 
time of analysis, for patients who achieved a CR, the median observed time in remission was 
5.5 months (range, 0.4 to 30 months). The observed time in remission was the time from the start 
of CR to the time of data cutoff date or relapse from CR. Median time to first CR or CRh for 
patients treated with the combination was 1.0 month (range, 0.7 to 8.9 months).
Azacitidine 75 mg/m2 (IV or SC) will be administered on Days 1 through 7 or Days 1 through 5, 8, 
and 9. Details regarding azacitidine are contained in the USPI and SmPC, respectively [29,30]. 
The amount of study drug (azacitidine) to be administered will be based on BSA. BSA will be 
calculated using a standard formula (see example in Appendix F) 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.
8.3
Dose Modification Guidelines
Toxicity will be evaluated according to the NCI CTCAE, version 5.0, 27 November 2017 [2].
8.3.1
Criteria for Retreatment and Dose Delays
8.3.1.1
Retreatment Within a Cycle
If dosing of any of the 3 study drugs 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 of azacitidine 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 venetoclax dosing is held for any reason, it may 
be resumed as soon as possible.
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 to ≤Grade 1 or to the patient’s 
baseline values, the dose of study drug may be reduced (see Section 8.3.2) in the next cycle. This 
will apply to toxicity at least possibly related to protocol therapy. 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 
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≤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 project clinician (or designee).
8.3.1.2
Initiation of a New Cycle
Treatment with study drugs will be repeated every 28 days. It is strongly recommended that dosing 
for the investigational arm (pevonedistat + venetoclax + azacitidine [Arm A]) and the control arm 
(venetoclax + azacitidine [Arm B]) 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, toxicity considered related to treatment with study 
drugs must have resolved to ≤Grade 1 or to the patient’s baseline values.
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 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 project clinician (or designee). When deciding on dose modifications for 
management of myelosuppression, consider dose modification of venetoclax first before 
modifications of azacitidine. Pevonedistat is generally not associated with myelosuppression.
For toxicity not related to drug (eg, disease-related toxicity), a similar dose reduction is permitted 
but is generally discouraged. If the 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.
For hematologic toxicity, a delay in the initiation of a cycle by 4 weeks or greater because of lack 
of recovery from treatment-related hematologic toxicity (resolved to ≤Grade 1, to patient’s 
baseline values, or to a level considered acceptable by the investigator) that is not related to 
leukemic infiltration will trigger a dose reduction if treatment resumes. If indicated, bone marrow 
evaluation will be performed to establish whether continued myelosuppression is related to 
persistent or progressing leukemic infiltration.
If criteria for resumption of therapy (described above) is not met, study treatments should be 
discontinued.
8.3.1.3
Venetoclax Dosing With CYP3A4 Inducers and Inhibitors
Moderate and strong CYP3A inducers and inhibitors are discouraged during venetoclax 
administration. If a patient requires use of CYP3A inducers, use with caution. However, in many 
instances, antifungal prophylaxis with “azole” therapy in neutropenic patients, CYP3A4 inhibitors 
may be required for management of infection in AML patients. Venetoclax should be administered 
at 200 mg (a 50% dose reduction from 400 mg) when given in the setting of moderate CYP3A 
inhibitors (ie, ciprofloxacin, diltiazem) and at 100 mg (75% dose reduction) in the setting of strong 
CYP3A inhibitors (ie, voriconazole), with the exception of coadministration with posaconazole 
where a dose reduction of venetoclax to 70 mg (83%) is required (refer to Table 7 in the USPI [16]). 
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The same dose reduction scheme is used if the patient is receiving venetoclax on Days 1 through 
21 of the 28-day cycle in the setting of moderate and strong CYP3A inhibitors. Treatment with the 
reduced venetoclax dose should continue for the duration of coadministration. In the event the 
co-administered CYP3A inhibitor is discontinued, the venetoclax at 400 mg dose should be 
resumed 2 to 3 days after discontinuation of the inhibitor.
8.3.1.4
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
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 (as specified in Section 8.3.3.1) 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 <25,000/μL and following agreement by the sponsor’s project 
clinician (or designee).
8.3.2.2
Venetoclax
Dose interruptions or modifications will be made for the following:

Grade 4 hematologic toxicities only if investigator feels strongly that the cytopenias are related 
to venetoclax and not related to underlying disease or the use of other agents. Patients with 
baseline neutropenia or those who have significant bone marrow involvement may be 
particularly at high risk.

If a patient achieves CRi or has a morphologically leukemia-free bone marrow after 
completing a cycle, venetoclax may be interrupted for up to 14 days after the last day of the 
cycle or until recovery of ANC >500/μL. Venetoclax may be resumed at the same dose level.

If a patient presents with new onset Grade 4 neutropenia for more than 1 week during 
subsequent cycles, unless it is thought to be due to the underlying disease, venetoclax dosing 
may be interrupted until ANC recovery to >500/µL, in consultation with the sponsor’s project 
clinician (or designee). Venetoclax may be re-initiated at a lower dose per discussion between 
the treating physician and the sponsor’s project clinician (or designee).

The dose levels for venetoclax dose adjustment are outlined in Table 8.a:
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Table 8.a
Dose Adjustments for Venetoclax
Current Dose of Venetoclax
Reduced Dose
400 mg
200 mg
200 mg
100 mg
100 mg
70 mg
70 mg
50 mg
50 mg
20 mg
Alternatively, the duration of venetoclax administration can be decreased (eg, decreased from 
21-day to 14-day administration in Cycle 2 and beyond) rather than the dose being reduced, after 
discussion with the project clinician (or designee).
8.3.2.3
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 project clinician (or 
designee).
Cytopenias are common in the patient population studied in this trial. Dose modification for 
azacitidine for Grade 3 to 4 hematologic toxicities will be considered only if the treating physician 
strongly that the cytopenias were related to azacitidine and after appropriate dose reductions of 
venetoclax have been made as in Table 8.a.
If dose reductions of azacitidine are to be performed, guidelines are provided in Table 8.b.
Table 8.b
Dose Reductions for Azacitidine
Current Dose of Azacitidine
Reduced Dose
75 mg/m2
50 mg/m2
50 mg/m2
37.5 mg/m2
37.5 mg/m2
Hold azacitidine
Further reductions beyond what is shown in the table above or alternative reductions (eg, 
75 mg/m2 × 5 days) may be allowed if recommended by the investigator and after discussion with 
the project clinician (or designee).

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 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. When deciding on 
dose modifications for management of myelosuppression, consider dose modification of 
venetoclax first before modifications of azacitidine. Pevonedistat is generally not associated with 
myelosuppression.
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8.3.3
Dose Modification for Nonhematologic Toxicities
8.3.3.1
Pevonedistat
Pevonedistat Dose Adjustment Based on Serum Transaminases and Total Bilirubin
It is anticipated that liver function tests (LFTs) (ie, 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 times the 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 times the 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 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) before first dosing, monitored during the study, 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. For other Grade 3 to 4 nonhematologic 
toxicities at least possibly related to pevonedistat, pevonedistat will be held. If the toxicity returns 
to ≤Grade 1 or the patient’s baseline status, pevonedistat may be re-started at 15 mg/m2 at the next 
cycle, and re-escalated to 20 mg/m2 at subsequent cycles at the discretion of the investigator as 
clinically indicated.
8.3.3.2
Venetoclax and Azacitidine
Although no dose adjustment is recommended in patients with mild or moderate hepatic 
impairment based on results of a population PK analysis, a trend for increased AEs was observed 
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in patients with moderate hepatic impairment; monitor these patients more closely for signs of 
toxicity during the initiation and dose ramp-up phase.
If Grade 3 or 4 nonhematologic toxicity is attributable to either agent (venetoclax or azacitidine), 
dose interruption of that agent is required. For patients who experience drug-related Grade 3 
nonhematologic toxicity, venetoclax and/or azacitidine should be interrupted (determined by the 
attribution of the toxicity). The drug may be resumed when the patient has recovered to ≤Grade 1, 
and the dose must be reduced 1 dose level. If a patient has drug-related Grade 4 nonhematologic 
toxicity, the drug should be discontinued permanently. The dose of the agent can be decreased 
during a cycle, at the discretion of the treating physician, for chronic Grade 2 nonhematologic 
toxicity. Other dose modifications may be considered as clinically indicated with documentation 
and approval of the project clinician (or designee). The dose reduction guidelines for venetoclax 
and azacitidine nonhematologic toxicity are the same as those for hematologic toxicity, as outlined 
in Table 8.a and Table 8.b, respectively.
8.4
Excluded Concomitant Medications and Procedures
Table 8.c provides the list of medications and procedures that are prohibited during the study.
Management of potential venetoclax interactions with CYP3A and P-gp inhibitors for patients 
with AML is summarized in Table 8.d.
Table 8.c
Excluded Concomitant Medications and Procedures
Therapy
Comment/Exceptions
Acetaminophen and acetaminophen-containing 
products
May be used judiciously but should not exceed a dose of 2 g in 
24 hours for patients receiving pevonedistat.
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.
Clinically significant enzyme inducers (see 
Appendix G)
Excluded.
Strong CYP3A inhibitors
Refer to Table 8.d.
Moderate CYP3A inhibitors and P-gp inhibitors
Refer to Table 8.d.
P-gp substrates with narrow therapeutic index
Refer to Table 8.d.
Warfarin
An 18% to 28% increase in warfarin Cmax and AUC of R- and 
S-warfarin is noted after single doses of venetoclax and warfarin. 
INR needs to be monitored closely.
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Table 8.c
Excluded Concomitant Medications and Procedures
Therapy
Comment/Exceptions
Known BCRP inhibitors (ie, cyclosporine)
For patients receiving pevonedistat, excluded, but limited use is
permitted only if clinically necessary and no suitable 
alternative exists. The patient may receive the BCRP inhibitor 
from 24 hours after the last pevonedistat dose until 72 hours 
before the next pevonedistat dose. For example, if a patient 
receives pevonedistat on a Monday (Day 1), Wednesday (Day 3), 
Friday (Day 5) schedule, then the BCRP inhibitor may be 
administered from the Saturday after the Day 5 dose (Day 6) up to 
the Friday (Day 26) before the Monday dose of the next cycle.
Any therapeutic agent other than pevonedistat
For example, androgens, supraphysiologic doses of 
corticosteroids (>10 mg/day prednisone or equivalent), 
erythropoietin, eltrombopag [Promacta], or romiplostim [Nplate]
are excluded.
Consumption of grapefruit or grapefruit juice
Patients should not consume food or beverages containing the 
fruit or juice of grapefruits or Seville oranges within 7 days before 
the first dose of study drug and throughout the study.
AUC: area under the plasma concentration-time curve; BCRP: breast cancer resistance protein; Cmax: maximum 
observed plasma concentration; CYP: cytochrome P450; INR: international normalized ratio.
Table 8.d
Management of Potential Venetoclax Interactions With CYP3A and P-gp 
Inhibitors for Patients With AML
Co-administered Drug
Initiation and Ramp-up Phase
Steady Daily Dose
Posaconazole
Day 1: 10 mg
Reduce venetoclax dose to 70 mg
Day 2: 20 mg
Day 3: 50 mg
Day 4: 70 mg
Other strong CYP3A inhibitor
(voriconazole)
Day 1: 10 mg
Reduce venetoclax dose to 100 mg
Day 2: 20 mg
Day 3: 50 mg
Day 4: 100 mg
Moderate CYP3A inhibitor
Reduce the venetoclax dose by at least 50%
P-gp inhibitor
Source: Based on information in the venetoclax USPI [16].
AML: acute myeloid leukemia; CYP: cytochrome P450; P-gp: P-glycoprotein.
8.5
Permitted Concomitant Medications and Procedures
Concomitant medications will be documented in the patient’s electronic medical record (electronic 
data capture [EDC]). Table 8.e lists concomitant medications and procedures permitted during the 
study.
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Table 8.e
Concomitant Medications and Procedures Permitted During the Study
Therapy
Comment
Anti-platelet agents (eg, 
aspirin, clopidogrel) and 
anticoagulants
May be used in patients who have controlled coagulopathy at baseline, as well as 
those who develop a coagulopathy on study. Note that patients with active 
uncontrolled coagulopathy are excluded from enrollment.
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 (MLFS), 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 <0.5 × 109/L) with or without fever may receive G-CSF or GM-CSF between 
days 28 through 42 after discussion and agreement with the project clinician (or 
designee).
Platelet transfusion
Permitted as medically necessary per institutional guidelines (eg, for platelets 
<10 × 109/L in the absence of clinical bleeding). Capture all transfusions in eCRF.
Red blood cell transfusion
To be considered for all patients with anemia, especially those with hemoglobin 
values ≤8 g/dL. Capture all transfusions in eCRF.
ANC: absolute neutrophil count; CR: complete remission; CRi: complete remission with incomplete blood count 
recovery; eCRF: electronic case report form; G-CSF: granulocyte colony-stimulating factor; GM-CSF: granulocyte 
macrophage colony-stimulating factor; MLFS: morphological leukemia-free state.
8.6
Precautions and Restrictions
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 and male patients should use effective methods of contraception through defined 
periods during and after study treatment as specified below.
Female patients must meet 1 of the following:

Postmenopausal for at least 1 year before the screening visit, OR

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 ICF through 6 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 patient. (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), must agree to 1 of the 
following:

Agree to practice effective barrier contraception during the entire study treatment period and 
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 patient. (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.)
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.
Male patients must agree to not donate sperm during the course of this study or 4 months after 
receiving their last dose of study drug(s).
Patients should not receive live vaccines while receiving study medication in this protocol and for 
2 weeks after completion of treatment, because of the possibility of receiving venetoclax.
8.7
Management of Clinical Events
8.7.1
Azacitidine
The most common adverse drug reactions for azacitidine are described in Section 4.7.3. Refer to 
the azacitidine USPI [29] or European Union (EU) SmPC [30], as applicable, for details regarding 
the management of clinical events attributed to azacitidine.
If unexplained reduction in serum bicarbonate levels to <20mEq/L occur, the dosage should be 
reduced by 50% on the next course. Similarly, if unexplained elevations of BUN or serum 
creatinine occur, the next cycle should be delayed until values return to normal or baseline and the 
dose should be reduced by 50% on the next treatment course (see azacitidine USPI [29]).
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
Pevonedistat in Combination With Azacitidine
Common AEs reported for patients receiving the combination of pevonedistat and azacitidine in 
the clinical program are provided in Section 4.3. Also see the current IB.
For administering pevonedistat in combination with azacitidine, follow the guidance as 
appropriate in this protocol.
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8.7.3
Venetoclax
Prophylaxis and Management of TLS
There is a potential for TLS with venetoclax-based therapies, especially in those with elevated 
pretreatment lactate dehydrogenase (LDH) levels, elevated leukocyte count, renal dysfunction, 
and dehydration. To mitigate the risk for TLS, patients will receive tumor lysis prophylaxis, 
including hydration (eg, oral and/or IV) and treatment with an agent to reduce the uric acid level 
(eg, allopurinol, rasburicase) before and during the venetoclax ramp-up during cycle 1. For 
patients who had dose delay or interruptions, TLS prophylactic measures may need to be 
implemented based on the disease status before resuming treatment. TLS prophylaxis must be 
initiated in all such patients before the first venetoclax dose or first new escalated dose. See 
venetoclax USPI [16] or SmPC [28] for details.
During Cycle 1:

All patients should have white blood cell count less than 25 × 109/L before initiation of 
venetoclax. Cytoreduction before treatment may be required.

An oral agent to reduce the uric acid level (eg, allopurinol or substitute) must be initiated 
before first venetoclax dose. Patients allergic to or otherwise unable to receive allopurinol 
must use another uric acid reducer or rasburicase prior to venetoclax dosing.

TLS chemistry tests (calcium, phosphorus, potassium, uric acid, and creatinine) predose on the 
first day of venetoclax and each day of a new dose before venetoclax dosing. TLS chemistry 
tests should also be checked between 4 to 12 hours after each new dose of venetoclax (ie, 
during the venetoclax ramp-up), and 24 hours after reaching final dose.

TLS chemistry test results (ie, calcium, phosphorus, potassium, uric acid, and creatinine) must 
be reviewed by the investigator or treating physician in real time and before the patient’s next 
dose to ensure appropriate patient management.

If a patient meets criteria for clinically significant laboratory or clinical TLS, no additional 
venetoclax dose should be administered until resolution.

For patients with risk factors for TLS (eg, circulating blasts, high burden of leukemia 
involvement in bone marrow, elevated pretreatment LDH levels, or reduced renal function) 
additional measures should be considered, including increased laboratory monitoring and 
reducing venetoclax starting dose.
8.7.4
Guidance for Clinical Assessment and Management of Hemodynamic 
Compromise
It is essential that the patients receiving the combination of pevonedistat, venetoclax, 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 
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with the combination of pevonedistat, venetoclax, 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/h 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.
8.7.5
Management of Cytopenia and Infection
Cytopenia is common in patients with AML. Patients with baseline neutropenia or those who have 
significant bone marrow involvement may be particularly at high risk. Patients receiving the 
combination of pevonedistat, venetoclax, and azacitidine are carefully evaluated at screening and 
before each dose of study drug for neutropenia and risk of infection and adequate prophylaxis as 
outlined below: 

If indicated, bone marrow evaluation will be performed to establish whether continued 
myelosuppression is related to persistent or progressing leukemic infiltration. When deciding 
on dose modifications for management of myelosuppression, consider dose modification of 
venetoclax first before modifications of azacitidine. Pevonedistat is generally not associated 
with myelosuppression.

As general guidance for patients with, or who are expected to experience, significant 
protracted neutropenia (defined as ANC ≤500/uL for 7 days or with fever) are therefore at high 
risk of infection, prophylactic treatment with antibiotics (eg, fluoroquinolone, ciprofloxacin), 
antifungals (eg, voriconazole, fluconazole, parconazole), and antiviral agents (eg, acyclovir, 
entecavir or tenofovir) should be initiated, and continued at least through Cycle 1, per 
institutional guidance.

Use of anti-infective prophylaxis should take into account possible DDI with study drugs (eg, 
CYP3A inhibitors) as described in Section 8.3.1 and in Table 8.d. Use of anti-infective agents 
are to be captured in eCRF. 

In general, the use of myeloid growth factors is discouraged and should be restricted. For 
patients in CR, CRi, or marrow CR (MLFS), growth factors may be used in specific 
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circumstances, per institutional guidelines and after discussion with the project clinician (or 
designee). Additionally, to avoid dose delays, patients who experience Grade 4 neutropenia 
(ANC <0.5 × 109/L) with or without fever may receive G-CSF or GM-CSF between Days 28 
through 42 after discussion and agreement with the project clinician (or designee).
8.7.6
Guidance Management of Leukostasis
Pevonedistat treatment should be withheld for patients who develop symptoms of leukostasis (see 
Section 8.3.2.1). Treatment may include leukapheresis and hydroxyurea administration, per 
institutional guidelines. When the WBC count is <25,000/μL and symptoms are improved, 
pevonedistat treatment may be restarted after consulting with the sponsor’s project clinician (or 
designee). Treatment with azacitidine and venetoclax may continue as clinically indicated.
8.7.7
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) who are directly involved in the study 
conduct will be blinded to the treatment assignment of patients in the trial.
As of Protocol Amendment 4, Takeda’s staff (or its designee) will be unblinded 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
Pevonedistat
The drug product is labeled Pevonedistat (TAK-924/MLN4924) Concentrate for Solution for 
Infusion.
Pevonedistat injection drug product formulation (as free base) consists of pevonedistat HCl in an 
aqueous solution of citric acid (anhydrous), trisodium citrate dihydrate, and ß-Cyclodextrin 
sulfobutyl ether at pH 3.3.
Each USP Type I glass vial of the compounded sterile solution is sealed with a Teflon-coated butyl 
rubber stopper and oversealed with an aluminum seal and a plastic cap.
Full details are available in the Pharmacy Manual.
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8.9.2
Venetoclax
Venetoclax may be supplied by the site from commercial sources, depending on regional 
availability. Commercially available venetoclax is supplied as tablets for oral usage. Refer to the 
Study/Pharmacy Manual and the venetoclax USPI [16] or the EU SmPC [28], as applicable, for 
additional information regarding venetoclax.
8.9.3
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 Pharmacy Manual and the azacitidine USPI [29] or EU SmPC [30], 
as applicable, for additional information regarding azacitidine.
8.10
Preparation, Reconstitution, and Dispensing
Pevonedistat
Pevonedistat is a cytotoxic anticancer drug, and as with other potentially toxic compounds, caution 
should be exercised when handling pevonedistat.
The specified number of injection drug product vials should be removed and allowed to equilibrate 
to room temperature before dilution. The vial must not be shaken at any time during dose 
preparation. Before use, Pevonedistat Concentrate for Solution for Infusion vials should be 
brought to ambient conditions (15°C to 30°C [59°F to 86°F]) by removing the vials from the 
refrigerator and placing them at room temperature. Store in the original carton until time of use. 
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 after removal from storage 
conditions of 2°C to 8°C (36°F to 46°F).
Using aseptic technique, the appropriate volume of drug should be withdrawn from vial(s), then 
injected into a 250 mL IV bag containing 5% dextrose solution or normal saline (0.9% sodium 
chloride) solution, and then gently inverted repeatedly to mix. The pevonedistat prepared IV bag 
must be used within 6 hours (time to the end of an injection) if stored at ambient temperature. 
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 
(time to the end of an injection) upon coming to ambient temperature.
The bag, needle, and syringe must be disposed of in a proper biohazard container.
Azacitidine
Refer to the azacitidine USPI [29] or the EU SmPC [30] for preparation and dispensing.
Venetoclax
Venetoclax is commercially available as a tablet for oral administration. Venetoclax may be 
sourced locally by the clinical sites when regulations allow for clinical site sourcing with 
appropriate drug labeling.
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8.11
Packaging and Labeling
Pevonedistat
Pevonedistat (TAK-924/MLN4924) will be provided in 10 mL glass vials at a concentration of 10 
mg/mL.
Venetoclax
Venetoclax is commercially available as a tablet for oral administration.
Azacitidine
Azacitidine is available as lyophilized powder in 100-mg, single-use vials from commercial 
supply. 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. Store in 
the original carton until time of use.
Details for the storage and handling of venetoclax are provided in the USPI [16] or the EU SmPC 
[28].
Details for the storage and handling of azacitidine are provided in the USPI [29] or the EU SmPC 
[30].
A drug dispensing log, including records of drug(s) received from the sponsor and drug(s) 
administered to the patients, will be provided. 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, GCP, applicable regulatory 
requirements, and 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. A full list of investigators is available in the sponsor’s investigator database.
For 24-hour contact information, please refer to the Study Manual.
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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 IRB/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 stratified by age (18 to <75 years, ≥75 years) and 
AML subtype (de novo AML; sAML). The first dose of study drugs must be administered 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
Following the implementation of Protocol Amendment 4 the frequency of study assessments and 
clinic visits will be reduced as shown in the Modified SOE (Appendix A).
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 
physician, if allowed per institutional and local guidelines) in situations where a site visit cannot be 
conducted, such as in a coronavirus disease 2019 (COVID-19) pandemic. The reason for 
telemedicine (eg, COVID-19 related) and the assessments performed are to be captured in the 
EDC.
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.
9.4.2
Reconsent of Patients
9.4.2.1
Reconsent of Patients who Meet the Criteria for PD and Continue Study Treatment
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 if, in the clinical judgment of the 
investigator, the patient is still receiving clinical benefit from this treatment, and the continuation 
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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.
9.4.2.2
Reconsent of Patients after Implementation of Protocol Amendment 4
Patients may be allowed to continue study treatment (either treatment arm) after implementation of 
Protocol Amendment 4 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 after implementation of Protocol 
Amendment 4 must be reconsented before dosing on Day 1 of the next full treatment cycle and 
must follow the Modified SOE (Appendix A).
9.4.3
Patient Demographics
The date of birth (outside European Economic Area) or age (European Economic Area), race, 
ethnicity (optional depending on country), and sex of the patient are to be recorded during 
screening.
9.4.4
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.
9.4.5
Medical History
During screening, a complete medical history will be compiled for each patient. The history will 
emphasize the background and diagnosis of the patient’s AML (see Section 7.1 Inclusion Criteria 
for the definition). Any history of prior hematologic disorder, such as myelodysplasia or other 
hematologic malignancies, should be documented as well as any treatments given for these 
disorders, including bone marrow transplantation, chemotherapy, hypomethylating agents, or 
other antineoplastic agents. Any prior history of chemotherapy or irradiation or bone marrow 
transplantation given for solid tumors also should be included as well as start and stop dates of 
each therapeutic agent and response to therapy. Medical conditions should also be documented, 
including, for example, cardiac disease (eg, cardiomyopathy, coronary artery disease, myocardial 
infarction, arrhythmias) as well as any medical condition that could impact the patient’s clinical 
course and/or interfere with planned treatment or procedures in the protocol or be life-threatening.
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 
specified times and as clinically indicated.
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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 azacitidine) to be administered will be based on BSA. 
BSA will be calculated using a standard formula (see example in Appendix F) 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
Modified Charlson Comorbidity Index Assessment
Patients will be assessed during screening using the Modified Charlson Comorbidity Index (refer 
to Appendix I).
9.4.10
ECOG Performance Status
ECOG performance status will be assessed during screening and at the specified times. Refer to 
Appendix E for the ECOG performance status grading scale.
9.4.11
Vital Signs
Vital signs, including diastolic and systolic blood pressure, heart rate, and body temperature will 
be collected during screening and at the specified times and as clinically indicated. Vital sign 
measurements will be taken with the patient in the supine or sitting position.
9.4.12
ECG
A 12-lead ECG will be performed during screening and at the specified time points. Additional 
ECGs may be performed as clinically indicated. Echocardiogram or MUGA scan will be 
performed at screening if data for these is not available within 3 months of screening.
9.4.13
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 
performed during screening.
9.4.14
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 
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administered in that cycle. A pregnancy test will also be performed for women of childbearing 
potential at the EOT visit (both treatment Arms A and B). Pregnancy tests may also be repeated 
during the study if requested by an IEC/IRB or if required by local regulations.
9.4.15
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. For additional details regarding excluded and permitted 
concomitant medications and procedures, see Section 8.4 and Section 8.5, respectively.
9.4.16
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.
9.4.17
Enrollment
Enrollment is achieved when the patient is randomized to 1 of the 2 study arms. Procedures for 
completion of the enrollment information are described in the IWRS and Study Manual.
9.4.18
Clinical Laboratory Evaluations
Following the implementation of Protocol Amendment 4, the clinical laboratory evaluations will 
be performed by a local laboratory and will no longer be performed at the central laboratory. 
Laboratory assessments will be carried out according to standard of care using local laboratory 
evaluations. Abnormal hematology and chemistry data will be collected and recorded in the eCRF 
only to the extent that they are needed to document or support an AE. Laboratory assessments to 
inform dosing decisions and routinely monitor patients do not need to be recorded in the eCRF.
Local laboratory evaluations may be done more frequently at the investigator’s discretion, for 
instance management of anemia.
BMA testing for the diagnosis and eligibility criteria will be determined per local laboratory 
results. Sites will provide local cytogenetic and mutation reports, as allowed per local regulations.
9.4.18.1
Clinical Chemistry, Hematology, and Urinalysis
Blood samples for analysis of clinical hematology parameters and serum chemistry and TLS 
panels are shown in Table 9.a and Table 9.b, respectively. Select serum chemistry panel is shown 
in Table 9.c. Urine samples for analysis of the parameters shown in Table 9.d will be obtained at 
specified times.
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Table 9.a
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 J.
Platelet (count)
ANC: absolute neutrophil count.
Table 9.b
Complete Serum Chemistry and Tumor Lysis Syndrome Panels
Complete Serum Chemistry Panel
Albumin
ALP
ALT
AST
Bilirubin (direct)
Bilirubin (total)
Blood uric acid
BUN
Calcium
CO2
Chloride
Creatinine
Glucose
LDH
Magnesium
Phosphate
Potassium
Sodium
TLS Panel
Blood uric acid
Calcium
Creatinine
Phosphate
Potassium
ALP: alkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase; BUN: blood urea 
nitrogen; CO2: carbon dioxide; LDH: lactate dehydrogenase; TLS: tumor lysis syndrome.
Table 9.c
Select Serum Chemistry Panel
Select Serum Chemistry Panel
ALP
ALT
AST
Bilirubin (total)
BUN
Creatinine
Phosphate
ALP: alkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase; BUN: blood urea 
nitrogen.
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Coagulation testing (prothrombin time and activated partial thromboplastin time [aPTT]) will be 
done at screening and at specified times.
Blood samples for analysis of reticulocyte counts and ferritin levels will be obtained at specified 
times.
Table 9.d
Urinalysis With Microscopic Analysis
Urinalysis
Glucose
Ketones
Leukocytes
Nitrite
Occult blood
Bilirubin
pH
Protein
Specific gravity
Turbidity and color
Microscopic assessment of leukocytes, erythrocytes, 
bacteria, casts, and crystals
Urinalysis assessments will be performed as in Table 9.d. These samples will be analyzed by a 
local laboratory.
Creatinine clearance will be estimated using the MDRD Study equation (Appendix K).
9.4.19
Disease Assessment
Formal disease assessments for study endpoints will be determined based on local BMA blast 
counts (blast counts from the bone biopsy may be used in the event the aspirate sample is 
inadequate and a biopsy was done) and clinical laboratory evaluations (performed at a local 
laboratory). The investigator’s assessment of disease will be entered in the eCRF for each time 
point. The blast percentage should be correlated with an estimate of the blast count from the 
marrow biopsy section.
Patients who receive myeloid growth factors will not be included in assessment of neutrophil 
response within 2 weeks of growth factor administration.
Assessments of disease response (see Table 9.e) are based on the criteria outlined in the European 
Leukemia Net 2017 guidelines [3].
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Table 9.e
Response Criteria
Category
Definition
Comment
Response
CRMRD-
If studied pretreatment, CR with negativity for a 
genetic marker by RT-qPCR, or CR with 
negativity by MFC.
Sensitivities vary by marker tested, and by 
method used; therefore, the test used and 
sensitivity of the assay should be reported; 
analyses should be done in experienced 
laboratories (centralized diagnostics).
CR
Bone marrow blasts <5%; absence of circulating 
blasts and blasts with Auer rods; absence of 
extramedullary disease; ANC ≥1.0 × 109/L 
(1000/µL); platelet count ≥100 × 109/L 
(100,000/µL).
MRD+ or unknown.
CRi
All CR criteria except for residual neutropenia 
(<1.0 × 109/L [1000/µL]) or thrombocytopenia 
(<100 × 109/L [100,000/µL]).
CRh
A response of CRh is defined as bone marrow 
with <5% blasts, peripheral blood neutrophil 
count >0.5 × 103/µL and peripheral blood platelet 
count >0.5 × 105/µL.
MLFS
Bone marrow blasts <5%; absence of blasts with 
Auer rods; absence of extramedullary disease; no 
hematologic recovery required.
Marrow should not merely be “aplastic”; at 
least 200 cells should be enumerated, or 
cellularity should be at least 10%.
PR
All hematologic criteria of CR; decrease of bone 
marrow blast percentage to 5% to 25%; and 
decrease of pretreatment bone marrow blast 
percentage by at least 50%.
Especially important in the context of 
phase 1-2 clinical trials.
Treatment failure
Primary 
refractory 
disease
No CR or CRi after 2 courses of intensive 
induction treatment; excluding patients with 
death in aplasia or death due to indeterminate 
cause.
Regimens containing higher doses of 
cytarabine are generally considered as the 
best option for patients not responding to a 
first cycle of 7 + 3; the likelihood of 
responding to such regimens is lower after 
failure of a first.
Death in aplasia
Deaths occurring ≥7 days following completion 
of initial treatment while cytopenic; with an 
aplastic or hypoplastic bone marrow obtained 
within 7 days of death, without evidence of 
persistent leukemia.
Death from 
indeterminate 
cause
Deaths occurring before completion of therapy, 
or <7 days following its completion; or deaths 
occurring ≥7 days following completion of initial 
therapy with no blasts in the blood, but no bone 
marrow examination available.
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Table 9.e
Response Criteria
Category
Definition
Comment
Response criteria for clinical trials only
Stable disease
Absence of CRMRD-, CR, CRi, PR, MLFS; and 
criteria for PD not met.
Period of stable disease should last at least 
3 months.
Progressive 
disease
Evidence for an increase in bone marrow blast 
percentage and/or increase of absolute blast 
counts in the blood:

>50% increase in marrow blasts over baseline 
(a minimum 15 percentage point increase is 
required in cases with <30% blasts at 
baseline; or persistent marrow blast 
percentage of >70% over at least 3 months; 
without at least a 100% improvement in ANC 
to an absolute level (>0.5 × 109/L [500/µL], 
and/or platelet count to >50 × 109/L 
[50,000/µL] nontransfused); or

>50% increase in peripheral blasts (WBC 
× % blasts) to >25 × 109/L (>25,000/µL) (in 
the absence of differentiation syndrome); or

New extramedullary disease.
Category mainly applies for older patient 
given low-intensity or single-agent 
“targeted therapies” in clinical trials.
In general, at least 2 cycles of a novel agent 
should be administered.
Some protocols may require blast increase 
in 2 consecutive marrow assessments at 
least 4 weeks apart; the date of progression 
should then be defined as of the first 
observation date.
Some protocols may allow transient 
addition of hydroxyurea to lower blast 
counts.
“Progressive disease” is usually 
accompanied by a decline in ANC and 
platelets and increased transfusion 
requirement and decline in performance 
status or increase in symptoms.
Relapse
Hematologic 
relapse (after 
CRMRD-, CR, or 
CRi)
Bone marrow blasts ≥5%; or reappearance of 
blasts in the blood; or development of 
extramedullary disease.
Molecular 
relapse (after 
CRMRD-)
If studied pretreatment, reoccurrence of MRD as 
assessed by RT-qPCR or by MFC.
Test applied, sensitivity of the assay, and 
cutoff values used must be reported; 
analyses should be done in experienced 
laboratories (centralized diagnostics).
Source: ELN 2017 guidelines [3].
AML: acute myelogenous leukemia; ANC: absolute neutrophil count, CR: complete remission; CRh: complete 
remission with partial hematologic recovery; CRi: complete remission with incomplete hematologic recovery; 
CRMRD-: CR without measurable residual disease; MFC: multiparameter flow cytometry; MLFS: morphologic 
leukemia-free state; MRD: measurable residual disease; PR: partial remission; RT-qPCR: real-time quantitative 
polymerase chain reaction; WBC: white blood cell.
9.4.20
Biomarker, Pharmacodynamic, and PK Samples
Details regarding the preparation, handling, and shipping of samples are provided in the central 
laboratory manual (Collection Flow Chart).
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9.4.20.1
Primary Specimen Collection
Primary specimen collections are summarized in Table 9.f. See Table 9.f footnote for specific 
changes in specimen collection following implementation of Protocol Amendment 4.
Table 9.f
Specimen Name in the Schedule of Procedures
No.
Specimen Name in the Schedule 
of Procedures
Primary 
Specimen
Primary 
Specimen 
Derivative 1
Primary 
Specimen 
Derivative 2
Description of 
Intended Use
Sample 
Collection
1
Locally generated pathology report
N/A
N/A
N/A
Cytogenetics 
abnormalities 
determination
Mandatory
2
Locally generated cytogenetic 
report
N/A
N/A
N/A
Cytogenetics 
abnormalities 
determination
Mandatory
3
Locally generated mutational 
report
N/A
N/A
N/A
Genetic 
abnormalities 
determination
Mandatory
4
Fresh BMA sample for molecular 
analysis (MOA and LSCs 
enumeration)
Fresh bone 
marrow
Fresh cells for 
flow
N/A
Biomarker 
measurements in 
fresh BMA
Mandatory
5
Fresh BMA sample for molecular 
analysis, MRD, and cytogenetic 
risk category
Fresh bone 
marrow
Fresh cell
DNA
RNA
Biomarker 
measurements in 
fresh BMA
Mandatory
6
Plasma samples for circulating 
biomarkers
Plasma
N/A
N/A
Biomarker 
measurements in 
plasma
Mandatory
7
Blood samples for MOA and LSCs 
enumeration
Peripheral 
blood
N/A
N/A
Biomarker 
measurements in 
blood
Mandatory
8
Blood samples for RNA
Peripheral 
blood
RNA
N/A
Biomarker 
measurements in 
blood
Mandatory
9
Serum samples for circulating 
biomarkers
Serum
N/A
N/A
Biomarker 
measurements in 
serum
Mandatory
10
Plasma samples for pevonedistat 
PK
Plasma
N/A
N/A
PK measurements
Mandatory
BMA: bone marrow aspirate; LSC: leukemic stem cell; MRD: measurable residual disease; MOA: mechanism of action; N/A: not 
applicable; PK: pharmacokinetics.
Collection of peripheral blood samples for exploratory analyses (MOA and LSC enumeration), plasma samples for circulating 
biomarkers, serum samples for circulating biomarkers, plasma samples for PK will be discontinued once Protocol Amendment 4 is
implemented. Collection of bone marrow aspirates will be reduced (see Modified Schedule of Events [Appendix A]).
9.4.20.1.1
Locally Generated Reports Collection
Locally generated reports will be submitted to sponsor when allowed per local regulations. The 
bone marrow pathology and cytogenetics reports from the local laboratories will be submitted to 
the sponsor for recording of cytogenetic abnormalities and risk categories determination per ELN 
[3] at screening and at every subsequent visit when available.
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Screening mutation reports from the local laboratories will be submitted to the sponsor for 
recording.
9.4.20.1.2
Fresh Bone Marrow Aspirate Sample Collection for Molecular Analysis
Fresh bone marrow aspirate samples will be collected. Two separate tubes will be collected and 
shipped to specialty laboratories for molecular characterization to:

Identify biomarkers that are predictive of efficacy and/or safety of the combination of 
pevonedistat + venetoclax + azacitidine versus venetoclax + azacitidine. A portion of the bone 
marrow aspirate sample obtained at screening will be sent to specialty laboratories for baseline 
molecular characterization of the patient’s tumor (analyses may include next-generation 
sequencing [NGS], RNAseq, gene expression, protein abundance and protein/pathway 
activation status of apoptosis-related and Bcl-2 family-related effector genes/ proteins, 
cytogenetic abnormalities and molecular markers associated with poor prognosis in AML).

Determine changes in apoptosis and survival mechanisms within both bulk leukemia and 
leukemic stem/progenitor cells isolated pre- and posttreatment in both treatment arms.

Determine impact of therapy on elimination of leukemic stem cells in pevonedistat + 
venetoclax + azacitidine versus venetoclax + azacitidine arms.

Determine depth and durability of response (MRD) over time and compare with response and 
kinetics of response in both treatment arms. Analysis will be done for disease burden before 
and following treatment using either flow cytometry, NGS, or proteomic based approaches.

Evaluate mechanisms of treatment-emergent resistance. Bone marrow aspirates obtained at 
relapse from patients who initially respond to pevonedistat + venetoclax + azacitidine or 
venetoclax + azacitidine therapies and then exhibit PD, will be evaluated for potential 
mechanisms of treatment-emergent resistance, such as new somatic mutations and key 
signaling pathways, or change in pathway activity.
9.4.20.1.3
Blood Sample Collection for RNA, Mechanism of Action, and Leukemic Stem Cells 
Enumeration
Blood samples will be collected and may be sent to a specialty laboratory for molecular 
characterization to:

Confirm pevonedistat target transcriptional modulation of CRL protein substrates (NQO1, 
SLC7A11) in the pevonedistat + venetoclax + azacitidine arm.

Determine impact of therapy on elimination of leukemic stem cells in pevonedistat + 
venetoclax + azacitidine versus venetoclax + azacitidine arms in peripheral blood.

Determine changes in apoptosis and survival mechanisms within both bulk leukemia and 
leukemic stem/progenitor cells isolated pre- and posttreatment from peripheral blood in both 
treatment arms.
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
Determine protein abundance and protein/pathway activation status of apoptosis-related and 
Bcl-2 family-related effector genes/proteins in tumor cells isolated from peripheral blood at 
screening and correlate with response.
9.4.20.1.4
Serum and Plasma Samples Collection for Circulating Biomarkers
Serum and plasma samples will be collected to evaluate circulating serum and plasma proteins and 
miRNA signatures associated with response or resistance to pevonedistat + venetoclax + 
azacitidine treatment.
9.4.21
PK Measurements
Following the implementation of Protocol Amendment 4, blood samples for PK analysis will not 
be collected (see Modified SOE [Appendix A]).
Blood samples for the determination of pevonedistat (and its metabolites, if appropriate) plasma 
concentrations will be collected from all patients from the pevonedistat + venetoclax + azacitidine. 
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.
Details regarding the amount of blood samples, preparation, handling, and shipping of samples are 
provided in the central laboratory (Collection Flow Chart).
9.4.22
Pharmacodynamic Measurements
All of the pharmacodynamic measurements to be done are exploratory and retrospective in nature 
and are as follows:

Baseline molecular characterization of the patient’s bone marrow and peripheral blood will 
allow the identification of subgroups (beyond demographics and clinical features) that can be 
correlated with response or resistance to the combination of pevonedistat + venetoclax + 
azacitidine. For example, these subgroups may be based on patients’ baseline abundance and 
activation status of Bcl-2 family effector proteins, such as: BCL2, NOXA BCL-XL, MCL1, 
BAX, BAK, and BH3 as well as subgroups based on AML biology, such as: cytogenetic 
profile and/or somatic mutations. In addition, comparing baseline with posttreatment 
molecular characterization of the patient’s bone marrow and peripheral blood will allow 
evaluation of the mechanism of action (MOA) of the triple combination; to confirm 
pevonedistat-induced target modulation of CRL protein substrates, such as NQO1 and 
SLC7A11, as well as to determine whether the survival signaling within cells is skewed toward 
one antiapoptotic BCL2 family member or another at baseline, whether there are differences in 
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modulation between the treatment arms and the general impact of adding pevonedistat to 
venetoclax + azacitidine.

In this study, identification of somatic mutations at screening in both treatment arms using 
next-generation sequencing and correlation with clinical efficacy and safety will be performed. 
In addition, relationship with molecular markers associated with poor prognosis in AML, such 
as FLT3 ITD, RUNX-1, EZH2, ASXL1, N-RAS, K-RAS, and TP53, in both treatment arms 
and correlation with clinical efficacy will be determined. Mutational data, such as FLT3 ITD, 
IDH1, and IDH2 are increasingly being used as a complementary tool to influence the 
selection of the most appropriate therapy in AML. Importantly, initial data form the phase1b 
Study C15009 single arm study of evaluating pevonedistat + azacitidine in elderly patients 
with AML shows notable activity of the combination in the hard-to-treat TP53 mutant patient 
population. Finally, the targeted DNA sequencing of BMA collected at screening in the Study 
C15009, was conducted to identify molecular subgroups correlated with clinical outcome. 
Based on this analysis, a decision tree model was developed to classify patients who respond to 
pevonedistat + azacitidine. This algorithm is being evaluated for its predictive and/or 
prognostic performance in the phase 2 study, Pevonedistat-2001. Similarly, the potential of the 
described algorithm to predict response to the triple combination of pevonedistat + venetoclax 
+ azacitidine will be evaluated in this study. 

Leukemic cells that remain in the bone marrow following treatment are a major cause of 
disease relapse. 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 1) could improve prognostication by identifying 
submicroscopic disease during remission [31]. Measurement of MRD is receiving recognition 
as a potential tool to assess the quality of response after chemotherapy and to plan 
postremission strategies. In this study, BMAs collected at screening and specified time points 
during treatment and/or at relapse will be used to evaluate and compare depth and duration of 
response between both treatment arms by following parameters such as residual tumor cells, 
residual mutation load, and emergent of new clones. BMAs obtained at relapse will be 
evaluated for potential mechanisms of treatment-emergent resistance. In addition, the 
hypothesis that high leukemic stem cells frequency at baseline predicts high MRD and poor 
survival [32] as well as the impact of therapy on elimination of leukemic stem cells in both 
treatment arms will be tested.
9.5
Completion of Study Treatment (for Individual Patients)
A patient will be considered to have completed study treatment once the patient enters 
posttreatment follow-up.
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9.6
Completion of Study (for Individual Patients)
A patient will also be considered to have completed the study if discontinued from study drug 
treatment (refer to Section 9.7) and 1 or more of the following situations occur:

Death.

Consent withdrawal.

Investigator decision.

Study terminated by the sponsor.

Lost to follow-up.

Transfer of patient to the PTA program.
The consequence of consent withdrawal is that no new information will be collected from the 
withdrawn patient and added to the existing data or any database.
Once the study has been completed, all study procedures outlined for the end of treatment visit will 
be completed as specified in the Modified SOE (Appendix A). After study completion, no new 
information will be collected from the completed patient and added to the existing data or any 
database.
9.7
Discontinuation of Treatment With Study Drug and Patient Replacement
Study drug(s) must be permanently discontinued for patients meeting any of the following criteria:

Study drug–related toxicity causing a study drug hold of >6 weeks.

Unacceptable toxicity.

PD.
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 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.
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
Study terminated by sponsor.

Withdrawal by patient.

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 Modified SOE (Appendix A). The primary reason for study drug 
discontinuation will be recorded on the eCRF, along with any other details. Patients who are 
randomized to a treatment arm but do not receive study drug for any reason will not be replaced.
In the case of study termination by the sponsor, eligible patients may have continued access to 
pevonedistat as described in Section 9.11.
9.8
Withdrawal of Patients From Study
The investigator also has the right to withdraw patients from the study treatment for any of the 
following reasons:

Lost to follow-up.

Study terminated by sponsor.

Withdrawal by patient.

Death.

Transfer of patient to the PTA program.

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.
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9.10
Posttreatment Follow-up Assessments (EFS, Response, and OS)
The Modified SOE (Appendix A) will be followed after implementation of Protocol 
Amendment 4. Long-term follow up visits (EFS/response and OS) will no longer be required; 
patients will complete an End of Treatment visit 30 (+10) days after the last dose of study drug(s) 
or before the start of antineoplastic therapy if that occurs sooner.
9.11
Posttrial Access
Where permitted by local regulations, and if the responsible investigator and the sponsor agree that 
the patient would derive benefit from or would be harmed without continued access to the assigned 
treatment regimen, patients may continue to receive access to the assigned treatment regimen after 
the study is completed. If a posttrial access (PTA) program should become an option for a patient, 
then pevonedistat + venetoclax + azacitidine or venetoclax + azacitidine, depending on treatment 
arm assignment, may be provided through the PTA program.
9.12
Duration of PTA
If a PTA program should become an option for a patient, as described in Section 9.11, the sponsor 
may continue to provide the assigned treatment regimen to that patient through the PTA program. 
Continued access to the assigned treatment regimen 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); if the benefit-risk no longer favors the individual, an appropriate alternative 
therapy becomes available, or the comparators, eg, venetoclax, become available either 
commercially or via another access mechanism. PTA may be terminated in a country or 
geographic region upon decision by the sponsor or where pevonedistat, venetoclax, or azacitidine 
can no longer be supplied.
10.0
ADVERSE EVENTS
10.1
Definitions
10.1.1
PTE Definition
A PTE is any untoward medical occurrence in a patient 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 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.
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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 that 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, 
on the basis of appropriate medical judgment, it may jeopardize the patient, require medical or 
surgical intervention to prevent one 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 
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 5.0, effective 27 November 2017 [2]. 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 white blood cell count of 1000/mm3 to 
less than 2000/mm3 is considered Grade 3 (severe) but may not be considered serious. Seriousness 
(not intensity) serves as a guide for defining regulatory reporting obligations.
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10.2
Procedures for Recording and Reporting AEs and SAEs
All AEs spontaneously reported by the patient 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 a single comprehensive event.
Regardless of causality, SAEs 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 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, then 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 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 study drug are not to be considered AEs unless the condition 
deteriorated in an unexpected manner during the study; eg, surgery was performed earlier or later 
than planned.
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. 
Severity (toxicity grade) for each AE, including any lab abnormality, will be determined using the 
NCI CTCAE, version 5.0, effective 27 November 2017 [2]. 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?
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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.

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 Global Pharmacovigilance Department 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 Global 
Pharmacovigilance Department (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 Global 
Pharmacovigilance Department (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 sending a completed pregnancy form to the Takeda Global 
Pharmacovigilance Department or designee. The pregnancy must be followed for the final 
pregnancy outcome.
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 sending a completed pregnancy 
form to the Takeda Global Pharmacovigilance Department (or designee). 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 email addresses provided in the Study Manual.
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A medication error is a preventable event that involves an identifiable patient and 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 email addresses provided in the Study Manual.
Product complaints and medication errors in and of themselves are not AEs. If a product complaint 
or a medication error results in an SAE, the SAE should be reported. 
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 (EMA), investigators, and IRBs and 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 expedited reports within 7 days for fatal and 
life-threatening events and within 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.
11.0
STUDY-SPECIFIC COMMITTEES
11.1
Takeda Safety Monitoring
Safety data will be reviewed and assessed routinely by a Global Pharmacovigilance Safety Team 
and a Safety Management Committee throughout the conduct of the study. These reviews will 
include a Global Safety Lead from the study team, as well as other representation from the Clinical 
Research, Pharmacovigilance, Biostatistics, Clinical Pharmacology, and Clinical Operations 
departments at Takeda. An initial safety assessment will be performed after 10 patients have 
completed at least 1 cycle of treatment.
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, 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 patient who signs an ICF.
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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 entry process, computer logic checks will be run to identify items such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by the sponsor (or 
designee) 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 the change.
The investigator must review the eCRFs for completeness and accuracy and must sign and date the 
appropriate eCRFs as indicated. Furthermore, the 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 designee) will be permitted to review the patient’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, 
except for authorized representatives of appropriate governmental health or regulatory authorities, 
without written permission of the sponsor.
12.2
Record Retention
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 patients, medical records, temporary media such as thermal-sensitive paper, source 
worksheets, all original signed and dated ICFs, patient authorization forms regarding the use of 
personal health information (if separate from the ICFs), electronic copies of eCRFs including the 
audit trail, and detailed records of drug disposition to enable evaluations or audits from regulatory 
authorities and the sponsor (or designees). Any source documentation printed on degradable 
thermal-sensitive paper should be photocopied by the site and filed with the original in the 
patient’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 for record retention. The 
investigator should contact and receive written approval from the sponsor before disposing of any 
such documents.
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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 2-sided 90% and 95% CIs for time-to-event data.
A statistical analysis plan (SAP) will be prepared. This document will provide further details 
regarding the definition of analysis variables and analysis methodology to address all study 
objectives. Deviations from the statistical analyses outlined in this protocol will be indicated in the 
SAP; any further modifications will be noted in the final CSR.
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 any of the study medications (pevonedistat, venetoclax, or azacitidine). Patients will be 
analyzed according to the actual treatment they receive. Patients who receive any dose of 
pevonedistat will be included in the pevonedistat + venetoclax + azacitidine arm (Arm A), and 
patients who did not receive any dose of pevonedistat and receive at least 1 dose of 
venetoclax + azacitidine will be included in the venetoclax + azacitidine arm (Arm B), 
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 do not have major protocol deviations, as determined by the 
study clinician.

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.
13.1.2
Analysis of Demographics and Other Baseline 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.
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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 the ITT population. The analysis of other secondary efficacy endpoints will be 
performed on the ITT population, unless specified otherwise.
13.1.3.1
Analyses for Primary Efficacy Endpoint
The primary endpoint of the study is EFS. The analysis of EFS will use the investigator assessment. 
EFS is defined as the time from study randomization to the date of failure to achieve CR or CRi, 
relapse from CR/CRi, or death from any cause, whichever occurs first. For patients who have 
achieved CR/CRi, if the relapse is not observed by the time of the analysis, patients will be 
censored at the date of last disease assessment. If patients fail to achieve CR or CRi, the date of 
treatment failure will be set on the day of randomization.
Detailed rules of handling missing assessments and censoring for the analysis of EFS will be 
described in the SAP. The stratified log-rank test statistic will be used to compare the treatment 
groups with respect to EFS at the 1-sided α = 5% significance level. A stratified unadjusted Cox 
model will be used to estimate the HR and its 2-sided 90% CIs for the treatment effect. The K-M 
survival curves and K-M medians (if estimable), along with their 2-sided 90% CIs, will also be 
provided for each treatment group. Two-sided 95% CIs for HR and median EFS will also be 
computed.
13.1.3.2
Analyses of Key Secondary Efficacy Endpoint
The key secondary efficacy endpoint is OS, which is defined as time from randomization to death 
from any cause. Patients without documentation of death at the time of analysis will be censored at 
the date last known to be alive.
The 1-sided log-rank test at the α = 5% significance level will be used to compare the treatment 
groups with respect to OS and calculate the p-value. In addition, a stratified unadjusted Cox model 
will be used to estimate the HR and its 2-sided 90% CIs for the treatment effect. The K-M survival 
curves and K-M medians (if estimable), along with their 2-sided 90% CIs, will also be provided for 
each treatment group. Two-sided 95% CIs for HR and median OS will also be computed. 
Additional sensitivity analyses for OS may be also conducted as appropriate.
13.1.3.3
Analyses of Other Secondary Efficacy Endpoints
Other secondary efficacy endpoints are: 30- and 60-day mortality rates; disease response rates: CR 
rate, CCR (CR + CRi) rate, ORR (CR + CRi + PR) rate, CR + CRh rate, leukemia response rate 
(CR + CRi + PR + MLFS[mCR]); duration of CR and CRi; time to first CR, CRi, and PR.
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Patients who receive myeloid growth factors will not be included in assessment of neutrophil 
response within 2 weeks of growth factor administration.
Disease response-related endpoints will be analyzed using investigator assessments.
30- and 60-Day Mortality Rates
The 30- and 60-day mortality rates are defined as the proportion of patients who survive at most 30 
and 60 days, respectively, from the first dose of study drug, which will be summarized by 
treatment arm in a table. The relative risk with its 2-sided 90% and 95% CIs will be calculated. The 
absolute rate difference will also be provided with its 90% and 95% CIs calculated using the 
asymptotic method.
Disease Response Rates: CR Rate, CCR (CR + CRi) Rate, ORR (CR + CRi + PR) Rate, 
CR + CRh Rate, Leukemia Response Rate (CR + CRi + PR + MLFS[mCR])
The disease response rates are defined as the proportion of patients who achieve the corresponding 
response in the corresponding group of patients. The number and percentage of patients for each 
definition of response will be summarized by treatment group. The relative risk with its 2-sided 90% 
and 95% CIs will be calculated. The absolute rate difference will also be provided with its 90% and 
95% CIs calculated using the asymptotic method.
The key analysis will be based on the ITT population, with response non-evaluable patients treated 
as nonresponders. Sensitivity analysis will be performed using the response-evaluable population.
Duration of CR and CRi
Duration of CR and CRi will be summarized descriptively using the K-M method based on the 
responders.
Time to First CR, CRi, and PR
Time to first CR, CRi, and PR is defined as time from randomization to the first documented CR or 
CRi or PR, whichever occurs first. The analysis will be performed using the K-M estimate, with 
the presentation of medians and associated 90% and 95% confidence intervals.
13.1.4
PK Analysis
13.1.4.1
PK Noncompartmental Analysis
PK parameters will be summarized using descriptive statistics. Individual pevonedistat 
concentration-time data and individual PK parameters will be presented in listings and also 
tabulated using summary statistics.
13.1.4.2
PK Sampling Intended for Population PK Analysis
The PK data collected in this study are intended to contribute to future population PK analyses of 
pevonedistat. These population PK analyses may additionally include data collected in other 
pevonedistat clinical studies. The plan for the population PK analysis will be defined separately 
and the results reported separately.
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13.1.5
Pharmacodynamic Analysis
Baseline cytogenetics data, mutation status, and apoptosis-related and Bcl-2 family-related 
effector genes/proteins status may be summarized descriptively by treatment arm and correlated 
with best response and other endpoints of interest in the subset of patients where the data are 
available.
Further changes in sample collection and/or exploratory analyses may be implemented based on 
emerging scientific knowledge. Results of available exploratory biomarkers may be reported 
outside of the CSR and/or added as an addendum to the CSR.
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 performance score, ECG results, and clinical 
laboratory results using the safety population. Exposure to study drug and reasons for 
discontinuation will be tabulated.
All AEs will be coded using the MedDRA. 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 System Organ Class, High-Level Term, and Preferred 
Term (PT), and will include the following categories:

TEAEs.

Drug-related TEAEs.

Treatment-emergent Grade 3, 4, and 5 AEs (presented by grade and overall).

Treatment-emergent drug-related 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.

Treatment-emergent drug-related SAEs.
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.
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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 + venetoclax + azacitidine.
Baseline and change from baseline ECOG performance score will be summarized.
All concomitant medications collected from screening through the study period will be classified 
to PT according to the WHO Drug Dictionary. All blood (RBC, platelet) transfusions will also be 
reviewed to determine transfusion dependence or independence.
The 30- and 60-day mortality rates are defined as the proportion of patients who survive at most 30 
and 60 days, respectively, 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.
13.2
IA and Event Size Re-estimation
One IA and one FA for statistical analyses of efficacy were initially planned; however, following 
decisions and changes made within the pevonedistat program after read-out from Study 
Pevonedistat-3001, the IA has been removed from Study Pevonesdistat-2002 and no event size 
re-estimation will be conducted. Only FA will be conducted, the timing of which will no longer be 
based on EFS events but instead it will be based on sponsor discretion. An updated analysis for 
safety data is planned at study closure. Upon implementation of Protocol Amendment 4, the 
frequency of study assessments and clinic visits will be reduced as shown in the Modified SOE 
(Appendix A).
13.3
Determination of Sample Size
The study was originally designed to have approximately 85 EFS events to provide 80% power to 
detect a HR of 0.58 (median EFS of 19 months in the investigational pevonedistat + venetoclax + 
azacitidine arm [Arm A] versus 11 months in the venetoclax + azacitidine control arm [Arm B], 
assuming exponential distribution of EFS) using a stratified log-rank test at 1-sided 5% 
significance level. 
Given the changes being made in the pevonedistat program as noted in Section 13.2, FA for EFS 
will be conducted after Protocol Amendment 4 is implemented using the number of EFS events 
observed at FA.
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. 
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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 
including, but not limited to, the investigator’s binder, study medication, patient medical records, 
informed consent documentation, documentation of patient 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 
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 patients. 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 patient’s source documents. In the event of 
a significant deviation, the site should notify the sponsor or its designee (and IRB or EC, as 
required). Significant deviations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the patient, or confound interpretation of the 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 patient 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.
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 FDA, EMA, the United Kingdom [UK] Medicines and 
Healthcare products Regulatory Agency [MHRA], the Pharmaceuticals and Medical Devices 
Agency of Japan [PMDA]). 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, patients) 
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 C. 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 
Federalwide Assurance number or comparable number assigned by the US 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 investigator’s brochure, a copy of 
the ICF, and, if applicable, patient recruitment materials and 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 patients 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 its exact protocol title, number, and version date; identify 
versions of other documents (eg, ICF) reviewed; and state the approval date. If required by country 
or regional regulations or procedures, approval from the competent regulatory authority will be 
obtained before commencement of the study or implementation of a substantial amendment. The 
sponsor will ship drug/notify site once the sponsor has confirmed the adequacy of site regulatory 
documentation and, when applicable, the sponsor has received permission from the 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 patients, 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 
designee).
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Patient incentives should not exert undue influence for participation. Payments to patients must be 
approved by the IRB or IEC and sponsor.
15.2
Patient Information, Informed Consent, and Patient 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, patient authorization form (if applicable), and patient 
information sheet (if applicable) describe the planned and permitted uses, transfers, and 
disclosures of the patient’s personal and personal health information for purposes of conducting 
the study. The ICF and the patient information sheet (if applicable) further explain the nature of the 
study, its objectives, and potential risks and benefits, and 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 patient authorization form. The ICF, patient authorization form (if 
applicable), and patient information sheet (if applicable) must be approved by both the IRB or IEC 
and the sponsor before use.
The ICF, patient authorization form (if applicable), and patient information sheet (if applicable) 
must be written in a language fully comprehensible to the prospective patient. It is the 
responsibility of the investigator to explain the detailed elements of the ICF, patient authorization 
form (if applicable), and patient information sheet (if applicable) to the patient. 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 patient is not capable of rendering adequate written informed consent, then 
the patient’s legally acceptable representative may provide such consent for the subject in 
accordance with applicable laws and regulations.
The patient, or the patient’s legally acceptable representative, must be given ample opportunity to 
(1) inquire about details of the study and (2) decide whether to participate in the study. If the 
patient, or the patient’s legally acceptable representative, determines that he or she will participate 
in the study, then the ICF and patient authorization form (if applicable) must be signed and dated 
by the patient, or the patient’s legally acceptable representative, at the time of consent and before 
the patient enters into the study. The patient or the patient’s legally acceptable representative 
should be instructed to sign using their legal names, not nicknames, using a ballpoint pen with 
either blue or black ink. The investigator must also sign and date the ICF and patient authorization 
(if applicable) at the time of consent and before the patient enters 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, patient authorization form (if applicable), and patient information 
sheet (if applicable) will be stored in the investigator’s site file. The investigator must document 
the date the patient signs the informed consent in the patient’s medical record. Copies of the signed 
ICF, the signed patient authorization form (if applicable), and patient information sheet (if 
applicable) shall be given to the patient.
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All revised ICFs must be reviewed and signed by relevant patients or the relevant patient’s legally 
acceptable representative in the same manner as the original informed consent. The date the 
revised consent was obtained should be recorded in the patient’s medical record, and the patient 
should receive a copy of the revised ICF.
15.3
Patient Confidentiality
The sponsor and designees affirm and uphold the principle of the patient’s right to protection 
against invasion of privacy. Throughout this study, a patient’s source data will be linked to the 
sponsor’s clinical study database or documentation only via a unique identification number. As 
permitted by all applicable laws and regulations, limited patient attributes, such as sex, age, or date 
of birth, and patient initials may be used to verify the patient and accuracy of the patient’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, US FDA, EMA, UK MHRA, PMDA), the sponsor’s designated auditors, 
and the appropriate IRBs and IECs to review the patient’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 patient’s study participation, and 
autopsy reports. Access to a patient’s original medical records requires the specific authorization 
of the patient as part of the informed consent process (see Section 15.2).
Copies of any patient source documents that are provided to the sponsor must have certain 
identifying personal information removed, eg, patient name, address, and other identifier fields not 
collected on the patient’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 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, as defined by Takeda policy/standards. 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 in finding 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 preferred by callers requesting trial information. Once patients 
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 
patient 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 for the US, 
clinicaltrialsregister.eu for studies conducted in the EU, and other publicly accessible websites 
(including the Takeda corporate site) and registries, as required by Takeda policy/standards, 
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 patient in the study must be insured in accordance with the regulations applicable to the site 
where the patient 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 patients. 
Refer to the clinical study site agreement regarding the sponsor’s policy on patient 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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2. Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. U.S. Department of 
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4. DiNardo CD, Pratz KW, Letai A, Jonas BA, Wei AH, Thirman M, et al. Safety and 
preliminary efficacy of venetoclax with decitabine or azacitidine in elderly patients with 
previously untreated acute myeloid leukaemia: a non-randomised, open-label, phase 1b study. 
Lancet Oncol 2018;19(2):216-28.
5. Liu Y, Hu M. Testing multiple primary endpoints in clinical trials with sample size adaptation. 
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gemtuzumab ozogamicin to low-dose Ara-C improves remission rate but does not significantly 
prolong survival in older patients with acute myeloid leukaemia: results from the LRF AML14 
and NCRI AML16 pick-a-winner comparison. Leukemia 2013;27(1):75-81.
8. Pollyea DA, DiNardo C, Thirman M, Letai A, Wei AH, Jonas BA, et al. Results of a phase 1b 
study of venetoclax plus decitabine or azacitidine in untreated acute myeloid leukemia patients 
≥65 years ineligible for standard induction therapy. J Clin Oncol 2016;34(15_suppl). 7009.
9. Wei AH, Strickland SA, Roboz GJ, Hou J, Fiedler W, Lin T, et al. Safety and Efficacy of 
VenetoclaxPlus Low-Dose Cytarabinein Treatment-Naïve Patients Aged ≥65 Years With 
Acute Myeloid Leukemia. Blood 2016;128(22). 102.
10. Stone R, Mandrekar S, Sanford B, Laumann K, Geyer S, Bloomfield C, et al. Midostaurin plus 
chemotherapy for acute myeloid leukemia with a FLT3 mutation. New England Journal of 
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11. Stein EM, DiNardo CD, Pollyea DA, Fathi AT, Roboz GJ, Altman JK, et al. Enasidenib in 
mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood 2017;130(6):722-31.
12. Knorr KL, Schneider PA, Meng XW, Dai H, Smith BD, Hess AD, et al. MLN4924 induces 
Noxa upregulation in acute myelogenous leukemia and synergizes with Bcl-2 inhibitors. Cell 
Death Differ 2015;22(12):2133-42.
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13. Konopleva M, Pollyea DA, Potluri J, Chyla B, Busman T, McKeegan E, et al. A Phase 2 Study 
of ABT-199 (GDC-0199) in Patients with Acute Myelogenous Leukemia (AML). Blood 
2014;124(21). 118.
14. Roberts AW, Davids MS, Pagel JM, Kahl BS, Puvvada SD, Gerecitano JF, et al. Targeting 
BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia. N Engl J Med 
2016;374(4):311-22.
15. Konopleva M, Pollyea DA, Potluri J, Chyla B, Hogdal L, Busman T, et al. Efficacy and 
Biological Correlates of Response in a Phase II Study of Venetoclax Monotherapy in Patients 
with Acute Myelogenous Leukemia. Cancer Discov 2016;6(10):1106-17.
16. Venclexta (venetoclax tablets). Prescribing Information. North Chicago, IL, US: AbbVie Inc., 
Revised 5/2019.
17. DiNardo CD, Pratz K, Pullarkat V, Jonas BA, Arellano M, Becker PS, et al. Venetoclax 
combined with decitabine or azacitidine in treatment-naive, elderly patients with acute 
myeloid leukemia. Blood 2019;133(1):7-17.
18. Souers AJ, Leverson JD, Boghaert ER, Ackler SL, Catron ND, Chen J, et al. ABT-199, a 
potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. 
Nature Medicine 2013;19(2):202-8.
19. Swords RT, Coutre S, Maris MB, Zeidner JF, Foran JM, Cruz J, et al. Pevonedistat, a 
first-in-class NEDD8-activating enzyme (NAE) inhibitor, combined with azacitidine, in 
patients with AML. Blood 2018;131(13):1415-24.
20. Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The 2016 
revision to the World Health Organization classification of myeloid neoplasms and acute 
leukemia. Blood 2016;127(20):2391-405.
21. Lancet JE, Uy GL, Cortes J, Newell LF, Lin TL, Ritchie E, et al. Final results of a phase III 
randomized trial of CPX-351 versus 7+3 in older patients with newly diagnosed high risk 
(secondary) AML. Journal of Clinical Oncology 2016;34(no. 15_suppl). 7000.
22. Bose P, Gandhi V, Konopleva M. Pathways and mechanisms of venetoclax resistance. Leuk 
Lymphoma 2017;58(9):1-17.
23. Soucy TA, Smith PG, Milhollen MA, Berger AJ, Gavin JM, Adhikari S, et al. An inhibitor of 
NEDD8-activating enzyme as a new approach to treat cancer. Nature 2009;458(7239):732-6.
24. Soucy TA, Smith PG, Rolfe M. Targeting NEDD8-activated cullin-RING ligases for the 
treatment of cancer. Clin Cancer Res 2009;15(12):3912-6.
25. Swords RT, Kelly KR, Smith PG, Garnsey JJ, Mahalingam D, Medina E, et al. Inhibition of 
NEDD8-activating enzyme: a novel approach for the treatment of acute myeloid leukemia. 
Blood 2010;115(18):3796-800.
26. Visconte V, Nawrocki ST, Espitia CM, Kelly KR, Possemato A, Beausoleil SA, et al. 
Comprehensive quantitative proteomic profiling of the pharmacodynamic changes induced by 
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MLN4924 in acute myeloid leukemia cells establishes rationale for its combination with 
azacitidine. Leukemia 2016;30(5):1190-4.
27. Swords RT, Erba HP, DeAngelo DJ, Bixby DL, Altman JK, Maris M, et al. Pevonedistat 
(MLN4924), a First in Class NEDD8-Activating Enzyme Inhibitor, in Patients with Acute 
Myeloid Leukemia and Myelodysplastic Syndromes: A Phase 1 study. Br J Haematol 2015 (in 
press).
28. Venclyxto (venetoclax). Summary of Product Characteristics. Maidenhead, UK: AbbVie Ltd, 
Revised 8 April 2020.
29. Vidaza (azacitidine for injection). Prescribing Information. Summit, NJ, USA: Celgene 
Corporation, Revised 03/2020.
30. Vidaza (azacitidine). Summary of Product Characteristics. Utrecht, Netherlands: Celgene 
Europe B. V., Revised 02 Apr 2019.
31. Ivey A, Hills RK, Simpson MA, Jovanovic JV, Gilkes A, Grech A, et al. Assessment of 
Minimal Residual Disease in Standard-Risk AML. New England Journal of Medicine 
2016;374(5):422-33.
32. van Rhenen A, Feller N, Kelder A, Westra AH, Rombouts E, Zweegman S, et al. High stem 
cell frequency in acute myeloid leukemia at diagnosis predicts high minimal residual disease 
and poor survival. Clin Cancer Res 2005;11(18):6520-7.
33. Cui L, Hung HM, Wang SJ. Modification of sample size in group sequential clinical trials. 
Biometrics 1999;55(3):853-7.
34. Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Finelli C, Giagounidis A, et al. Efficacy 
of azacitidine compared with that of conventional care regimens in the treatment of higher-risk 
myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncology 
2009;10(3):223-32.
35. Silverman LR, McKenzie DR, Peterson BL, Holland JF, Backstrom JT, Beach CL, et al. 
Further analysis of trials with azacitidine in patients with myelodysplastic syndrome: studies 
8421, 8921, and 9221 by the Cancer and Leukemia Group B. Journal of Clinical Oncology 
2006;24(24):3895-903.
36. Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and 
response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 
1982;5(6):649-55.
37. The Criteria Committee of New York Heart Association. Nomenclature and Criteria for 
Diagnosis of Diseases of the Heart and Great Vessels. 9 ed. Boston, MA: Little, Brown & Co; 
1994.
38. Etienne A, Esterni B, Charbonnier A, Mozziconacci MJ, Arnoulet C, Coso D, et al. 
Comorbidity is an independent predictor of complete remission in elderly patients receiving 
induction chemotherapy for acute myeloid leukemia. Cancer 2007;109(7):1376-83.
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Appendix A
Modified Schedule of Events
Upon implementation of Protocol Amendment 4, this modified SOE will be followed for patients continuing on the study. The original 
(Protocol Amendment 2) SOE has been moved to Appendix L for reference purposes.
Treatment Cycle (28 Days) a, b
EOT c
Day 1
Day 3
Day 5
Day 15
Informed reconsent d
X
Complete physical examination
X
Symptom-directed physical examination e
X
Weight f
X f
X
ECOG performance status
X
X
Vital signs g
X
X
X
X
12-lead ECG h
X
X
Pregnancy test i
X
X
Hematology j
X
X
X j
X
Coagulation k
X
X
Complete chemistry panel j,l
X
X
X l
X
Select chemistry panel j,m
X
Urinalysis with microscopic analysis n
X
BMA/biopsy and investigator disease 
assessment o
Collect BMA at suspected relapse o
SAE collection p
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
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.
Study Drug Administration: Combination Azacitidine, Venetoclax, and Pevonedistat or Venetoclax Plus Azacitidine q, r, s
Azacitidine administration t
Days 1 through 7 of each cycle or Days 1 through 5, 8, and 9
Venetoclax administration
Days 1 through 28 of Cycle 1; Days 1 through 28 Cycle 2 and beyond
Pevonedistat infusion t
Days 1, 3, and 5 of each cycle
AE: adverse event; ALP: alkaline phosphatase; ALT: alanine aminotransferase; aPTT: activated partial thromboplastin time; AST: aspartate aminotransferase; BMA: bone marrow 
aspirate; BSA: body surface area; BUN: blood urea nitrogen; COVID-19: coronavirus disease 2019; C1D1: Cycle 1 Day 1; ECG: electrocardiogram; ECOG: Eastern Cooperative 
Oncology Group; eCRF: electronic case report form; EDC: electronic data capture; EOT: end of treatment; IEC: independent ethics committee; IRB: independent review board; IV: 
intravenous(ly); LDH: lactate dehydrogenase; PO: oral administration (orally); PT: prothrombin time; SAE: serious adverse event; SC: subcutaneous(ly); SOE: Schedule of Events; 
TEAE: treatment-emergent adverse event.
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 institutional and local guidelines) in situations where a site visit cannot be conducted, such as in a COVID-19 pandemic. The reason for telemedicine 
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Treatment Cycle (28 Days) a, b
EOT c
Day 1
Day 3
Day 5
Day 15
(eg, COVID-19–related) and the assessments performed are to be captured in the EDC.
a On dosing days, all procedures are to be performed before dosing, unless specified otherwise.
b For a new cycle of treatment with study drugs to begin, toxicities considered to be related to treatment with study drugs must have resolved to Grade ≤1 or patient’s baseline, as 
defined in Section 8.3.
c 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.
d Before dosing on Day 1 of the next full treatment cycle upon implementation of this modified SOE, patients must be reconsented (Section 9.4.2). Reconsenting should be done in 
person.
e Symptom-directed physical examination should be taken within 2 days of Day 1 of each cycle per standard of care.
f 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 F) on 
C1D1, 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.
g 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. Vital sign measurements will be taken with the patient in the supine or sitting position.
h ECG will be performed prior to study dose administration on Day 1 in each treatment cycle. Additional ECGs may be performed as clinically indicated.
i A pregnancy test must 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.
j Clinical laboratory evaluations will be performed by a local laboratory. All central laboratory assessments are discontinued. Patients should be assessed and treated according to 
standard of care using local laboratory evaluations. Abnormal hematology and chemistry data are to be collected and recorded in the eCRF only to the extent that they are needed to 
document or support an AE. Laboratory assessments to inform dosing decisions and routinely monitor patients do not need to be recorded in the eCRF.
k Coagulation panel includes PT and aPTT (to be performed by the central laboratory). Coagulation samples will be collected up to 3 days before Day 1 dosing in each treatment cycle 
and at EOT.
l The complete chemistry panel will include the following: BUN, creatinine, sodium, potassium, chloride, carbon dioxide, glucose, blood uric acid, total bilirubin, direct bilirubin, 
ALP, LDH, AST, ALT, albumin, magnesium, phosphate, and calcium.
m The select chemistry panel will include: BUN, creatinine, blood phosphate, total bilirubin, ALP, AST, and ALT.
n 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. Samples will be analyzed by a central laboratory.
o BMA samples will be collected for bone marrow blast count (local analyses) as clinically indicated. If relapse is suspected and a BMA sample is collected per standard of care, a 
portion of the sample may be used for additional disease assessment by the sponsor.
p SAEs will be entered in the eCRF. 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).
q Investigational pevonedistat + venetoclax + azacitidine arm (Arm A) only: See Section 8.10 for pevonedistat dosing instructions.
r All patients will receive azacitidine 75 mg/m2 IV or SC on Days 1 through 7 of each cycle or Days 1 through 5, 8, and 9 in accordance with Section 8.1.
s All patients will receive venetoclax 400 mg PO daily on Days 1 through 28 of a 28-day cycle. 
t In the Investigational Arm A (pevonedistat + venetoclax + azacitidine), azacitidine will be administered first followed by pevonedistat.
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Appendix C
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 (nonroutine/nonstandard panel) 
screening assessments, are NOT performed on potential patients 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 Code of Federal Regulations (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 patients. 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 50, ICH and local 
regulations, are met.
9. Obtain valid informed consent from each patient who participates in the study, and document 
the date of consent in the patient’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each ICF should contain a patient authorization section that 
describes the uses and disclosures of a patient’s personal information (including personal 
health information) that will take place in connection with the study. If an ICF does not include 
such a patient authorization, then the investigator must obtain a separate patient authorization 
form from each patient or the patient’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.
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 D
Investigator Consent to Use of Personal Information
Takeda will collect and retain personal information of the investigator, including his or her name, 
address, and other identifying personal information. In addition, the investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
UK, 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.
The 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 the 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.
The 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 the investigator’s 
own country.
The 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 E
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, 1982 [36].
ECOG: Eastern Cooperative Oncology Group.
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Appendix F
Body Surface Area
BSA should be calculated using a standard formula. An example formula is as follows:
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Appendix G
Excluded Moderate and Strong CYP3A Inducers
Use of the CYP3A inducers listed in the table below should be avoided during therapy unless 
otherwise noted in the protocol.
In Vivo Inducers of CYP3A
Moderate Inducers: 50%-80% Decrease in AUC
Strong Inducers: ≥80% Decrease in AUC
Bosentan
Carbamazepine
Efavirenz
Phenytoin
Modafinil
Phenobarbital
Primidone
Rifabutin
Rifampin
Rifapentine
St. John’s Wort
AUC: area under the curve; CYP: cytochrome P450.
This is not an exhaustive list; refer to the following sources: medicine.iupui.edu/flockhart/table htm and 
fda.gov/CDER/drug/drugInteractions/tableSubstrates.htm for additional information.
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Appendix H
New York Heart Association Classification of Cardiac Disease
The following table presents the New York Heart Association classification of cardiac disease.
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
Source: New York Heart Association [37].
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Appendix I
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: Etienne et al, 2007 [38].
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Appendix J
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 K
Modification of Diet in Renal Disease Study Equation
eGFR (mL/min/1.73 m2) = 175 × (Scr, std)-1.154 × (Age)-0.203 × (0.742 if female) × (1.212 if African 
American).
Where, eGFR is estimated glomerular filtration rate; Scr is serum creatinine.
The eGFR calculated above will be an estimate of creatinine clearance.
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Appendix L
Schedule of Events
Upon implementation of Protocol Amendment 4, the modified SOEschedule of events (Appendix A) will be followed for patients 
continuing on the study.
Screening 
a,b
Treatment Cycle (28 Days) c,d,e
Follow-up
Cycle 1
Cycle 2 and beyond
EFS f
Response g
OS
Days
1
3
5
8
15
21
1
3
5
EOT h
Every
Month
Upon PD or 
Suspected 
Relapse or
Relapse
Every
3 
Months
Procedures 
Window
±1 
Day
±1 
Day
+10 
Days
±2 
Weeks
±2
Weeks
±2 
Weeks
Informed consent
X
Inclusion/exclusion i
X
Demographics
X
Complete medical history
X
Modified Charlson comorbidity 
index assessment j
X
Complete physical examination 
X
X
Symptom-directed physical 
examination k
X
X
X
X
Height
X
Weight l
X
X l
X l
X
ECOG performance status
X
X
X
Vital signs m
X
X
X
X
X
X
X
X
12-lead ECG n
X
X
X
X
Chest x-ray o
X
Pregnancy test p
X
X
X
X
Hematology q
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation r
X
X
X
X
Complete chemistry panel q,s
X
X
X
X
X
X
X
X
X
Select chemistry panel q,t
X
X
X
X
Reticulocyte count and ferritin u
X
X
X
X
Urinalysis with microscopic 
analysis v
X
X
EORTC-QLQ-C30 w and 
supplemental items
X
X
X
X
X
X
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Screening 
a,b
Treatment Cycle (28 Days) c,d,e
Follow-up
Cycle 1
Cycle 2 and beyond
EFS f
Response g
OS
Days
1
3
5
8
15
21
1
3
5
EOT h
Every
Month
Upon PD or 
Suspected 
Relapse or
Relapse
Every
3 
Months
Procedures 
Window
±1 
Day
±1 
Day
+10 
Days
±2 
Weeks
±2
Weeks
±2 
Weeks
EQ-5D-5L w
X
X
X
X
X
X
Hospitalization assessment w
X
X
X
X
X
Plasma samples for pevonedistat 
PK 
X
X x
X x
X y
Blood samples for 
RNA z
X
Plasma samples for circulating 
biomarkers aa
X
X
Blood samples for
MOA and LSCs bb
X
X
X
BMA/biopsy and investigator 
disease assessment
See Appendix L, Table 1 for Bone Marrow Collection and Assessment Schedule
Serum sample for circulating 
biomarkers cc
X
X
X
SAE collection dd
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
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 ee
X
X
X
X
Survival follow-up contact
X
Study Drug Administration: Combination Azacitidine, Venetoclax, and Pevonedistat or Venetoclax Plus Azacitidine e,ff,gg,hh
Azacitidine administration ii
Days 1 through 7 of each cycle or Days 1 through 5, 8, and 9
Venetoclax administration
Days 1 through 28 of Cycle 1; Days 1 through 28 Cycle 2 and beyond
Pevonedistat infusion ii
Days 1, 3, and 5 of each cycle
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Screening 
a,b
Treatment Cycle (28 Days) c,d,e
Follow-up
Cycle 1
Cycle 2 and beyond
EFS f
Response g
OS
Days
1
3
5
8
15
21
1
3
5
EOT h
Every
Month
Upon PD or 
Suspected 
Relapse or
Relapse
Every
3 
Months
Procedures 
Window
±1 
Day
±1 
Day
+10 
Days
±2 
Weeks
±2
Weeks
±2 
Weeks
AE: adverse event; ALP: alkaline phosphatase; ALT: alanine aminotransferase; AML: acute myeloid leukemia; aPTT: activated partial thromboplastin time; AST: aspartate 
aminotransferase; BMA: bone marrow aspirate; BSA: body surface area; BUN: blood urea nitrogen; C1D1: Cycle 1 Day 1; ECG: electrocardiogram; ECOG: Eastern Cooperative 
Oncology Group; eCRF: electronic case report form; EFS: event-free survival; EORTC-QLQ-C30 European Organisation for the Research and Treatment of Cancer Core Quality of 
Life Questionnaire; EOT: end of treatment; EQ-5D-5L: EuroQoL 5 dimensions 5 levels; HRQOL: health-related quality of life; IEC: independent ethics committee; IRB: independent 
review board; IV: intravenous(ly); LDH: lactate dehydrogenase; LSC: leukemic stem cell; MOA: mechanism of action; OS: overall survival; PD: progressive disease; PK: 
pharmacokinetics; PT: prothrombin time; RBC: red blood cell; SAE: serious adverse event; SC: subcutaneous(ly); TLS: tumor lysis syndrome.
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 institutional and local guidelines) in situations where a site visit cannot be conducted, such as in a COVID-19 pandemic. The reason for telemedicine 
(eg, COVID-19–related) and the assessments performed are to be captured in the electronic data capture (EDC).
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 C1D1 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 dosing unless specified otherwise.
d For a new cycle of treatment with study drugs to begin, toxicities considered to be related to treatment with study drugs must have resolved to Grade ≤1 or patient’s baseline, as 
defined in Section 8.3.
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 drugs 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 of azacitidine should 
not be exceeded. If dosing is adjusted, study procedures should be performed on the actual day of dosing.
f EFS follow-up is monthly, but BMA is taken during the beginning of the EFS follow-up and then once every 3 months thereafter, or upon suspected relapse from CR or CRi.
g Response visits apply to patients whom have discontinued treatment for a reason other than PD.
h 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 will enter EFS follow-up if their disease has not progressed and they have not started subsequent therapy. Patients will enter OS follow-up when they have started subsequent 
therapy.
i Confirmation of patient eligibility by the study medical monitor is required prior to randomization. A patient eligibility checklist must be completed and submitted by the investigator 
for review and approval by the sponsor or designee prior to patient randomization.
j See Appendix I for the modified Charlson comorbidity index.
k Symptom-directed physical examination should be taken within 2 days of Day 1 of each cycle per standard of care.
l 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 F) on 
C1D1, 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.
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Screening 
a,b
Treatment Cycle (28 Days) c,d,e
Follow-up
Cycle 1
Cycle 2 and beyond
EFS f
Response g
OS
Days
1
3
5
8
15
21
1
3
5
EOT h
Every
Month
Upon PD or 
Suspected 
Relapse or
Relapse
Every
3 
Months
Procedures 
Window
±1 
Day
±1 
Day
+10 
Days
±2 
Weeks
±2
Weeks
±2 
Weeks
m 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. Vital sign measurements will be taken with the patient in the supine or sitting position.
n ECG will be performed prior to study dose administration on Day 1 in each treatment cycle. Additional ECGs may be performed as clinically indicated. Note: Echocardiogram or 
multigated acquisition (MUGA) scan will be performed at screening if data for these is not available within 3 months of screening.
o If a chest x-ray or chest CT scan was performed within 2 months prior to randomization, the chest x-ray does not need to be performed during screening.
p 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.
q Clinical laboratory evaluations will be performed by a central laboratory. The central laboratory results should be used for determination of eligibility by the sponsor’s project 
clinician (or designee) prior to 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 lab 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. Note: An additional sample for hematology evaluation will be collected on Cycle 2 Day 15.
r Coagulation panel includes PT and aPTT (to be performed by the central laboratory). Coagulation samples will be collected up to 3 days before Day 1 dosing in each treatment cycle 
and at EOT.
s The complete chemistry panel will include the following: BUN, creatinine, sodium, potassium, chloride, carbon dioxide, glucose, blood uric acid, total bilirubin, direct bilirubin, 
ALP, LDH, AST, ALT, albumin, magnesium, phosphate, and calcium. Note: An additional sample for complete chemistry evaluation will be collected on Cycle 2 Day 15. The 
TLS panel will include calcium, phospate, potassium, blood uric acid and creatinine. TLS panel will be done at a local laboratory at predose on Day 1 of venetoclax dosing and 
at predose on Day 1 of each new venetoclax dose level (see Section 8.1). TLS panel will be checked between 4 to 12 hours after each new venetoclax dose level (ie, during the 
venetoclax ramp-up), and 24 hours after reaching final dose (see Section 8.7.3).
t The select chemistry panel will include the following: BUN, creatinine, blood phosphate, total bilirubin, ALP, AST, and ALT.
u 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.
v 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.
w 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 drugs administered. The EORTC-QLQ-C30 and EQ-5D-5L will be completed.
x Investigational pevonedistat + venetoclax + azacitidine (Arm A) only: blood samples for the determination of pevonedistat plasma concentrations will be collected during Cycle 1 at 
the following time points: 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 at the end of the pevonedistat infusion (immediately before stopping the infusion); and Day 5 predose (within 10 minutes before 
azacitidine dosing), at the end of the pevonedistat infusion (immediately before stopping the infusion), and at 4 hours (± 45 minutes) after completion of the pevonedistat infusion. The 
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Screening 
a,b
Treatment Cycle (28 Days) c,d,e
Follow-up
Cycle 1
Cycle 2 and beyond
EFS f
Response g
OS
Days
1
3
5
8
15
21
1
3
5
EOT h
Every
Month
Upon PD or 
Suspected 
Relapse or
Relapse
Every
3 
Months
Procedures 
Window
±1 
Day
±1 
Day
+10 
Days
±2 
Weeks
±2
Weeks
±2 
Weeks
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 Investigational pevonedistat + venetoclax + azacitidine (Arm A) only: blood samples 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). 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.
z Investigational pevonedistat + venetoclax + azacitidine treatment arm (Arm A) only: Blood samples for RNA will be collected at C1D1 prior to study dose administration, at 4 hours 
(±45 minutes) and 8 hours (±45 minutes) after completion of the pevonedistat infusion.
aa Plasma samples for circulating biomarkers will be collected C1D1 prior to study dose administration, at 4 hours (±45 minutes) and 8 hours (±45 minutes) postdose and at suspected 
relapse or relapse in both treatment arms. The exact date and time of each sample collection should be recorded accurately. Details regarding the preparation, handling, and shipping 
of samples are provided in the Study Manual.
bb Blood samples for MOA and LSCs will be collected on C1D1 at predose and 4 hours postdose and on C2D1 and C4D1 at predose and 3 hours postdose and at suspected relapse or 
relapse in both treatment arms. Use the same methodology for this assessment throughout the study. The exact date and time of each sample collection should be recorded accurately. 
Details regarding the preparation, handling, and shipping of samples are provided in the Study Manual.
cc Serum sample for circulating biomarkers. Blood samples for serum biomarker analysis will be collected at C1D1 before study dose administration and at 8 hours (±45 minutes) 
postdose and on C2D1 at predose and 3 hours postdose and at suspected relapse or relapse in both treatment arms.
dd SAEs will be entered in the eCRF. Serious pretreatment events (occurring before the first dose of any study drug) will be reported to the Takeda Global Pharmacovigilance 
Department (or designee) and will be recorded in the eCRF. 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).
ee Subsequent therapy is defined as an agent(s) with antileukemic activity.
ff Investigational pevonedistat + venetoclax + azacitidine arm (Arm A) only: See Section 8.10 for pevonedistat dosing instructions. Subsequent pevonedistat doses may be reduced 
because of toxicity in accordance with Section 8.3.3.1 (nonhematologic toxicities) and Section 8.3.2.1 (hematologic toxicities).
gg All patients will receive azacitidine 75 mg/m2 IV or SC on Days 1 through 7 of each cycle or Days 1 through 5, 8, and 9 in accordance with Section 8.1. The azacitidine dose may 
be reduced due to toxicity in accordance with Section 8.3.2.3.
hh During Cycle 1 only, venetoclax will be administered at the ramp-up doses of 100 mg on Day 1, 200 mg on Day 2, and 400 mg Days 3 through 28. From Cycle 2 and subsequent 
cycles, all patients will receive venetoclax 400 mg PO daily on Days 1 through 28 of a 28-day cycle. If remission is confirmed in Cycle 1 or thereafter, Venetoclax (400 mg) can be 
administered on Days 1 through 21 of a 28-day cycle in subsequent cycles, to prevent potential prolonged myelosuppression and treatment delays. If, in the opinion of the investigator, 
venetoclax (400 mg) administered on Days 1 through 21 (of a 28-day cycle) is well tolerated, venetoclax (400 mg) may be administered at full dosing frequency (400 mg given on 
Days 1 through 28 of 28-day cycle) in subsequent cycles.
ii In the investigational arm, azacitidine will be administered first followed by pevonedistat.
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Table 1
Bone Marrow Collection and Assessment Schedule
Assessment
Screening
Cycle 1
Cycle 3
Cycle 6
Cycle 9
Suspected
Relapse or 
Relapse
EFS/Response 
Follow-up
(Every 3 Months)
Bone marrow blast count
(local and central analyses)
X a
X b
X b,c
X b,c
X b,c
X
X c
Fresh BMA sample for 
molecular analysis (MOA 
and LSCs enumeration)
X d
X d
X d
X d
X d
X e
Fresh BMA sample for 
molecular analysis, MRD, 
and cytogenetic risk 
category
X d,f
X d
X d
X d
X d
X e
Mutation analysis
(local analysis report only)
X g
Locally generated pathology 
report
X f
Locally generated 
cytogenetic report
X f
BMA: bone marrow aspirate; CR: complete remission; CRi: complete remission with incomplete blood count recovery; eCRF: electronic case report form; EFS: event-free survival; 
LSC: leukemic stem cell; MOA: mechanism of action; MRD: measurable residual disease; PCR: polymerase chain reaction; PD: progressive disease.
a BMA will be collected at screening and indicated time points (up to -7 days), at relapse or PD, and as clinically indicated (see Section 9.4.20.1 for detailed examples). A bone 
marrow biopsy may be collected only at screening to confirm the diagnosis. A bone marrow biopsy may be collected with BMA in accordance with institutional guidelines. If a biopsy 
was performed within 28 days before randomization, this archival sample may be used to confirm diagnosis and does not need to be repeated. However, a BMA for molecular analysis 
is still required at screening (see footnote d below). The bone marrow pathology report(s) will be submitted to the central laboratory.
b A BMA for blast count (to inform disease burden assessment) will be performed at screening, Cycle 1, Cycle 3, and every 3 cycles thereafter, or at suspected relapse or relapse. 
Results must be available before dosing starts in the next cycle.
c For patients who achieve CR at any cycle, BMA will be performed only as clinically indicated or at suspected relapse or at relapse. Additional BMA may be performed if warranted 
by changes in peripheral blood counts.
d Fresh BMA will be obtained at screening, Cycle 1, Cycle 3, and every 3 cycles thereafter, or at suspected relapse or at relapse for baseline and longitudinal molecular 
characterization. For patients who achieve CR at any cycle, BMA will be performed only as clinically indicated or at suspected relapse or at relapse. Patients who achieve a CR are 
encouraged, but not required, to have a BMA on the indicated time points. Patients who have a CRi are required to have BMA on the indicated time points. BMA samples will be sent 
to a central laboratory for molecular analysis. 
e 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).
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Table 1
Bone Marrow Collection and Assessment Schedule
Assessment
Screening
Cycle 1
Cycle 3
Cycle 6
Cycle 9
Suspected
Relapse or 
Relapse
EFS/Response 
Follow-up
(Every 3 Months)
f Cytogenetics analysis will be done at a central laboratory. A BMA sample taken within 28 days of randomization will be shipped for analysis at the central laboratory (per 
instructions in the Laboratory Manual). In addition, whenever cytogenetic analysis is performed locally at the clinical site the cytogenetic report(s)/pathology report(s) will be 
submitted to the central laboratory.
g Results of mutation analysis to be performed locally at the clinical site according to institutional guidelines/standard practice (eg, genomic analysis or PCR analysis) will be collected 
from sites. If mutation analysis is not performed routinely per country/institutional guidelines, it is not required. Mutation analysis report(s) will be submitted to the central laboratory.
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Appendix M Protocol History
Amendment History:
Date
Amendment No.
Amendment Type
Region
21 January 2022
4
Substantial
Global
08 July 2021
3
Substantial (not implemented)
Global
28 July 2020
2
Substantial
Global
10 July 2020
1
Substantial
Global
21 November 2019
Initial Protocol
Not applicable
Global
Protocol Amendment 3 Summary and Rationale:
Protocol Amendment 3 (dated 08 July 2021), which converted the phase 2 study to a 
registration-enabling phase 3 study and included a change in the primary endpoint, expansion of 
sample size, and increase in number of sites, will not be implemented. Thus, the changes in 
reference to the protocol incorporating Amendment 3 are not shown here.
Rationale for Amendment 2
This document describes the changes in reference to the protocol incorporating Amendment 2. 
The primary reason for this amendment is to incorporate changes requested by Global Health 
Authorities.
In this amendment, minor grammatical, editorial, formatting, and administrative changes not 
affecting the conduct of the study are included for clarification and administrative purposes only.
Protocol Amendment 2
Summary of Changes Since the Last Version of the Approved Protocol
Description of Each Change and Rationale
Sections Affected by Change
Description
Rationale
Location
1.
Updated dose modification 
guidelines for drug-related 
toxicity to include toxicity at 
least possibly related to study 
drug
Change made in response to 
protocol review by Global Health 
Authorities
Section 8.3.1.1 Retreatment Within 
a Cycle
2.
Updated dose modification 
guidelines for drug-related 
toxicity of Grade 3 to 4 at least 
possibly related to study drug
Change made in response to 
protocol review by Global Health 
Authorities
Section 8.3.3.1 Pevonedistat
Paragraph relating to Pevonedistat 
Dose Adjustment for Other 
Toxicities
3.
Required additional 
hematology panel on Day 15 of 
Cycle 2
Change made in response to 
protocol review by Global Health 
Authorities
Appendix A Schedule of Events, 
footnote “q”
4.
Required additional complete 
chemistry panel on Day 15 of 
Cycle 2
Change made in response to 
protocol review by Global Health 
Authorities
Appendix A Schedule of Events, 
footnote “s”
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Protocol Amendment 2
Summary of Changes Since the Last Version of the Approved Protocol
Description of Each Change and Rationale
Sections Affected by Change
Description
Rationale
Location
5.
Defined tumor lysis syndrome 
(TLS) panel
Provided analytes in TLS in Clinical 
Laboratory Evaluations section of 
the protocol
Section 9.4.18 Clinical Laboratory 
Evaluations and Table 9.b Complete 
Serum Chemistry and Tumor Lysis 
Syndrome Panels
6.
Added potassium to TLS panel 
and clarified TLS collection 
times relative to venetoclax 
dosing
Updated missing analyte and 
included the collection times in the 
Schedule of Events for consistency 
with text in the body of the protocol
Appendix A Schedule of Events, 
footnote “s”
7.
Updated citations for US 
Prescribing Information and 
Summary of Product 
Characteristics for venetoclax 
and azacitidine
Editorial update to provide current 
information
Section 16.0 REFERENCES and 
throughout the document
Rationale for Amendment 1
This document describes the changes in reference to the protocol incorporating Amendment 1. 
The primary reason for this amendment is to incorporate changes requested by Global Health 
Authorities.
In this amendment, minor grammatical, editorial, formatting, and administrative changes not 
affecting the conduct of the study are included for clarification and administrative purposes only.
Protocol Amendment 1
Summary of Changes Since the Last Version of the Approved Protocol
Description of Each Change and Rationale
Sections Affected by Change
Description
Rationale
Location
1.
Clarified use of strong 
cytochrome P450 (CYP)3A 
inhibitors
Change made in response to 
protocol review by Global Health 
Authorities
Section 4.7.2.3 Drug Interactions
Section 8.3.1.3 Venetoclax Dosing 
With CYP3A4 Inducers and 
Inhibitors
Table 8.d Management of Potential 
Venetoclax Interactions With 
CYP3A and P-gp Inhibitors for 
Patients With AML
2.
Clarified criteria for resumption 
of therapy after toxicity in 
initiation of new cycle of 
treatment
Change made in response to 
protocol review by Global Health 
Authorities
Section 8.3.1.2 Initiation of a New 
Cycle
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Protocol Amendment 1
Summary of Changes Since the Last Version of the Approved Protocol
Description of Each Change and Rationale
Sections Affected by Change
Description
Rationale
Location
3.
Added guidance in a new 
protocol section on 
management of cytopenia and 
infection
Change made in response to 
protocol review by Global Health 
Authorities
Section 8.7.5 Management of 
Cytopenia and Infection
4.
Specified that nonessential 
protocol visits that do not 
require on-site sample 
collection and assessment may 
be completed via telemedicine
Provide general guidance
Section 9.4 Study Procedures
Appendix A Schedule of Events, 
Note below Table
5.
Required additional 
coagulation panel tests on 
Day 1 of each treatment cycle
Change made in response to 
protocol review by Global Health 
Authorities
Section 9.4.18 Clinical Laboratory 
Evaluations
Appendix A Schedule of Events
6.
Required additional ECG 
measurement on Day 1 of each 
treatment cycle
Change made in response to 
protocol review by Global Health 
Authorities
Appendix A Schedule of Events
7.
Revised the timeframe of 
contraception (and donation of 
eggs) in women of childbearing 
potential from 4 months to 6 
months
Change made in response to 
protocol review by Global Health 
Authorities
Section 7.1 Inclusion Criteria
Section 7.2 Exclusion Criteria
Section 8.6 Precautions and 
Restrictions
8.
Updated Sponsor contact 
information
Updated Corporate name and 
change of headquarter location
Title Page
Section 2.0 Study Summary
Section 3.4 Corporate Identification
9.
Deleted exploratory objective 
and endpoint related to 
potential of a biomarker based 
on the mutation status of select 
AML genes
The biomarker was found to lack 
predictive ability in a previous study 
and its predictive potential to the 
triple combination was no longer 
considered valid
Section 5.1.4 Exploratory 
Objectives
Section 5.2.4 Exploratory Endpoints
10. Updated number of sites to 
approximately 85 globally 
(increased from approximately 
70 sites globally)
Allow flexibility and faster 
enrollment into the study
Section 2.0 Study Summary
Section 6.2 Number of Patients
For non-commercial use only

Pevonedistat (TAK-924/MLN4924)
Study No. Pevonedistat-2002
Page 130 of 131
Protocol Incorporating Amendment No. 4
21 January 2022
CONFIDENTIAL
Protocol Amendment 1
Summary of Changes Since the Last Version of the Approved Protocol
Description of Each Change and Rationale
Sections Affected by Change
Description
Rationale
Location
11. Clarified venetoclax dosing 
information for Cycle 1 and 
subsequent cycles (provided 
dosing guidelines in case of 
confirmed remission or if 
venetoclax is well tolerated)
Change made in response to 
protocol review by Global Health 
Authorities
Section 2.0 Study Summary
Section 4.6.4 Rationale for Dose and 
Schedule of Study Drugs
Section 6.1 Overview of Study 
Design
Section 8.1Study Drug 
Administration: Pevonedistat With 
Venetoclax and Azacitidine
Section 8.2 Reference/Control 
Therapy: Venetoclax Plus 
Azacitidine
Appendix A Schedule of Events
12. Modified inclusion criteria to 
avoid enrolling patients with 
not suitable intensive 
chemotherapy
Change made in response to 
protocol review by Global Health 
Authorities
Section 2.0 Study Summary
Section 7.1 Inclusion Criteria, 
criterion #3
13. Defined supraphysiologic doses 
of corticosteroids (>10 mg/d 
prednisone or equivalent)
Increase clarity
Section 8.4 Excluded Concomitant 
Medications and Procedures, Table 
8.c
14. Clarified sequence of drug 
administrations in the 
investigational arm
Increase clarity
Section 8.1 Study Drug 
Administration: Pevonedistat With 
Venetoclax and Azacitidine
Appendix A Schedule of Events, 
footnote “ii”
15. Clarified the role of Central and 
Local Laboratories
Increase clarity
Section 9.4.18 Clinical Laboratory 
Evaluations
16. Added echocardiogram or 
multigated acquisition scan and 
their timeframe
Change made in response to 
protocol review by Global Health 
Authorities
Section 7.2 Exclusion Criteria
Section 9.4.12 ECG
Appendix A Schedule of Events
17. Required additional 
hematology panel on Day 5 of 
subsequent cycles, complete 
chemistry panel on Cycle 1 
Days 1 and 5 and on Day 5 of 
subsequent cycles, and 
additional time points for 
Coagulation were added
Change made in response to 
protocol review by Global Health 
Authorities
Appendix A Schedule of Events, 
including footnote “r”
18. Added tumor lysis syndrome 
chemistry panel to chemistry 
panel in Cycle 1
Change made in response to 
protocol review by Global Health 
Authorities
Appendix A Schedule of Events
For non-commercial use only

Pevonedistat (TAK-924/MLN4924)
Study No. Pevonedistat-2002
Page 131 of 131
Protocol Incorporating Amendment No. 4
21 January 2022
CONFIDENTIAL
Protocol Amendment 1
Summary of Changes Since the Last Version of the Approved Protocol
Description of Each Change and Rationale
Sections Affected by Change
Description
Rationale
Location
19. Added dose modification 
language for azacitidine based 
on serum levels of bicarbonate, 
blood urea nitrogen or 
creatinine
Change made in response to 
protocol review by Global Health 
Authorities
Section 8.7.1 Azacitidine
20. Clarified time points for 
collection of bone marrow 
aspirate and bone marrow 
biopsy
Increase clarity
Section 6.1 Overview of Study 
Design
Appendix A Schedule of Events, 
Table 1, footnote “a”
21. Indicated that Modification of 
Diet in Renal Disease Study 
equation should be used for 
calculation of creatinine 
clearance (not Cockcroft-Gault 
formula)
Updated procedural change
Section 2.0 Study Summary
Section 7.1 Inclusion Criteria, 
criterion #4
Section 9.4.18 Clinical Laboratory 
Evaluations
Appendix K
Modification of Diet 
in Renal Disease Study Equation
22. Indicated that an initial safety 
assessment will be performed 
after 10 patients have 
completed at least 1 cycle of 
treatment
Change made in response to 
protocol review by Global Health 
Authorities
Section 11.3 Takeda Safety 
Monitoring
For non-commercial use only

For non-commercial use only