Conditions: Myelodysplastic Syndromes Leukemia, Myelomonocytic, Chronic Leukemia, Myeloid, Acute Renal Insufficiency Liver Disease Neoplasms
Keywords: Drug therapy
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 17
Healthy volunteers: no

Brief summary:
Pevonedistat is a medicine to treat people with blood cancers or solid tumors.

The main aim of the study is to learn about the levels of pevonedistat in the blood of participants with blood cancers or solid tumors, who also have severe kidney problems or mild to moderate liver problems. The information from this study will be used to work out the best dose of pevonedistat to give people with these conditions in future studies. At the first visit, the study doctor will check who can take part in the study.

This study is in 2 parts: A and B.

Part A Participants will be placed into 1 of 4 treatment groups depending on how severe their kidney and liver problems are. All participants will receive 1 dose of pevonedistat as a slow injection in their vein (infusion). Then, the study doctors will check the levels of pevonedistat in the blood of the participants for 3 days after the infusion. They will also check if the participants have any side effects from pevonedistat.

Participants will be asked to continue to Part B. Those who don't want to continue will visit the clinic 30 days later for a final check-up.

Part B Participants who agree to participate into Part B will receive an infusion of pevonedistat on specific days during a 21-day or 28-day cycle. The cycle time will depend on what type of cancer the participants have. Participants will also be treated with standard of care medicines for their kidney and liver problems during this time. In the first cycle, the study doctors will also check the levels of pevonedistat in the blood and urine of participants for 3 days after the infusion. Participants will continue with cycles of treatment together with standard of care medicines until their condition gets worse or they have too many side effects from the treatment.

When treatment has finished, participants will visit the clinic 10 days later for a final check-up.

Detailed description:
The drug being tested in this study is called pevonedistat. The study will characterize the PK of pevonedistat, assess the safety, and determine the dose of pevonedistat, in combination with azacitidine, docetaxel OR paclitaxel plus carboplatin in participants with higher-risk myelodysplastic syndromes (HRMDS), myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), acute myelogenous leukemia (AML), or advanced solid tumors who also have severe renal impairment or mild or moderate hepatic impairment.

The study will enroll approximately 42 participants. Participants with solid tumors or hematologic malignancies will be assigned to one of the four treatment groups on the basis of their renal and hepatic function:

* Control Arm (Normal Renal and Hepatic Function)
* Renal Arm (Severe Renal Impairment)
* Mild Hepatic Arm (Mild Hepatic Impairment)
* Moderate Hepatic Arm (Moderate Hepatic Impairment)

The study will be conducted in 2 parts: Part A and Part B. Part A will include single dose administration of pevonedistat. Eligible participants from Part A who will opt to continue treatment in Part B will be treated with pevonedistat in combination with standard of care (SOC) agents (azacitidine, docetaxel OR paclitaxel plus carboplatin) in Part B.

Intrapatient dose escalation of pevonedistat and SOC agents will be based on the safety data from Cycle 1 of Part B as mentioned below:

* In renal arm (severe renal impairment ) based on the safety data from Cycle 1 of Part B, pevonedistat may be increased to 15 mg/m\^2 on Days 1, 3, and 5 of Cycle 2 Part B and in subsequent Cycles, to a maximum dose of 25 mg/m\^2. Participants may be eligible for intrapatient dose escalation to paclitaxel 175 mg/m\^2 in Cycle 2 or beyond if the lower dose is well tolerated. Intrapatient dose escalation of carboplatin to AUC5 will be allowed if treatment with AUC4 in Cycle 1 of Part B is safe and tolerable.
* In mild hepatic arm (mild hepatic impairment), the starting dose for pevonedistat and azacitidine in combination are not escalated in the cohort. Intrapatient dose escalation of carboplatin to AUC5 will be allowed if treatment with AUC4 in Cycle 1 of Part B is safe and tolerable.
* In moderate hepatic arm (moderate hepatic impairment) based on the safety data from Cycle 1 of Part B, pevonedistat may be increased to 15 mg/m\^2 on Days 1, 3, and 5 of Cycle 2 Part B and in subsequent Cycles, to a maximum dose of 20 mg/m\^2. Intrapatient dose escalation of carboplatin to AUC5 will be allowed if treatment with AUC4 in Cycle 1 of Part B is safe and tolerable.

This multi-center trial will be conducted in the United States and Spain. The overall time to participate in this study is approximately 3.5 years. Participants will attend end of the study visit 30 days after the last dose of study drug or before the start of subsequent therapy, if that occurs sooner for safety follow up.

Arms:
arm 1: Pevonedistat 20 milligram per square meter (mg/m\^2), infusion, intravenously, once, on Day 1 of Part A in participants with hematologic malignancies, followed by a washout period of approximately 4 to 7 days, further followed by azacitidine 75 mg/m\^2, injection, subcutaneously in Cycle 1 or subcutaneously or intravenously in Cycle 2 and subsequent cycles, once on Day 1 through Day 7 or Day 1 through Day 5, and on Days 8 and 9 in combination with pevonedistat 20 mg/m\^2, infusion, intravenously, once, on Days 1, 3, and 5 in each 28-day treatment cycle in participants with hematologic malignancies until symptomatic deterioration or PD, discontinuation for any reason, study stopped by the sponsor, or up to 12 cycles. arm 2: Pevonedistat 20 mg/m\^2, infusion, intravenously, once, on Day 1 of Part A in participants with hematologic malignancies, followed by a washout period of approximately 4 to 7 days, further followed by azacitidine 75 mg/m\^2, injection, subcutaneously in Cycle 1 or subcutaneously or intravenously in Cycle 2 and subsequent cycles, once on Day 1 through Day 7 or Day 1 through Day 5, and on Days 8-9 in combination with a starting dose of pevonedistat 10 mg/m\^2 to a maximum dose of pevonedistat 15 mg/m\^2, infusion, intravenously, once, on Days 1, 3, and 5 in each 28-day treatment cycle in participants with hematologic malignancies until symptomatic deterioration or PD, discontinuation for any reason, study stopped by the sponsor, or up to 12 cycles. arm 3: Pevonedistat 20 mg/m\^2, infusion, intravenously, once, on Day 1 of Part A in participants with hematologic malignancies, followed by a washout period of approximately 4 to 7 days, further followed by azacitidine 75 mg/m\^2, injection, subcutaneously in Cycle 1 or subcutaneously or intravenously in Cycle 2 and subsequent cycles, once on Day 1 through Day 7 or Day 1 through Day 5, and on Days 8 and 9 in combination with a starting dose of pevonedistat 10 mg/m\^2 to a maximum dose of pevonedistat 20 mg/m\^2, infusion, intravenously, once, on Days 1, 3, and 5 in each 28-day treatment cycle in participants with hematologic malignancies until symptomatic deterioration or PD, discontinuation for any reason, study stopped by the sponsor, or up to 12 cycles.

Interventions: intervention 1: Azacitidine intervention 2: Pevonedistat
Intervention descriptions: intervention 1: Azacitidine subcutaneous or intravenous injection. intervention 2: Pevonedistat intravenous infusion.

Protocol document:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL 
NCT Number: 
Study Title: 
Study Number: 
NCT03814005 
A Phase 1/1b Study of Pevonedistat in Combination With Select 
Standard of Care Agents in Patients With Higher-Risk 
Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, 
Acute Myelogenous Leukemia, or Advanced Solid Tumors With 
Severe Renal Impairment or Mild or Moderate Hepatic Impairment 
Pevonedistat-1016
Protocol Version and Date: 
Version 4.0: 01-June-2021 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


1.0 TITLE PAGE
PROTOCOL
A Phase 1/1b Study of Pevonedistat in Combination With Select Standard of Care Agents in 
Patients With Higher-Risk Myelodysplastic Syndromes, Chronic Myelomonocytic 
Leukemia, Acute Myelogenous Leukemia, or Advanced Solid Tumors With Severe Renal 
Impairment or Mild or Moderate Hepatic Impairment
Pevonedistat Plus Select Standard of Care Agents Administered in Cancer Patients
With Renal or Hepatic Impairment
Sponsor:
Takeda Development Center Americas, Inc. 
95 Hayden Avenue
Lexington, MA 02421
Study Number:
Pevonedistat-1016
EudraCT Number:
2018-004049-17
Compound:
Pevonedistat (TAK-924/MLN4924) 
Date:
27 May 2021
Version/Amendment 
Number:
4
Amendment History:
Date
Amendment No.
Amendment Type
Region
27 May 2021
4
Substantial
Global
04 November 2020
3
Substantial
Global
29 June 2020
2
Substantial
Global
25 February 2019
1
Substantial
Global
07 November 2018
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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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 Development Center–sponsored investigators per individual country requirements will be 
provided with emergency medical contact information cards to be carried by each subject.
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site. Information on service providers is given in Section 3.1 and relevant guidelines 
provided to the site.
Contact Type/Role
North America
Europe
Serious adverse event and pregnancy reporting
See Section 10.0
See Section 10.0
Medical Monitor
(medical advice on protocol and compound)
Refer to Study Manual
Refer to Study Manual
Responsible Medical Officer
(carries overall responsibility for the conduct of the 
study)
Refer to Study Manual
Refer to Study Manual
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1.2
Approval
REPRESENTATIVES OF TAKEDA
This study will be conducted with the highest respect for the individual participants in accordance 
with the requirements of this clinical study protocol and also in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Council for Harmonisation (ICH) E6 Good Clinical Practice (GCP): 
Consolidated Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws, clinical 
trial disclosure laws, and regulations.
SIGNATURES
The signature of the responsible Takeda medical officer (and other signatories, as applicable) can 
be found on the signature page.
Electronic Signatures may be found on the last page of this document.
 MD
(or designee)
Date
PhD
(or designee)
Date
 PhD
(or designee)
Date
PhD
(or designee)
Date
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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 subjects in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Council for Harmonisation, E6 Good Clinical Practice: Consolidated Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting serious adverse events (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 C 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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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 reason for this amendment is to update the name of the legal entity to Takeda 
Development Center Americas, Inc. and to update its address. In addition, the text on the posttrial 
access (PTA) program and its duration are clarified, a clarification in the schedule of events is 
provided, and a corrected study diagram is provided.
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 4
Summary of Changes Since the Last Version of the Approved Protocol
Change 
Number
Sections Affected by Change
Description of Each Change and Rationale
Location
Description
Rationale
1.
Title page
Section 2.0 STUDY 
SUMMARY
Section 3.4 Corporate 
Identification
Updated the name and address 
of legal entity to Takeda 
Development Center Americas, 
Inc., 95 Hayden Avenue, 
Lexington, MA 02421
Update to name of the legal entity 
and its address.
2.
Section 6.3.5 PTA
Updated and clarified text on 
the posttrial access program 
and its duration.
Change made to include the current 
approach by the sponsor.
3.
Section 7.2 Exclusion 
Criteria Item 20.
Added multigated acquisition scan 
for the determination of left 
ventricular ejection fraction
(LVEF) at screening.
Change made to increase flexibility 
of measurements.
4.
Appendix A SOE
SOE for Part A: Single Agent 
Pevonedistat and PK (All 
Patients) Footnotes
Updated Schedule of Events 
(SOE) table to include (LVEF) 
screening timing.
Clarified timing of LVEF in the SOE 
previously included in the Exclusion 
Criteria.
5.
Appendix B Study Diagrams
Replaced Study Diagram for 
patients with hematologic 
malignancies
Correction of an error in the 
designation of study days in Part A of 
the Study Diagram (no change made 
to study conduct/assessments).
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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 ....................................................................................................12
3.0
STUDY REFERENCE INFORMATION ......................................................................20
3.1
Study-Related Responsibilities.................................................................................20
3.2
Principal Investigator/Coordinating Investigator ......................................................20
3.3
List of Abbreviations ...............................................................................................21
3.4
Corporate Identification...........................................................................................23
4.0
INTRODUCTION.........................................................................................................24
4.1
Background .............................................................................................................24
4.1.1
Study Drug ......................................................................................................24
4.1.2
Nonclinical Background ..................................................................................25
4.1.3
Clinical Background Information.....................................................................25
4.1.4
Potential Risks and Benefits.............................................................................28
4.1.5
Potential for DDIs............................................................................................33
4.1.6
Summary of Risks and Benefits .......................................................................33
4.2
Rationale for the Proposed Study.............................................................................34
4.3
Rationale for the Dose .............................................................................................35
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................38
5.1
Objectives................................................................................................................38
5.1.1
Primary Objectives ..........................................................................................38
5.1.2
Secondary Objectives ......................................................................................39
5.1.3
Safety Objective ..............................................................................................39
5.1.4
Exploratory Objectives ....................................................................................39
5.2
Endpoints.................................................................................................................39
5.2.1
Primary Endpoints ...........................................................................................39
5.2.2
Secondary Endpoints .......................................................................................40
5.2.3
Exploratory Endpoints .....................................................................................40
5.2.4
Safety Endpoints..............................................................................................40
6.0
STUDY DESIGN..........................................................................................................40
6.1
Overview of Study Design.......................................................................................40
6.2
Number of Patients ..................................................................................................42
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6.3
Duration of Study ....................................................................................................42
6.3.1
Duration of an Individual Patient’s Study Participation....................................42
6.3.2
End of Study/Study Completion Definition and Planned Reporting..................43
6.3.3
Timeframes for Primary and Secondary Endpoints to Support Disclosures ......43
6.3.4
Total Study Duration .......................................................................................44
6.3.5
PTA.................................................................................................................45
7.0
STUDY POPULATION................................................................................................45
7.1
Inclusion Criteria .....................................................................................................45
7.1.1
All Patients......................................................................................................45
7.1.2
Patients With Hematologic Malignancies.........................................................46
7.1.3
Patients With Advanced Solid Tumors.............................................................47
7.2
Exclusion Criteria ....................................................................................................48
7.2.1
All Patients......................................................................................................48
7.2.2
Patients With Hematologic Malignancies.........................................................50
7.2.3
Patients With Advanced Solid Tumors.............................................................50
8.0
STUDY DRUG .............................................................................................................51
8.1
Study Drug Administration......................................................................................51
8.1.1
Instructions for Pevonedistat and Azacitidine Dosing.......................................54
8.1.2
Instructions for Pevonedistat and Docetaxel Dosing.........................................55
8.1.3
Instructions for Pevonedistat and Carboplatin Plus Paclitaxel Dosing ..............55
8.2
Reference/Control Therapy......................................................................................56
8.3
Dose Modification Guidelines..................................................................................56
8.3.1
Dose Modifications for Hematologic Toxicities...............................................56
8.3.2
Dose Modifications for Nonhematologic Toxicities .........................................58
8.3.3
Intrapatient Dose Escalation (Part B) ...............................................................60
8.4
Excluded Concomitant Medications and Procedures ................................................61
8.5
Permitted Concomitant Medications and Procedures................................................62
8.6
Precautions and Restrictions ....................................................................................63
8.7
Management of Clinical Events ...............................................................................65
8.7.1
Combination Pevonedistat Plus Standard of Care Agents.................................65
8.8
Blinding and Unblinding..........................................................................................66
8.9
Description of Investigational Agents ......................................................................67
8.9.1
Azacitidine ......................................................................................................67
8.9.2
Pevonedistat ....................................................................................................67
8.9.3
Docetaxel, Carboplatin, and Paclitaxel.............................................................67
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8.10
Preparation, Reconstitution, and Dispensation..........................................................67
8.11
Packaging and Labeling...........................................................................................68
8.12
Storage, Handling, and Accountability.....................................................................68
8.13
Other Protocol-Specified Materials ..........................................................................68
9.0
STUDY CONDUCT......................................................................................................69
9.1
Study Personnel and Organizations..........................................................................69
9.2
Arrangements for Recruitment of Patients................................................................69
9.3
Treatment Group Assignments.................................................................................69
9.4
Study Procedures.....................................................................................................71
9.4.1
Informed Consent ............................................................................................71
9.4.2
Inclusion/Exclusion Confirmation....................................................................71
9.4.3
Patient Demographics......................................................................................72
9.4.4
Medical History...............................................................................................72
9.4.5
Physical Examination ......................................................................................72
9.4.6
Patient Height..................................................................................................72
9.4.7
Patient Weight .................................................................................................72
9.4.8
ECOG PS ........................................................................................................73
9.4.9
Vital Signs.......................................................................................................73
9.4.10
Pregnancy Test ................................................................................................73
9.4.11
Concomitant Medications and Procedures........................................................73
9.4.12
AEs .................................................................................................................74
9.4.13
Enrollment.......................................................................................................74
9.4.14
ECG ................................................................................................................74
9.4.15
Clinical Laboratory Evaluations.......................................................................74
9.4.16
Assessment of Hepatic and Renal Function for Treatment Group Assignment .76
9.4.17
Disease Assessment.........................................................................................77
9.4.18
Biomarker, Pharmacodynamic, and PK Samples..............................................78
9.4.19
PK Measurements............................................................................................78
9.4.20
Pharmacodynamic Measurements....................................................................79
9.4.21
DNA Measurements ........................................................................................79
9.4.22
Banked Tumor Specimen Measurements .........................................................79
9.5
Completion of Study Treatment (for Individual Patients) .........................................80
9.6
Completion of Study (for Individual Patients)..........................................................80
9.7
Discontinuation of Treatment With Study Drug and Patient Replacement................80
9.8
Withdrawal of Patients From Study .........................................................................81
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9.9
Study Compliance....................................................................................................82
10.0
ADVERSE EVENTS ....................................................................................................82
10.1
Definitions...............................................................................................................82
10.1.1
Pretreatment Event Definition..........................................................................82
10.1.2
AE Definition ..................................................................................................82
10.1.3
SAE Definition................................................................................................82
10.2
Procedures for Recording and Reporting AEs and SAEs..........................................83
10.3
Monitoring of AEs and Period of Observation .........................................................84
10.4
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events.........84
10.5
Procedures for Reporting Product Complaints or Medication Errors (Including 
Overdose) ................................................................................................................85
10.6
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities...........85
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................85
12.0
DATA HANDLING AND RECORDKEEPING............................................................86
12.1
eCRFs......................................................................................................................86
12.2
Record Retention .....................................................................................................86
13.0
STATISTICAL METHODS..........................................................................................87
13.1
Statistical and Analytical Plans ................................................................................87
13.1.1
Analysis Sets ...................................................................................................87
13.1.2
Demographics and Other Baseline Characteristics ...........................................88
13.1.3
Efficacy Analysis.............................................................................................88
13.1.4
PK Analysis.....................................................................................................88
13.1.5
Pharmacodynamic Analysis.............................................................................89
13.1.6
PK/Pharmacodynamic Analysis.......................................................................89
13.1.7
Immunogenicity Analyses................................................................................89
13.1.8
Safety Analysis................................................................................................89
13.2
Interim Analysis ......................................................................................................90
13.3
Determination of Sample Size..................................................................................90
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................91
14.1
Study Site Monitoring Visits....................................................................................91
14.2
Protocol Deviations..................................................................................................91
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................91
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................92
15.1
IRB and/or IEC Approval ........................................................................................92
15.2
Subject Information, Informed Consent, and Subject Authorization .........................93
15.3
Subject Confidentiality ............................................................................................94
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15.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................94
15.4.1
Publication.......................................................................................................94
15.4.2
Clinical Trial Registration................................................................................95
15.4.3
Clinical Trial Results Disclosure......................................................................95
15.5
Insurance and Compensation for Injury....................................................................96
16.0
REFERENCES..............................................................................................................96
LIST OF IN-TEXT TABLES
Table 6.a
Primary and Secondary Endpoints for Disclosures .............................................44
Table 8.a
Starting Doses for Patients With Mild Hepatic Impairment ................................52
Table 8.b
Starting Doses for Patients With Moderate Hepatic Impairment .........................53
Table 8.c
Starting Doses for Patients With Severe Renal Impairment ................................54
Table 8.d
Dose Modification Guidelines for Specific Hematologic Toxicities in Patients
With Advanced Solid Tumors............................................................................58
Table 8.e
Dose Modification Guidelines for Specific Nonhematologic Toxicities in 
Patients With Advanced Solid Tumors...............................................................60
Table 8.f
Concomitant Medications Excluded While Receiving Study Treatment: 
Combination Pevonedistat Plus SOC agents.......................................................62
Table 8.g
Concomitant Medications and Procedures Permitted During the Study...............63
Table 9.a
Laboratory Value Requirements per Treatment Arm for eGFR, Total Bilirubin, 
and ALT (Patients With Hematologic Malignancies Only).................................69
Table 9.b
Laboratory Value Requirements per Treatment Arm for eGFR, Total Bilirubin, 
and ALT (Patients With Advanced Solid Tumors Only).....................................70
Table 9.c
Hematology Tests ..............................................................................................74
Table 9.d
Complete Serum Chemistry Panel......................................................................75
Table 9.e
Select Serum Chemistry Panel ...........................................................................75
Table 9.f
Coagulation Panel..............................................................................................75
Table 9.g
Urinalysis With Microscopic Analysis ...............................................................76
Table 9.h
Primary Specimen Collection.............................................................................78
LIST OF APPENDICES
Appendix A
SOE...................................................................................................................99
Appendix B
Study Diagrams ...............................................................................................112
Appendix C
Responsibilities of the Investigator...................................................................113
Appendix D
ECOG Scale for Performance Status ................................................................115
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Appendix E
Definition of Postmenopausal ..........................................................................116
Appendix F
Acceptable Methods of Contraception Considered Highly Effective.................117
Appendix G
New York Heart Association Classification of Cardiac Disease........................118
Appendix H
BSA Calculation ..............................................................................................119
Appendix I
Formula for ANC Calculation ..........................................................................120
Appendix J
Response Criteria for MDS, CMML, AML, and Solid Tumors.........................121
Appendix K
Drugs Associated With Nephrotoxicity ............................................................126
Appendix L
Hematologic Toxicity of Carboplatin Alone and in Combination With 
Paclitaxel .........................................................................................................127
Appendix M
Excluded Strong CYP3A Inhibitors and Inducers.............................................129
Appendix N
Protocol History...............................................................................................130
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2.0
STUDY SUMMARY
Name of Sponsor(s): Takeda Development Center 
Americas, Inc.
Compound: Pevonedistat
(TAK-924; MLN4924)
Title of Protocol: A Phase 1/1b Study of Pevonedistat in 
Combination With Select Standard of Care Agents in 
Patients With Higher-Risk Myelodysplastic Syndromes, 
Chronic Myelomonocytic Leukemia, Acute Myelogenous 
Leukemia, or Advanced Solid Tumors With Severe Renal 
Impairment or Mild or Moderate Hepatic Impairment
EudraCT No.: 2018-004049-17
Study Number: Pevonedistat-1016
Phase: 1/1b
Study Design:
This study is an open-label, multicenter, 2-part study. The study has been designed to characterize the 
pharmacokinetics (PK) of pevonedistat and assess the safety of pevonedistat in combination with select standard of 
care (SOC) agents in patients with myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), 
acute myelogenous leukemia (AML), or advanced solid tumors who also have severe renal impairment or 
mild/moderate hepatic impairment. Patients will be assigned to 1 of 4 arms based on their renal and/or hepatic 
function: normal renal and hepatic function (Control Arm), severe renal impairment (Renal Arm), mild hepatic 
impairment (Mild Hepatic Arm), and moderate hepatic impairment (Moderate Hepatic Arm).
Part A of the study will be a single-agent PK assessment period with pevonedistat. All eligible patients will be 
administered a single dose of pevonedistat 20 mg/m2 via an approximately 1-hour intravenous (IV) infusion on Day 1. 
Plasma PK samples will be collected at a series of predetermined time points up to 72 hours (Day 4) following the 
single dose of pevonedistat. There will be an approximate 4- to 7-day washout period before the start of Part B.
In Part B, patients will receive pevonedistat in combination with SOC agents (azacitidine, docetaxel, or 
carboplatin plus paclitaxel).
Patients with hematologic malignancies (MDS, CMML, or AML) may receive pevonedistat on Days 1, 3, and 5 in 
combination with azacitidine (75 mg/m2,) on Days 1 through 7 or Days 1 through 5, 8, and 9 in 28-day cycles. Patients 
will receive azacitidine subcutaneously (SC) in Cycle 1. Azacitidine will be given SC or IV during Cycle 2 and 
beyond. During Cycle 1 of Part B, plasma and urine PK samples for measurement of pevonedistat and azacitidine will 
be collected at predetermined time points or intervals on Day 3. Plasma PK samples for measurement of pevonedistat 
will also be collected on Days 4 and 5 of Cycle 1.
Patients with advanced solid tumors may receive pevonedistat in combination with docetaxel or carboplatin plus 
paclitaxel on Day 1 and pevonedistat alone on Days 3 and 5 in 21-day cycles. During Cycle 1 of Part B, plasma PK 
samples for measurement of pevonedistat will be collected on Days 3, 4, and 5.
Following sponsor and investigator discussion of safety data from Cycle 1, patients in the organ impairment arms who 
tolerate pevonedistat well at a low starting dose may be eligible for intrapatient dose escalation starting in Cycle 2 of 
Part B or soon thereafter. Patients who tolerate treatment well at low starting doses of SOC agents may also be eligible 
for intrapatient dose escalation of those agents, per United States Prescribing Information/Summary of Product 
Characteristics recommendations.
Patients may continue to receive the combination treatment (in 28-day cycles in combination with azacitidine or in 
21-day cycles in combination with docetaxel or carboplatin plus paclitaxel) in Part B until they experience 
symptomatic deterioration or disease progression, treatment is discontinued for another reason, or until the study is
stopped by the sponsor.
Treatment with the study drug will be discontinued early if a patient experiences study drug–related toxicities. Patients 
may discontinue therapy at any time. Patients will attend the end of study (EOS) visit 30 (+10) days after receiving 
their last dose of study drug or before the start of subsequent antineoplastic therapy, if that occurs sooner.
Adverse events (AEs) and Eastern Cooperative Oncology Group performance status (ECOG PS) will be assessed, and 
electrocardiograms, clinical laboratory values (with select chemistry panel during Part B), and vital signs will be 
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obtained, to evaluate the safety and tolerability of the study drug treatments. Toxicity will be evaluated according to 
National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0, effective date 27 November 
2017 [1]. Guidelines for dose modifications are provided as per the study protocol.
Measures of disease response (complete response [CR] or partial response [PR] for AML and solid tumors; CR, PR, or 
hematologic improvement [HI] for MDS and CMML), including response rate and duration of response, will be based 
on the investigator’s assessment (Part B only).
Primary Objectives:
The primary objectives (Part A) are as follows:

To characterize the PK of pevonedistat in patients with severe renal impairment.

To characterize the PK of pevonedistat in patients with mild hepatic impairment.

To characterize the PK of pevonedistat in patients with moderate hepatic impairment.
Secondary Objectives:
The secondary objectives (Part B) are as follows:

To evaluate disease response in patients with severe renal impairment or mild or moderate hepatic impairment 
that may be observed in the combination of pevonedistat with chemotherapy (azacitidine, docetaxel, or 
carboplatin plus paclitaxel).

To characterize the PK of pevonedistat and azacitidine in the combination setting in patients with hematologic 
malignancies and severe renal impairment or mild or moderate hepatic impairment.

To characterize the PK of pevonedistat in combination with docetaxel or carboplatin plus paclitaxel in patients 
with advanced solid tumors and severe renal impairment or mild or moderate hepatic impairment.
Safety Objective:
The safety objective (Part A and Part B) is as follows:

To evaluate the safety of pevonedistat following a single dose or in combination with chemotherapy (azacitidine, 
docetaxel, or carboplatin plus paclitaxel) in patients with normal organ function and in patients with organ 
impairment.
Patient Population: Male or female patients aged 18 years or older with higher-risk (HR) MDS, HR CMML, AML, 
or advanced solid tumors, with various degrees of renal or hepatic function.
Number of Patients:
Approximately 42 patients will be enrolled in the study.
Number of Sites:
There will be approximately 25 to 30 sites in the 
United States and European Union.
Dose Level(s):
Part A
Single dose of pevonedistat 20 mg/m2 via a 1-hour IV 
infusion.
Part B
After completion of Part A, all patients will be given an 
opportunity to continue treatment in Part B.
Patients with hematologic malignancies may receive 
pevonedistat on Days 1, 3, and 5 in combination with 
azacitidine (75 mg/m2) on Days 1 through 7 or Days 1 
through 5, 8, and 9 in 28-day cycles. Patients will receive 
azacitidine SC in Cycle 1. Azacitidine will be given SC or 
IV during Cycle 2 and beyond.
Starting doses: pevonedistat 20 mg/m2 and azacitidine 
75 mg/m2 (Control Arm and Mild Hepatic Arm); 
Route of Administration:
Pevonedistat, docetaxel, carboplatin, and 
paclitaxel: IV
Azacitidine: IV or SC
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pevonedistat 10 mg/m2 and azacitidine 75 mg/m2 (Moderate 
Hepatic Arm); pevonedistat 15 mg/m2 and azacitidine 
75 mg/m2 (Renal Arm).
Based on available safety data, patients who tolerate 
treatment well at the initially assigned dose of pevonedistat 
may be allowed to increase their dose of pevonedistat in 
increments of 5 mg/m2 per cycle.
Maximum doses: pevonedistat 20 mg/m2 and azacitidine 
75 mg/m2.
Patients with advanced solid tumors may receive 
pevonedistat in combination with docetaxel or carboplatin 
plus paclitaxel on Day 1 and pevonedistat alone on Days 3 
and 5 in 21-day cycles. Only patients in the Renal Arm will 
receive treatment with pevonedistat in combination with 
docetaxel.
Starting doses: pevonedistat 20 mg/m2 and carboplatin area 
under the plasma concentration-time curve (AUC)4 plus 
paclitaxel 135 mg/m2 (Mild Hepatic Arm); pevonedistat 
10 mg/m2 and carboplatin AUC4 plus paclitaxel 90 mg/m2
(Moderate Hepatic Arm); pevonedistat 15 mg/m2 and 
docetaxel 75 mg/m2 or carboplatin AUC4 plus paclitaxel 
135 mg/m2 (Renal Arm).
Maximum doses: pevonedistat 20 mg/m2 and carboplatin 
AUC5 plus paclitaxel 135 mg/m2(Mild Hepatic Arm);
pevonedistat 20 mg/m2 and carboplatin AUC5 plus 
paclitaxel 90 mg/m2 (Moderate Hepatic Arm); pevonedistat 
25 mg/m2 and docetaxel 75 mg/m2; pevonedistat 20 mg/m2
and carboplatin AUC5 plus paclitaxel 175 mg/m2 (Renal 
Arm).
Duration of Treatment:
Part A: Approximately 4 to 7 days, including the 
pevonedistat single-dose PK assessment and washout.
Part B: The maximum duration of treatment with 
pevonedistat in combination with SOC agents (azacitidine, 
docetaxel, or carboplatin plus paclitaxel) is 12 cycles 
(28-day cycles for patients with hematologic malignancies 
and 21-day cycles for patients with advanced solid tumors), 
unless the investigator and sponsor (or designee) agree that 
a patient would benefit from continued treatment.
Period of Evaluation:
Screening: Within 28 days before the first dose of 
study drug in Part A.
Part A:
Pevonedistat single-dose for PK assessment: 
Days 1 to 4.
Washout: 4 to 7 days.
Part B: Patients may continue to receive the 
combination treatment in Part B until they experience 
symptomatic deterioration or disease progression, 
treatment is discontinued for another reason, or until 
the study is stopped by the sponsor.
Follow-up: Patients will attend an EOS visit 30 days 
(+10 days) after the last dose of study drugs or before 
the start of subsequent alternative anticancer therapy, if 
that occurs sooner.
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Main Criteria for Inclusion:
All Patients:

Male and female patients aged 18 years or older.

Expected survival of at least 3 months from the date of enrollment in the study.

ECOG PS of 0, 1, or 2.

Recovered (ie, Grade ≤1 toxicity) from the reversible effects of prior anticancer therapy.

Prothrombin time (PT) and activated partial thromboplastin time (aPTT) ≤1.5 × upper limit of the normal range 
(ULN) at screening or within 7 days before the first dose of study drug.

Female patients who:
–
Are postmenopausal for at least 1 year before the screening visit, OR
–
Are surgically sterile, OR
–
Agree, if they are of childbearing potential, 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 subject.

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 subject.

Suitable venous access for the study-required blood sampling (ie, PK sampling).

Voluntary written consent must be given by the patient or the patient's legally acceptable representative before 
performance of any study-related procedure not part of standard medical care, with the understanding that consent 
may be withdrawn by the patient or the patient’s legally acceptable representative at any time without prejudice to 
future medical care.
Patients with Hematologic Malignancies:

Previously untreated hematologic malignancies not suitable for induction therapy.

Morphologically confirmed diagnosis of MDS or nonproliferative CMML (ie, with white blood cells [WBC] 
<13,000/µL) at study entry, based on one of the following:
French-American-British Classifications [2]:
–
Refractory anemia with excess blasts (RAEB), defined as having 5% to 20% myeloblasts in the bone marrow.
–
CMML with 10% to 19% myeloblasts in the bone marrow and/or 5% to 19% blasts in the blood.
OR
World Health Organization (WHO) Classifications [3]:
–
RAEB-1, defined as having 5% to 9% myeloblasts in the bone marrow.
–
RAEB-2, defined as having 10% to 19% myeloblasts in the bone marrow and/or 5% to 19% blasts in the 
blood.
–
CMML-2, defined as having 10% to 19% myeloblasts in the bone marrow and/or 5% to 19% blasts in the 
blood.
–
CMML-1 (although CMML-1 is defined as having <10% myeloblasts in the bone marrow and/or <5% blasts 
in the blood, these patients may enroll only if bone marrow blasts ≥5%).
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
All patients with MDS or CMML must also have one of the following Prognostic Risk Categories at study entry, 
based on the Revised International Prognostic Scoring System [4]:
–
Very high (>6 points).
–
High (>4.5-6 points).
–
Intermediate (>3-4.5 points): A patient determined to be in the Intermediate Prognostic Risk Category is only 
allowable in the setting of ≥5% bone marrow myeloblasts.

Patients with WHO-defined AML at study entry, including leukemia secondary to prior chemotherapy or 
resulting from an antecedent hematologic disorder, who have failed to achieve CR or who have relapsed after 
prior therapy and are not candidates for potentially curative treatment.

Patients with relapsed or refractory MDS at study entry, who have previously been treated with an 
hypomethylating agents.
For patients with hematologic malignancies, laboratory value requirements per study arms for estimated glomerular 
filtration rate (eGFR), total bilirubin, and alanine aminotransferase (ALT) are provided in the table, below:
Treatment Arm
eGFR (mL/min/1.73 m2)
Total Bilirubin
ALT
Control
≥90
≤ULN
≤ULN
Renal
<30
≤ULN
≤2.5 × ULN
Mild Hepatic
≥60
ULN <bilirubin ≤1.5 × ULN
(not secondary to 
transfusions)
Any
Moderate Hepatic
≥60
1.5 × ULN <bilirubin 
≤3.0 × ULN
(not secondary to 
transfusions)
Any
Patients with Advanced Solid Tumors:

Adult patients who have a histologically or cytologically confirmed metastatic or locally advanced solid tumor
that is appropriate for treatment with pevonedistat in combination with either docetaxel or carboplatin plus 
paclitaxel in Part B of this study, or have progressed despite standard therapy, or for whom conventional therapy 
is not considered effective.

For patients with advanced solid tumors, clinical laboratory values as specified below:
–
Hemoglobin ≥8 g/dL. Patients may be transfused to achieve this value.
–
For patients to be treated with pevonedistat plus docetaxel in Part B, total bilirubin must be ≤ULN.
–
ALT, aspartate aminotransferase (AST), and alkaline phosphatase ≤2.5 × ULN.

For patients to be treated with pevonedistat plus docetaxel in Part B, AST and ALT must be 
≤1.5 × ULN. Only patients with severe renal impairment may be considered for this combination.
–
Absolute neutrophil count ≥1,500/mm3.
–
Platelet count ≥100,000/mm3.
–
Albumin ≥2.7 g/dL.

Computerized tomography scan or magnetic resonance imaging (MRI) of the chest, abdomen, and pelvis within 
28 days of the first dose of study drug.
For patients with advanced solid tumors, laboratory value requirements per study arms for eGFR, total bilirubin, and 
ALT are provided in the table, below:
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Treatment Arm
eGFR 
(mL/min/1.73 m2)
Total Bilirubin
ALT
Renal
<30
≤ULN
≤1.5 × ULN (for 
pevonedistat plus docetaxel)
≤2.5 × ULN (for 
pevonedistat plus carboplatin 
plus paclitaxel)
Mild hepatic 
≥60
ULN <bilirubin ≤1.5 × ULN
Any
Moderate hepatic 
≥60
1.5 × ULN <bilirubin ≤3.0 × ULN
Any
Main Criteria for Exclusion:
All Patients:

Any serious medical or psychiatric illness that could, in the investigator’s opinion, potentially interfere with the 
completion of study procedures or could limit expected patient survival to less than 6 months.

End-stage renal disease requiring hemodialysis at study entry.

Gilbert syndrome.

Treatment with any investigational products or participation in any interventional studies within 21 days before 
the first dose of any study drug.

Known hypersensitivity to pevonedistat or its excipients.

Active uncontrolled infection or severe infectious disease, such as severe pneumonia, meningitis, or septicemia. 
Prophylactic treatment with antibiotics is allowed.

Major surgery within 14 days before first dose or a scheduled surgery during study period; insertion of a venous 
access device (eg, catheter, port) is not considered major surgery.

Life-threatening illness unrelated to cancer.

Known HIV seropositive.

Known hepatitis B surface antigen seropositive, or known or suspected active hepatitis C infection.

Known hepatic cirrhosis or severe pre-existing hepatic impairment.

Known cardiopulmonary disease defined as unstable angina, clinically significant arrhythmia, congestive heart 
failure (New York Heart Association Class III or IV), and/or myocardial infarction within 6 months before first 
dose.

Prolonged rate corrected QT interval ≥500 msec, calculated according to institutional guidelines.

Treatment with strong cytochrome P450 (CYP3A) inducers within 14 days before the first dose of pevonedistat.

Female patients who are lactating and breastfeeding or have a positive serum pregnancy test during the screening 
period or a positive urine pregnancy test on Day 1 of Part A, before first dose of study drug.

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).

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).

Diagnosed or treated for a different malignancy within 2 years before randomization or previously diagnosed with 
a different malignancy with any current evidence of residual disease.

High blood pressure that cannot be controlled by standard treatments.

Left ventricular ejection fraction <50% within 6 months prior to study enrollment.

Severe uncontrolled ventricular arrhythmias or torsade de pointes; electrocardiographic evidence of acute 
ischemia or active conduction system abnormalities; or clinically significant arrhythmia.

Severe symptomatic pulmonary hypertension requiring pharmacologic therapy or patients with chronic 
respiratory disease that require continuous oxygen.
Patients with Hematologic Malignancies:

Acute promyelocytic leukemia as diagnosed by morphologic examination of bone marrow, by fluorescent in situ 
hybridization or cytogenetics of peripheral blood or bone marrow, or by other accepted analysis.
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
Patients with AML with a WBC count ≥50,000/μL. Patients who are cytoreduced with leukapheresis or with 
hydroxyurea may be enrolled if they otherwise meet the eligibility criteria.

Patients with either clinical evidence of or history of central nervous system (CNS) involvement by AML.

Known hypersensitivity to azacitidine or its excipients.

For patients with hematologic malignancies, PT or aPTT >1.5 × ULN or active uncontrolled coagulopathy or 
bleeding disorder. Patients therapeutically anticoagulated with warfarin, direct thrombin inhibitors, direct factor 
Xa inhibitors, or heparin are excluded from enrollment.
Patients with Advanced Solid Tumors:

Prior treatment with radiation therapy involving ≥25% of the hematopoietically active bone marrow.

Known hypersensitivity or history of severe intolerance or toxicity to chemotherapeutic agents, including known 
history of severe hypersensitivity reactions to docetaxel (polysorbate 80-based formulations) for patients to be 
treated with pevonedistat in combination with docetaxel; history of hypersensitivity to carboplatin for patients to 
be treated with pevonedistat plus carboplatin plus paclitaxel; or history of severe hypersensitivity to paclitaxel 
(Cremophor-based formulations) for patients to be treated with pevonedistat with carboplatin plus paclitaxel.

CNS metastasis, except for patients who have received prior treatment (radiation or resection) and have stable 
CNS disease (eg, stable MRI, no steroid requirement).
Main Criteria for Evaluation and Analyses:
Primary Endpoints:

Area under the plasma concentration-time curve from time zero to infinity (AUC∞) following a single dose of 
pevonedistat in patients with normal renal and hepatic function, severe renal impairment, or mild or moderate 
hepatic impairment.

Area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration 
(AUClast) following a single dose of pevonedistat in patients with normal renal and hepatic function, severe renal 
impairment, or mild or moderate hepatic impairment.

Maximum observed plasma concentration (Cmax) of pevonedistat following a single dose of pevonedistat in 
patients with normal renal and hepatic function, severe renal impairment, or mild or moderate hepatic 
impairment.
Secondary Endpoints:

Terminal disposition phase half-life (t1/2z) of pevonedistat following single- and multiple-dose administration.

Cmax of pevonedistat following multiple-dose administration.

Fraction of unbound drug in plasma (fu) of pevonedistat.

Cmax of azacitidine following multiple-dose administration.

Time of first occurrence of maximum observed concentration of azacitidine following multiple-dose
administration.

t1/2z of azacitidine following multiple-dose administration.

Area under the concentration-time curve from time zero to the end of the dosing interval of pevonedistat and 
azacitidine following multiple-dose administration.

Clearance of pevonedistat and apparent clearance of azacitidine.

Renal clearance of pevonedistat and azacitidine.

Volume of distribution at steady-state (Vss) of pevonedistat and apparent Vss of azacitidine.

Measures of disease response (CR, complete remission with incomplete blood count recovery [CRi] or PR for 
AML; CR, PR, or HI for MDS and CMML; CR or PR for solid tumors using the Response Evaluation Criteria In 
Solid Tumors [RECIST] version 1.1 criteria); including response rate and duration of response, based on the 
investigator’s assessment (Part B only).
Safety Endpoints:
AEs, serious AEs, assessments of clinical laboratory values, vital signs measurements, and ECOG PS.
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Statistical Considerations:
Analyses will be primarily descriptive in nature. No formal statistical hypothesis testing will be performed. A 
statistical analysis plan will be prepared and finalized before database lock. This document will provide further details 
regarding the definition of analysis variables and analysis methodology to address all study objectives.
Summary tabulations will be presented to display the number of observations, mean, standard deviation, median, 
minimum, and maximum for continuous variables along with the number and percentage (calculated using 
nonmissing values) per category for categorical data, unless specified otherwise.
PK: Individual and mean pevonedistat plasma concentration-time data following a single dose of pevonedistat during 
the PK assessment in Part A will be plotted and listed by organ function group. Individual and mean pevonedistat 
and/or azacitidine plasma concentration-time data following multiple-dose administration during Cycle 1 of Part B 
will be plotted and listed by organ function group and by dose levels. Plasma pevonedistat and/or azacitidine PK 
parameters for each patient will be calculated using noncompartmental analysis methods.
The analysis for the effects of organ impairment on pevonedistat PK will be based on unbound pevonedistat plasma 
exposure (AUC) following a single dose of pevonedistat in Part A. To assess the effects of severe renal impairment or 
mild or moderate hepatic impairment on pevonedistat PK (unbound AUClast and AUC∞), an analysis of variance 
(ANOVA) on the natural log-transformed PK parameters will be performed for severe renal impairment (Renal Arm) 
versus the normal group (Control Arm), mild hepatic impairment (Mild Hepatic Arm) versus the normal group 
(Control Arm), and moderate hepatic impairment (Moderate Hepatic Arm) versus the normal group (Control Arm). 
The ANOVA results will be used to estimate the ratios of LS geometric means (severe renal impairment vs normal, 
and mild or moderate hepatic impairment vs normal) and corresponding 90% CIs for pevonedistat unbound AUC. The 
PK-evaluable population will be used for these analyses.
Efficacy: Efficacy measures will include disease response and duration of disease response. Analysis of all efficacy 
measures will be descriptive. Disease response in AML will be based on the overall response rate (CR + PR) using the 
Revised Recommendations of the International Working Group (IWG) for Diagnosis, Standardization of Response 
Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in AML [5]. For AML patients, all CR 
includes both CR and CRi. Disease response in patients with MDS or CMML will be based on the best overall 
response (CR + PR + HI) as determined by the investigator using the revised IWG response criteria for MDS [6].
Disease response to pevonedistat in combination with docetaxel or carboplatin plus paclitaxel will be based on the best 
overall response as determined by the investigator using RECIST version 1.1 guidelines. 
The duration of response will be defined in all patients with disease response as the time between the first 
documentation of response and the first documentation of PD or death if no prior PD is documented. Responders 
without disease progression will be censored at the last clinical assessment of response.
Safety:
A safety analysis will be conducted separately for Part A and Part B. The safety population will be used for the safety 
analysis. Safety will be evaluated on the basis of the incidence of AEs, severity and type of AEs, and by changes from 
baseline in the patient’s vital signs, weight, and clinical laboratory values using the safety population. Exposure to the 
study drugs and reasons for discontinuation will be tabulated.
Sample Size Justification: The sample size calculation is based on the number of patients required to adequately 
characterize the PK of pevonedistat in the organ impairment arms (severe renal impairment or mild or moderate 
hepatic impairment) in comparison to the control group. Based on these considerations, the expected sample size is 
approximately 9 for the Control Arm (normal renal and hepatic function) and 9 to 12 patients in each of the 3 organ 
impairment arms. Patients who are considered nonevaluable may be replaced. The sample size of approximately 
9 patients specified as being required for the PK-evaluable population in each group in Part A is based on typical 
sample sizes utilized in organ impairment PK studies in cancer patients, rather than on specific statistical 
considerations. With a sample size of 9 patients per group, if the ratio of geometric means (impaired organ function vs 
control) of AUC∞is X, the associated 90% CI is expected to be (0.688X, 1.45X) based on the percent coefficient of 
variation in pevonedistat AUC∞of 43.8% (Study C15011).
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3.0
STUDY REFERENCE INFORMATION
3.1
Study-Related Responsibilities
The sponsor will perform all study-related activities with the exception of those identified in the 
Clinical Study Supplier List. The identified vendors 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 myelogenous leukemia
ANC
absolute neutrophil count
ANOVA
analysis of variance
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AUC
area under the plasma concentration-time curve 
AUClast
area under the plasma concentration-time curve from time zero to the time of the last quantifiable 
concentration
AUC∞
area under the plasma concentration-time curve from time 0 to infinity
AUCτ
area under plasma concentration-time curve from time zero to the end of the dosing interval
BCRP
breast cancer resistance protein
BDC
bile in bile duct–cannulated
BSA
body surface area
CDLs
cullin-dependent ubiquitin E3 ligases
CL
total clearance
CL/F
apparent clearance
CLR
renal clearance
CMML
chronic myelomonocytic leukemia
Cmax
maximum observed plasma concentration
CNS
central nervous system
COVID-19
coronavirus disease 2019
CR
complete response/remission
CRi
complete remission with incomplete blood count recovery
CrCL
creatinine clearance
CRO
contract research organization
CSR
clinical study report
CT
computerized tomography
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
eGFR
estimated glomerular filtration rate
EOS
end of study
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ET
early termination
EU
European Union
FDA
[United States] Food and Drug Administration
fu
fraction of unbound drug in plasma
FSH
follicle stimulating hormone
GCP
Good Clinical Practice
G-CSF
granulocyte-colony stimulating factor
GFR
glomerular filtration rate
HI
hematologic improvement
HR CMML
higher-risk chronic myelomonocytic leukemia
HR MDS
higher-risk myelodysplastic syndromes
IB
investigator’s brochure
ICF
informed consent form
ICH
International Council for Harmonisation
IEC
independent ethics committee
IPSS-R
Revised International Prognostic Scoring System
IRB
institutional review board
ITT
intent-to-treat
IV
intravenous(ly)
IWG
International Working Group 
LVEF
left ventricular ejection fraction 
MDRD
Modification of Diet in Renal Disease
MDS
myelodysplastic syndromes
MHRA
Medicines and Healthcare products Regulatory Agency
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
NAE
NEDD8-activating enzyme
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NEDD8
neural precursor cell expressed, developmentally down-regulated 8
ORR
overall response rate
PBPK
physiologically based pharmacokinetic(s)
PD
progressive disease
P-gp
P-glycoprotein
PK
pharmacokinetic(s)
PMDA
Pharmaceuticals and Medical Devices Agency
PR
partial response/remission
PS
performance status
PT
prothrombin time
PTA
posttrial access
PTE
pretreatment event
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RAEB
refractory anemia with excess blasts
RBC
red blood cells
RECIST
Response Evaluation Criteria in Solid Tumors
RP2D
recommended phase 2 dose
SAE
serious adverse event
SmPC
Summary of Product Characteristics
SOC
standard of care
SOE
schedule of events
SC
subcutaneous(ly)
SUSAR
suspected unexpected serious adverse reaction
t1/2z
terminal disposition phase half-life
TEAE
treatment-emergent adverse event
Tmax
time of first occurrence of maximum observed concentration
UK
United Kingdom
ULN
upper limit of the normal range
US
United States
USP
United States Pharmacopeia
USPI
US Prescribing Information
Vss
volume of distribution at steady-state
WBC
white blood cell
WHO
World Health Organization
3.4
Corporate Identification 
TDC Americas
Takeda Development Center Americas, Inc.
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4.0
INTRODUCTION
4.1
Background
As of 22 January 2020, an estimated 794 patients received active treatment with pevonedistat, 
either as a single agent or in combination with other therapeutic agents in hematologic 
malignancies (N = 508) or in solid tumors (N = 286).
Pevonedistat is currently in phase 2/3 of clinical development for higher-risk myelodysplastic 
syndromes (HR MDS), HR chronic myelomonocytic leukemia (HR CMML), and low-blast acute 
myelogenous leukemia (AML). The recommended phase 2 dose (RP2D) of pevonedistat 
administered as a single agent in patients with advanced hematologic malignancy is 50 mg/m2 on 
Days 1, 3, and 5 in 21-day cycles.
Pevonedistat is currently under development as a component of regimens with azacitidine. Two 
clinical studies with pevonedistat and azacitidine are ongoing as of 22 January 2020; 
Pevonedistat-2001 (P2001), a phase 2 study, and Pevonedistat-3001 (P3001), a phase 3 study, are 
both in patients with HR MDS, HR CMML, or low-blast AML. Preliminary data from interim 
analysis 2 of Study P2001 suggest potential clinical benefit in terms of longer overall survival and 
event-free survival among patients with HR MDS/CMML or low-blast AML receiving the 
combination treatment of pevonedistat plus azacitidine versus azacitidine alone.
Pevonedistat is also being evaluated in combination therapy with standard of care (SOC) agents 
(eg, pevonedistat plus docetaxel or pevonedistat plus carboplatin/paclitaxel) for patients with 
solid tumors. Additive/synergistic effects of docetaxel and carboplatin/ paclitaxel in combination 
with pevonedistat have been studied in a number of in vitro and in vivo models by the sponsor 
[7,8]. In patients with solid tumors, the maximum tolerated dose (MTD) and RP2D of pevonedistat 
in combination with docetaxel is 25 mg/m2 pevonedistat dosed on Days 1, 3, and 5, and 75 mg/m2 
docetaxel on Day 1 in 21-day cycles. The MTD and RP2D of pevonedistat in combination with 
carboplatin/paclitaxel is 20 mg/m2 pevonedistat dosed on Days 1, 3, and 5 and 175 mg/m2
paclitaxel plus area under the plasma concentration-time curve (AUC)5 carboplatin on Day 1 in 
21-day cycles.
4.1.1
Study Drug
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. NAE, an E1 activating enzyme, is an essential component of the 
NEDD8 conjugation pathway, which controls the activity of cullin-dependent ubiquitin E3 ligases 
(CDLs). Once activated, CDLs are able to transfer ubiquitin to specific protein substrates, which 
targets them for proteasomal degradation. CDLs thereby control the timely ubiquitination and 
degradation of many proteins with important roles in cell cycle progression and signal transduction. 
Inhibitors of NAE activity may be of therapeutic value in the treatment of various cancers, by 
preventing neddylation and activation of the CDLs, thus disrupting proteasomal degradation of a 
variety of critical regulatory proteins integral to tumor cell growth, proliferation, and survival.
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4.1.2
Nonclinical Background
Pevonedistat is a potent and selective inhibitor of NAE activity. Pevonedistat also inhibits human 
carbonic anhydrase II, which may explain the extensive partitioning of pevonedistat in red blood 
cells (RBCs) that has been observed in animal species and humans.
Pevonedistat showed medium permeability in Caco-2 cells.
Plasma clearance ranged from relatively low in chimpanzees, to moderate in dogs and monkeys, to 
relatively high in rats. The plasma terminal disposition phase half-life (t1/2z), calculated as ln(2)λz
varied from 1 hour in rats to approximately 15 hours in monkeys.
The major elimination pathway of pevonedistat in animals is through the hepatic route. Urinary 
excretion of unchanged pevonedistat was negligible in rats, monkeys, and chimpanzees. After an 
intravenous (IV) dose of [14C]pevonedistat, radioactivity was primarily excreted in the feces in 
intact rats and in bile in bile duct–cannulated (BDC) rats; excretion was almost complete by 
24 hours postdose. Similar to results in intact rats, IV infusion of [14C]pevonedistat to intact beagle 
dogs resulted in most of the administered dose being eliminated in the feces. In BDC beagle dogs, 
however, most of the dose was eliminated in the urine and bile. In both intact and BDC beagles, 
most of the radioactivity in the excreta was recovered over 24 hours after the start of infusion.
Detailed information regarding the nonclinical pharmacology and toxicology of pevonedistat may 
be found in the current investigator’s brochure (IB).
4.1.3
Clinical Background Information
4.1.3.1
Clinical Pharmacokinetics
Population pharmacokinetic (PK) analysis was conducted using data from pevonedistat 
single-agent studies (Studies C15001, C15002, C15003, and C15005) and pevonedistat in 
combination with SOC chemotherapy (Studies C15009, C15010, Pevonedistat-1012 [P1012], and 
P2001) in patients with solid tumor or hematologic malignancies. As of 22 January 2020, the 
database contained 416 evaluable patients contributing 4689 PK observations. Pevonedistat 
plasma concentration-time profiles were well described by a 2-compartment model with linear 
elimination. Coadministration with azacitidine or docetaxel did not appear to affect the total 
clearance (CL) of pevonedistat, whereas concurrent administration of carboplatin and paclitaxel 
decreased the CL of pevonedistat by approximately 50%, translating to an approximately 100% 
higher pevonedistat exposure (AUC) during coadministration with carboplatin and paclitaxel, 
consistent with pevonedistat concentration data observed in Study C15010. Race, sex, age, tumor 
type (hematologic vs solid), mild or moderate renal impairment (creatinine clearance [CrCL] 
≥30 mL/min), and mildly impaired liver function, to the extent represented in this dataset (ie, total 
bilirubin ≤upper limit of the normal range [ULN] and alanine aminotransferase [ALT]/aspartate 
aminotransferase [AST] ≤2.5 × ULN), had no impact on pevonedistat PK.
An open-label drug-drug interaction (DDI) Study C15011 evaluated the cytochrome 
P450 (CYP)3A-mediated inhibitory effects of fluconazole and itraconazole on pevonedistat PK in 
patients with advanced solid tumors. The results indicated that itraconazole, a strong CYP3A/ 
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P-glycoprotein (P-gp) inhibitor, and fluconazole, a moderate CYP3A inhibitor, had no clinically 
meaningful effects on pevonedistat PK.
Study Pevonedistat-1015 (P1015) indicated that rifampin, a strong CYP3A inducer, had no 
clinically meaningful impact on pevonedistat systemic exposures. Despite results of 
Studies C15011 and P1015, in the current study, use of strong CYP3A inducers and inhibitors 
remains prohibited in order to interpret the effects of organ impairment on pevonedistat PK 
without other confounding factors.
Study P1012 is a phase 1/1b, open-label study of pevonedistat as single agent and in combination 
with azacitidine in adult East Asian patients with AML or MDS enrolled in Japan, South Korea, 
and Taiwan. Pevonedistat 20 mg/m2 in combination with 75 mg/m2 azacitidine was determined to 
be the MTD/RP2D in Asian patients. The analysis indicated that the systemic exposure of 
pevonedistat was similar among major East Asian races, ie, Japanese, Korean, and Chinese. 
Furthermore, the systemic exposures of pevonedistat was comparable between East Asian and 
Western patients. These results support the same RP2/3D of pevonedistat in combination with 
azacitidine in global patient population.
4.1.3.2
Clinical Experience
As of 22 January 2020, an estimated 794 patients received active treatment with pevonedistat, 
including 508 patients with hematologic indications and 286 patients with solid tumor indications. 
These include 227 patients diagnosed with advanced malignancies, including solid tumors, AML, 
melanoma, lymphoma, multiple myeloma, HR MDS, and acute lymphoblastic leukemia, who 
participated in studies of single-agent pevonedistat.
In completed combination studies in patients with hematologic malignancies, 64 elderly patients 
with treatment-naïve AML (Study C15009) were treated with pevonedistat plus azacitidine [9]; 
and 23 East Asian patients with World Health Organization (WHO)-defined AML or HR MDS 
have received a single IV dose of pevonedistat alone and in combination with azacitidine 
(Study P1012).
In completed combination studies in patients with solid tumors, 64 patients have received 
combination treatments with docetaxel, gemcitabine, or a combination of carboplatin and 
paclitaxel (Study C15010); and 51 patients have received a single IV dose of pevonedistat alone 
and in combination with the CYP3A inhibitor probes itraconazole or fluconazole (36 of these 
51 patients then continued receiving pevonedistat plus SOC, either docetaxel, or carboplatin plus 
paclitaxel) (Study C15011).
Eight patients with advanced solid tumors have received a single dose of [14C]-pevonedistat (7 of 
these 8 patients then continued receiving pevonedistat plus SOC, either docetaxel, or carboplatin 
plus paclitaxel) (Study Pevonedistat-1013 [P1013]).
In ongoing combination studies, 58 patients with HR MDS, CMML, or low-blast AML have 
received combination treatment with azacitidine and pevonedistat (Study P2001), and it is 
estimated that 222 patients with HR MDS, CMML, or low-blast AML have received combination 
treatment with azacitidine and pevonedistat in Study P3001.
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Pevonedistat has reported single-agent clinical activity in a phase 1 study (Study C15003) in 
patients with relapsed/refractory AML. In Study C15003, a total of 66 patients with AML were 
treated in a variety of patient settings, including after relapse following allogeneic transplant as 
well as with therapy-related AML, and primary refractory AML. In the phase 1 trial, 7 responses 
(2 complete remissions [CR] and 5 partial remissions [PR]) were observed among 
55 response-evaluable patients with AML who received pevonedistat monotherapy. Investigators 
should note that some patients may benefit from continued treatment even though their bone 
marrow blast counts may fluctuate over the course of the first 4 cycles. For example, 2 of the 
7 responders to pevonedistat given as a single agent in Study C15003 had asymptomatic, transient 
increases in bone marrow blasts after achieving a response. In these 2 cases, bone marrow blasts 
increased from less than 5% to more than 20%, and then went down. In addition, another 
responder in that study had an asymptomatic, transient increase in bone marrow blasts before 
achieving a response. In that case, bone marrow blasts almost doubled before response. These 
3 patients were allowed to remain on study because their investigators felt they were clinically 
benefiting from continued treatment despite changes in their bone marrow blast counts.
Pevonedistat has clinical activity when administered in combination with azacitidine. 
Study C15009 evaluated the combination of escalating doses of pevonedistat plus azacitidine in 
64 treatment-naïve patients with AML. The MTD was determined to be 20 mg/m2 pevonedistat in 
combination with 75 mg/m2 azacitidine. A total of 61 patients were treated at the MTD. Overall 
response rate (ORR) in the 64-patient intent-to-treat (ITT) cohort was 50% (20 CR, 5 complete 
remission with incomplete blood count recovery [CRi], 7 PR); median duration of remission was 
8.3 months. Pevonedistat PK was not altered by the addition of azacitidine. The nature and 
frequency of the reported toxicities (excluding dose-limiting toxicities [DLTs]) were similar to 
previous reports for azacitidine alone [9]. Additional efficacy and safety information from 
Study C15009 is provided in Section 4.1.4.2.
Pevonedistat has clinical activity when administered in combination therapy with docetaxel or 
carboplatin plus paclitaxel. In Study C15010, the ORR for patients treated with pevonedistat in 
combination with docetaxel was 16% (3 PRs in a response-evaluable population of 19 patients) [7]. 
For patients treated with pevonedistat in combination with carboplatin plus paclitaxel the ORR 
(CR + PR) was 35% (2 CRs and 6 PRs in a response-evaluable population of 23 patients). In 
Study C15011, the ORR (CR + PR) among 28 patients who received treatment with pevonedistat 
in combination with chemotherapy was 14.3% (10.5% in the pevonedistat plus docetaxel arm and 
22.2% in the pevonedistat plus carboplatin plus paclitaxel arm; 2 patients in each arm). A total of 
4 patients (14.3%) achieved PR and 16 patients (57.1%) had stable disease (SD); 8 patients 
(28.6%) had a best response of progressive disease (PD). Ongoing studies that include patients 
with solid tumors (Studies Pevonedistat-1014 and P1015) have not resulted in any new safety 
signals for the combination of pevonedistat with docetaxel or carboplatin plus paclitaxel.
Refer to the IB, which will be updated regularly throughout the duration of this study, for further 
details on the clinical development program for pevonedistat.
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4.1.4
Potential Risks and Benefits
4.1.4.1
Azacitidine
In clinical studies, adverse reactions to azacitidine were qualitatively similar between the IV and 
subcutaneous (SC) routes of administration [10]. 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, and included thrombocytopenia, 
neutropenia, anemia, nausea, vomiting, injection site erythema/pain/bruising/reaction, 
constipation, petechiae, dizziness, anxiety, hypokalemia, and insomnia. There did not appear to be 
any adverse reactions that increased in frequency over the course of treatment.
Adverse reactions that appeared to be specifically associated with the IV route of administration 
included infusion site reactions (eg, erythema or pain) and catheter site reactions (eg, infection, 
erythema, or hemorrhage).
Adverse reactions identified during postmarketing use of azacitidine include interstitial lung 
disease, tumor lysis syndrome, injection site necrosis, Sweet’s syndrome (acute febrile 
neutrophilic dermatosis), and necrotizing fasciitis (including fatal cases).
Refer to the VIDAZA (azacitidine) United States Prescribing Information (USPI) [10], or the 
European Union (EU) Summary of Product Characteristics (SmPC) [11], as applicable, for the 
most recent information regarding the anticipated risks and benefits of azacitidine.
4.1.4.1.1
Anemia, Neutropenia, and Thrombocytopenia
Azacitidine causes anemia, neutropenia, and thrombocytopenia. Monitor complete blood counts 
frequently for response and/or toxicity, at a minimum, before each dosing cycle. After 
administration of the recommended dosage for the first cycle, adjust dosage for subsequent cycles 
based on nadir counts and hematologic response (see Section 8.3).
4.1.4.1.2
Severe Pre-existing Hepatic Impairment
Caution is needed in patients with liver disease when administering azacitidine. Patients with 
extensive tumor burden due to metastatic disease have been reported to experience progressive 
hepatic coma and death during azacitidine treatment, especially in such patients with baseline 
albumin <30 g/L [12]. Azacitidine is contraindicated in patients with advanced malignant hepatic 
tumors.
4.1.4.1.3
Renal Abnormalities
Patients with renal impairment should be closely monitored for toxicity because azacitidine and its 
metabolites are primarily excreted by the kidneys. Renal abnormalities ranging from elevated 
serum creatinine to renal failure and death have been reported in patients treated with IV 
azacitidine in combination with other chemotherapeutic agents for non-MDS conditions. Renal 
tubular acidosis, defined as a fall in serum bicarbonate to <20 mEq/L in association with an 
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alkaline urine and hypokalemia (serum potassium <3 mEq/L), developed in 5 patients with 
CMML treated with azacitidine and etoposide.
4.1.4.2
Pevonedistat Plus Azacitidine
Study C15009 was a phase 1b study that evaluated the MTD of pevonedistat on Days 1, 3, and 5 in 
combination with 75 mg/m2 azacitidine (administered on a 5-on/2-off [weekend]/2-on schedule) 
in a 28-day treatment cycle in patients aged 60 years or older with treatment-naïve AML who were 
unlikely to benefit from standard induction therapy. A total of 64 patients were treated (ITT 
population) at 2 dose levels. Pevonedistat dosing started at 20 mg/m2 (n = 6) and increased to 
30 mg/m2 (n = 3) in the absence of DLTs. During dose escalation, at the 30 mg/m2 dose level, 2 of 
the 3 patients experienced a DLT: 1 patient had persistent Grade 2 bilirubin elevation, and 
1 patient had reversible Grade 4 AST elevation. Transaminase and bilirubin elevations were 
transient and clinically inconsequential in both patients (resolving to Grade 1 or baseline levels 
within 1 week after withdrawal from study). The MTD was determined to be 20 mg/m2
pevonedistat in combination with 75 mg/m2 azacitidine. An additional 55 patients were treated at 
the MTD, for a total of 61 patients treated at the MTD.
Patients in the ITT cohort (n = 64) received a median of 4 cycles (range, 1-37), and 23 of 
64 patients (36%) received ≥6 cycles of pevonedistat plus azacitidine. The most common adverse 
events (AEs) were constipation (48%), nausea (42%), fatigue (42%), and anemia (39%). 
Fifty-three patients (82%) experienced Grade ≥3 AEs; the most frequent (≥15%) were anemia, 
febrile neutropenia (each 30%), thrombocytopenia (23%), neutropenia (20%), and pneumonia 
(17%). AST/ALT elevations Grade ≥3 were reported in 6% of patients. Forty-four patients (69%) 
experienced serious adverse events (SAEs); the most frequent (≥10%) were febrile neutropenia 
(25%) and pneumonia (14%). In addition to the 2 patients who withdrew because of DLTs, 
2 patients withdrew from the study because of therapy-related toxicity (febrile neutropenia). In the 
MTD expansion cohort (n = 55), 2 additional patients experienced DLTs (Grade ≥3 transaminase 
elevation) and were successfully rechallenged with a reduced dose of pevonedistat. Both patients 
remained on study without further hepatic toxicity. There were 11 on-study deaths unrelated to 
study therapy. Pevonedistat PK was not altered by the addition of azacitidine.
The most detailed information on risks is provided in the IB and the Developmental Core Safety 
Information located within the IB.
Overall identified risks of pevonedistat include increased heart rate, diarrhea, nausea, vomiting, 
abnormal liver function tests, pyrexia, myalgia, and musculoskeletal pain.
Hepatotoxicity: Hepatotoxicity has been noted following administration of pevonedistat in patients 
with advanced malignancy, including elevations of liver transaminases (up to Grade 4), alkaline 
phosphatase (ALP; up to Grade 3), and bilirubin (up to Grade 3). Grade 1 through Grade 4 
increases in ALT and AST have been observed in patients receiving single-agent pevonedistat for 
relapsed and/or refractory AML. The patients experiencing these changes in laboratory values 
have been asymptomatic. This type of elevation in transaminases had been observed previously in 
patients treated with pevonedistat. The elevations in laboratory values have been reversible with 
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dose modification including dose delay and reduction. Patients with elevated transaminases have 
been successfully rechallenged at lower doses.
Some events are considered potential risks of pevonedistat because of the occurrence of these 
events in phase 1 clinical studies in which single-agent pevonedistat was administered at doses 
substantially higher than those being used in current clinical trials. Those events included 
multiorgan failure that could result in death, renal failure, myelosuppression with increased 
susceptibility to infection, bleeding, anemia, acute phase response, gastrointestinal toxicity 
including or resulting in dehydration, electrolyte imbalance, and hypophosphatemia. Reported 
instances of cardiac arrhythmias were all supraventricular in origin, and all except 1 were deemed 
unrelated: the case of atrial fibrillation assessed by the investigator as related occurred in a patient 
with cardiovascular risk factors.
Other events, such as fatigue, chills, decreased appetite, febrile neutropenia, and gastrointestinal 
bleeding (all events assessed by an investigator as unrelated, the majority occurring in the setting 
of thrombocytopenia), are considered potential risks that are confounded by underlying disease or 
malignancy.
Potential risks that are derived from findings in animal studies in rats and dogs include myocardial 
degeneration and thrombosis; cardiovascular changes that could result in tachycardia; decreased or 
increased systolic blood pressure; increased diastolic blood pressure; pulmonary hypertension; 
enteropathy (including dehydration and electrolyte loss) with secondary sepsis; effects on testes 
and ovaries that represent a reproductive hazard, including sterility and increased developmental 
risk to fetus or embryo. Decreased trabecular bone (graded minimal to moderate) was noted in the 
femur and in the sternum in rats at all dose groups (low, medium, high); this finding was 
considered adverse in the high-dose group, but no bone fractures were noted at any of the doses. 
Prolongation of the activated partial thromboplastin time (aPTT) and potential risk for local tissue 
injury are also associated with pevonedistat SC administration. Additional details may be found in 
the current IB.
Based on the known individual safety profiles of pevonedistat and azacitidine, the following 
potential risks of combination therapy may apply: myelosuppression, gastrointestinal events, 
electrolyte imbalances, hypophosphatemia, decreased renal function, hepatotoxicity, cardiac 
arrhythmias, cardiomyopathies, musculoskeletal pain, bleeding, and injection site reactions.
In Study C15009, patients received azacitidine as either an IV infusion or SC injection. Data from 
Study C15009 indicate that the route of azacitidine administration has no apparent effect on the 
safety profile of pevonedistat plus azacitidine.
4.1.4.3
Docetaxel
Treatment-related mortality increases with abnormal liver function, at higher doses, and in patients 
with non‒small cell lung cancer who received prior platinum-based therapy receiving docetaxel at 
100 mg/m2.
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Severe hypersensitivity, including very rare, fatal anaphylaxis, has been reported in patients who 
received dexamethasone premedication. Severe reactions require immediate discontinuation of 
docetaxel and administration of appropriate therapy.
Docetaxel is contraindicated if the patient has a history of severe hypersensitivity reactions to 
docetaxel or to drugs formulated with polysorbate 80.
Severe fluid retention may occur despite dexamethasone premedication.
For more details, refer to the docetaxel SmPC [13] or USPI [1].
4.1.4.3.1
Hepatotoxicity Warning
Docetaxel should not be given if total bilirubin is >ULN or if AST or ALT is ≥1.5 × ULN. Patients 
with elevations of bilirubin or abnormalities of transaminase concurrent with ALP are at increased 
risk for the development of Grade 4 neutropenia, febrile neutropenia, infections, severe 
thrombocytopenia, severe stomatitis, severe skin toxicity, and toxic death. Patients with isolated 
elevations of transaminase >1.5 × ULN also had a higher rate of Grade 4 febrile neutropenia but 
did not have an increased incidence of toxic death. For this reason, patients with mild or moderate 
hepatic impairment will not be enrolled in the Part B arm incorporating docetaxel. Bilirubin, AST 
or ALT, and ALP values should be obtained prior to each cycle of docetaxel therapy and reviewed 
by the investigator.
4.1.4.3.2
Hematologic Warning
Docetaxel should not be given if the absolute neutrophil count (ANC) is less than 1500 cells/mm3.
4.1.4.4
Pevonedistat Plus Docetaxel
The following potential risks, based on the known individual safety profiles of pevonedistat 
plus docetaxel, of combination therapy may apply: death, hypersensitivity, hepatotoxicity, 
neutropenia, and fluid retention (cardiac/pulmonary).
4.1.4.5
Carboplatin
Anaphylaxis-like reactions to carboplatin have been reported and may occur within minutes of 
carboplatin administration. Epinephrine, corticosteroids, and antihistamines have been employed 
to alleviate symptoms.
Vomiting is another frequent drug–related side effect.
Carboplatin injection is contraindicated in patients with a history of severe allergic reactions to 
cisplatin or other platinum-containing compounds.
Carboplatin injection should not be employed in patients with severe bone marrow depression or 
significant bleeding.
For more details, refer to the carboplatin USPI [14] or SmPC [15].
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4.1.4.5.1
Nephrotoxicity Warning
The major route of elimination for carboplatin is renal excretion. Renal effects of nephrotoxic 
compounds [16] (see Appendix K) may be potentiated by carboplatin. For patients with impaired 
renal function, carboplatin is given at 200 mg/m2 or at a dose determined using the Calvert formula 
based on the glomerular filtration rate (GFR) of the patient. Treatment with carboplatin for patients 
with hepatic or renal impairment is administered at no higher than AUC5 based on safety profile of 
pevonedistat plus carboplatin plus paclitaxel in Study C15010.
4.1.4.5.2
Hematologic Warning
Bone marrow suppression is dose related and may be severe, resulting in infection or bleeding. 
Peripheral blood counts should be frequently monitored during carboplatin treatment and, when 
appropriate, until recovery is achieved.
Anemia may be cumulative and may require transfusion support.
4.1.4.6
Paclitaxel
Anaphylaxis and severe hypersensitivity reactions characterized by dyspnea and hypotension 
requiring treatment; angioedema; and generalized urticaria have occurred in 2% to 4% of patients 
receiving paclitaxel in clinical studies. Fatal reactions have occurred in patients despite 
premedication. All patients should be pretreated with corticosteroids, diphenhydramine, and 
H2 antagonists. Patients who experience severe hypersensitivity reactions to paclitaxel should not 
be rechallenged with the drug.
Severe conduction abnormalities have been documented in less than 1% of patients during 
paclitaxel therapy and, in some cases, require pacemaker placement. If patients develop significant 
conduction abnormalities during paclitaxel infusion, appropriate therapy should be administered, 
and continuous cardiac monitoring should be performed during subsequent therapy with 
paclitaxel.
Paclitaxel is contraindicated in patients who have a history of hypersensitivity reactions to 
paclitaxel or other drugs formulated in Cremophor EL (polyoxyethylated castor oil).
For more details, refer to the paclitaxel USPI [16] or SmPC [17].
Paclitaxel injection therapy should not be given to patients with solid tumors who have baseline 
neutrophil counts of less than 1500 cells/mm3. To monitor for the occurrence of bone marrow 
suppression and primarily neutropenia, which may be severe and result in infection, it is 
recommended that frequent peripheral blood cell counts be performed on all patients receiving 
paclitaxel injection.
There is limited evidence that the myelotoxicity of paclitaxel may be exacerbated in patients with 
serum total bilirubin >2 × ULN. For patients with total bilirubin levels of 1.26 to 2 × ULN, 
paclitaxel should be given at 135 mg/m2 over a 3-hour infusion period.
The effect of renal dysfunction on the disposition of paclitaxel has not been investigated.
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4.1.4.7
Pevonedistat and Carboplatin Plus Paclitaxel
The following potential risks of combination therapy with pevonedistat and carboplatin plus 
paclitaxel may apply: bone marrow suppression, hypersensitivity/anaphylaxis reactions, and 
hepatotoxicity. A summary of hematologic toxicity of carboplatin alone and in combination with 
paclitaxel is provided in Appendix L.
4.1.5
Potential for DDIs
No formal clinical assessments of DDIs between azacitidine and other agents have been conducted. 
Please consult the VIDAZA USPI (Clinical Pharmacology [Section 12.3], Drug-Drug Interactions) 
for additional information [10]. Urinary excretion is the primary route of elimination of azacitidine 
and its metabolites. Pevonedistat is not a strong inhibitor or inducer for major CYP enzymes and 
drug transporters. The concomitant administration of pevonedistat is not expected to have 
clinically meaningful impact on azacitidine PK.
Pevonedistat concentration-time data were obtained from 64 treatment-naïve patients with AML 
who were administered pevonedistat in combination with azacitidine in Study C15009. 
Pevonedistat systemic exposures were not altered in the presence of azacitidine when compared 
with historical pevonedistat single-agent data (Study C15003), indicating that coadministration of 
azacitidine has no effects on pevonedistat PK.
Concurrent administration of carboplatin and paclitaxel decreased the CL of pevonedistat by 
approximately 50%, translating to an approximately 100% higher pevonedistat exposure (AUC).
The potential risk of DDIs between pevonedistat and concomitantly administered drugs is 
currently informed by available nonclinical and clinical data (see IB). Study C15011 assessed the 
effect of multiple doses of fluconazole (a moderate CYP3A inhibitor) as well as the effect of 
multiple doses of itraconazole (a strong CYP3A/P-gp inhibitor) on pevonedistat PK. The result 
indicated that fluconazole or itraconazole has no clinically meaningful impact on pevonedistat PK. 
In Study P1015, co-administration of rifampin, a strong CYP3A inducer, with pevonedistat did not 
result in clinically meaningful alteration of pevonedistat systemic exposures [18]. Despite results 
of Studies C15011 and P1015, in the current study, use of strong CYP3A inducers and inhibitors 
remains prohibited in order to interpret the effects of organ impairment on pevonedistat PK 
without other confounding factors. As a general precaution, patients receiving concomitant 
medications, particularly those with narrow therapeutic indices, should be carefully monitored as 
the DDI potential between pevonedistat and other drugs has not been formally studied in humans. 
Patients should also be instructed to consult with the investigator before taking any new 
medications, including over-the-counter products and herbal supplements.
See Section 8.4 for information on concomitant medications that are prohibited and Section 8.5 for 
information on medications that are permitted during this study.
4.1.6
Summary of Risks and Benefits
Analyses of safety data from more than 130 patients treated with pevonedistat plus azacitidine at 
the dose and schedule to be used in this phase 1/1b study demonstrate that pevonedistat adds little 
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toxicity to azacitidine alone and that toxicities are manageable. Efficacy data from a phase 1 study 
using this combination demonstrated a 50% ORR based on an ITT analysis (20 CR, 5 CRi, 7 PR), 
with an 8.3-month median duration of remission in untreated, older patients with AML for whom 
intensive induction chemotherapy was considered inappropriate. In patients receiving ≥6 cycles of 
therapy (n = 23, 44%), ORR was 83%. In total, 6 out of 8 patients with a TP53 mutation achieved 
CR/CRi/PR, and 4 of 6 remained on study for >10 cycles. Baseline bone marrow blast percentage 
or cytogenetic/molecular risk did not influence ORR [9]. Thus, the benefit-risk ratio supports 
further study of the combination of pevonedistat and azacitidine in a randomized controlled trial in 
patients with HR MDS or CMML, or AML.
A number of patients with solid tumors treated with pevonedistat as a single agent demonstrated 
clinical benefit based primarily on prolonged SD. In addition, pevonedistat has clinical activity 
when administered in combination therapy with docetaxel or carboplatin plus paclitaxel. On the 
basis of findings from Study C15010 and Study C15011, these combinations have shown evidence 
of clinical benefit in the form of multiple PRs, limited CRs, and extended durations of SD. 
Therefore, it is considered that docetaxel and carboplatin plus paclitaxel may serve as reasonable 
partners in combination with pevonedistat for investigations in patients with various advanced 
solid tumors in this study.
4.2
Rationale for the Proposed Study
Pevonedistat is being developed in combination with azacitidine for the treatment of HR MDS, HR 
CMML, and AML and in combination with docetaxel or carboplatin plus paclitaxel for treatment 
of advanced solid tumors. Based on the preliminary results from the clinical radiolabeled mass 
balance study (Study P1013), pevonedistat undergoes extensive biotransformation with 41% and 
53% of administered radioactivity recovered in urine and feces, respectively. Oxidative 
biotransformation pathways represented the major clearance mechanisms for pevonedistat, as 
inferred from metabolite profiling studies of excreta.
A population PK analysis of pevonedistat has been conducted with a wide range of renal function 
represented in the analysis population of cancer patients (CrCL, 26.3-301 mL/min; estimated 
glomerular filtration rate [eGFR] 24-267 mL/min/1.73 m2). The analysis dataset included patients 
with renal impairment ranging from mild (N = 114 with CrCL of 60-89 mL/min; N = 157 with 
eGFR of 60-89 mL/min/1.73 m2) or moderate (N = 57 with CrCL of 30-59 mL/min; N = 75 with 
eGFR of 30-59 mL/min/1.73 m2). Renal function was not identified as a covariate in the 
population PK model, and it was concluded that mild or moderate renal impairment had no 
clinically meaningful impact on the PK of pevonedistat. Although renal clearance of parent drug is 
only a minor (2.5%) contributor to overall pevonedistat clearance, the possibility of severe renal 
impairment altering drug metabolism and impacting pevonedistat PK cannot be ruled out.
Azacitidine and its metabolites are primarily excreted by the kidneys. Azacitidine exposures 
increase (70% following single-dose and 40% following multiple-dose administration) in patients 
with severe renal impairment. This increase in azacitidine exposure was not correlated with an 
increase in AEs in the single-agent setting. Therefore, a Cycle 1 dose modification of azacitidine 
for patient with severe renal impairment is not recommended [10] in its single-agent setting of 
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approved use. This study will also evaluate the safety of pevonedistat in combination with 
azacitidine in patients with severe renal impairment.
The effects of severe renal impairment or mild or moderate hepatic impairment on pevonedistat 
PK will be evaluated in this study. The results of this study will guide development of posology 
adjustments that may be needed for pevonedistat in these special patient populations. In Part A, 
administration of a single dose of pevonedistat will allow for the characterization of the effects of 
severe renal impairment or mild or moderate hepatic impairment on pevonedistat PK. In Part B, 
the safety and PK of pevonedistat in combination with SOC agents will be assessed. For patients 
with hematologic malignancies, the PK of both pevonedistat and azacitidine in the combination 
setting will be assessed. For patients with solid tumors, the PK of pevonedistat will be assessed in 
the combination setting.
Patients with advanced solid tumors will be eligible for enrollment in the organ impairment arms 
of the study. Based on the population PK analysis in 416 patients with advanced malignancies, 
tumor type (hematologic vs solid tumor) did not impact the PK of pevonedistat. Therefore, it is 
appropriate to broaden participation in this study to include patients with solid tumors. After 
completing Part A (single dose of pevonedistat), patients with advanced solid tumors will have the 
option to continue into the second part of the study (Part B), in which they will receive 
combination treatment with pevonedistat and docetaxel or carboplatin plus paclitaxel.
The choice of the above chemotherapy agents in combination with pevonedistat in this study is 
based on the following considerations:

These chemotherapy agents have been well recognized as SOC in a number of malignancies in 
first-line (carboplatin plus paclitaxel) or in various relapse settings (both regimens).

The safety profiles, risks, and benefits have been widely studied and reported.

Additive/synergistic effects of these agents in combination with pevonedistat have been 
studied in a number of in vitro and in vivo models by the sponsor.
4.3
Rationale for the Dose
Single dose of pevonedistat (Part A)
The recommended clinical dose of pevonedistat as a single agent is 50 mg/m2 or higher on Days 1, 
3, and 5 in 21-day cycles.
In this study, all eligible patients will receive a single dose of 20 mg/m2 pevonedistat in Part A. A 
single dose of 20 mg/m2 pevonedistat in patients with severe renal impairment or mild or moderate 
hepatic impairment is considered to be safe and is expected to be well-tolerated, as it is at least 
2.5-fold below the upper end of the tolerated dose range of single-agent pevonedistat.
Based on the population PK analysis in 416 patients receiving pevonedistat over a dose range of 10 
to 278 mg/m2, levels of ALT and AST did not have meaningful impact on pevonedistat exposures. 
Tumor type (hematologic vs solid) showed no impact on pevonedistat systemic exposure. In 
addition, renal clearance plays a minor role in pevonedistat elimination pathways. Patients will be 
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closely monitored for toxicities. After administration of the first dose of pevonedistat, there will be 
a period of 4 to 7 days (washout period) without further dosing with pevonedistat.
Multiple dosing of pevonedistat in combination with standard of care agents (Part B)
After completion of Part A, patients will have the opportunity to participate in Part B and receive 
pevonedistat in combination with SOC agents.
In patients with hematologic malignancies (MDS, CMML, or AML), pevonedistat is being 
developed in combination with azacitidine. The RP2D is determined to be 20 mg/m2 on Days 1, 3, 
and 5 plus 75 mg/m2 azacitidine on Days 1 through 5, 8, and 9 in 28-day cycles (Study C15009).
In patients with advanced solid tumors, pevonedistat is being developed in combination with 
carboplatin plus paclitaxel or docetaxel. The RP2D in combination with carboplatin plus paclitaxel 
is determined to be 20 mg/m2 on Days 1, 3, and 5 with 175 mg/m2 paclitaxel plus AUC5 
carboplatin on Day 1 in 21-day treatment cycles (Study C15010). The RP2D of pevonedistat in 
combination with docetaxel is 25 mg/m2 on Days 1, 3, and 5 with 75 mg/m2 docetaxel on Day 1 in 
21-day treatment cycles (Study C15010).
For patients with normal renal and hepatic function
In patients with hematologic malignancies and normal renal and hepatic function, starting in 
Cycle 1 of Part B, patients will receive 20 mg/m2 pevonedistat on Days 1, 3, and 5 in combination 
with 75 mg/m2 azacitidine on Days 1 through 5, 8, and 9 in 28-day cycles.
As of Amendment 02, the Control Arm of the study completed enrollment. Patients with advanced 
solid tumors with normal renal and hepatic function will not be enrolled in the Control Arm.
For patients with mild hepatic impairment
Three patients with hematologic malignancies and mild hepatic impairment have been enrolled in 
Study Pevonedistat-1016 and received 10 mg/m2 pevonedistat in combination with azacitidine. No 
new safety signals were reported. Therefore, as of Amendment 02, patients with mild hepatic 
impairment and hematologic malignancies or solid tumors will receive 20 mg/m2 pevonedistat in 
combination therapy in Part B.
Starting in Cycle 1 of Part B, patients with hematologic malignancies and mild hepatic impairment 
will receive 20 mg/m2 pevonedistat on Days 1, 3, and 5 in combination with 75 mg/m2 azacitidine 
on Days 1 through 7 or Days 1 through 5, 8, and 9 in 28-day cycles. The starting doses for 
pevonedistat and azacitidine in combination are not to be escalated in this cohort.
Patients with advanced solid tumors and mild hepatic impairment who are considered to benefit 
from treatment with pevonedistat in combination with carboplatin plus paclitaxel will receive 
20 mg/m2 pevonedistat on Days 1, 3, and 5 in combination with 135 mg/m2 paclitaxel plus AUC4 
carboplatin on Day 1 of each 21-day treatment cycle.
The dose of paclitaxel (135 mg/m2) selected for patients with mild hepatic impairment is based on 
USPI recommendations in patients with bilirubin <2 mg/dL [19] and is not to be escalated.
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The lower starting dose of carboplatin (AUC4) is selected to provide a window of safety for 
patients with mild hepatic impairment. Starting in Cycle 2 or in subsequent cycles, intrapatient 
dose escalation of carboplatin to AUC5 will be allowed if treatment with AUC4 in Cycle 1 is 
judged to be safe and tolerable.
According to the docetaxel USPI, patients with bilirubin >ULN or AST or ALT ≥1.5 × ULN 
should not receive docetaxel. Docetaxel will therefore not be dosed in patients with mild or 
moderate hepatic impairment.
For patients with moderate hepatic impairment
For patients with moderate hepatic impairment, a lower starting dose of pevonedistat (10 mg/m2) 
is selected to provide an adequate safety window for potentially increased pevonedistat exposures 
in this patient population.
Starting in Cycle 1 of Part B, patients with hematologic malignancies and moderate hepatic 
impairment will receive 10 mg/m2 pevonedistat on Days 1, 3, and 5 in combination with 75 mg/m2
azacitidine on Days 1 through 7 or Days 1 through 5, 8, and 9 in 28-day cycles.
Patients with advanced solid tumors and moderate hepatic impairment who are considered to 
benefit from treatment with pevonedistat in combination with carboplatin plus paclitaxel will 
receive a starting dose of 10 mg/m2 pevonedistat on Days 1, 3, and 5 in combination with 
90 mg/m2 paclitaxel plus AUC4 carboplatin on Day 1 of each 21-day treatment cycle.
Following sponsor and investigator discussion of safety data from Cycle 1, patients with moderate 
hepatic impairment who tolerate pevonedistat well at lower doses may be eligible for intrapatient 
pevonedistat dose escalation in dose increments of 5 mg/m2 per cycle starting in Cycle 2 (eg, 
pevonedistat may be increased to 15 mg/m2 on Days 1, 3, and 5 of Cycle 2) and in subsequent 
cycles, to a maximum dose of 20 mg/m2.
The dose of paclitaxel (90 mg/m2) selected for patients with moderate hepatic impairment is based 
on USPI recommendations in patients with bilirubin >2 × ULN [19] and is not to be escalated.
As in patients with mild hepatic impairment, carboplatin dosing will begin at AUC4 for patient 
safety. Starting in Cycle 2 or in subsequent cycles, intrapatient dose escalation of carboplatin to 
AUC5 will be allowed if treatment with AUC4 in previous cycles is judged to be safe and tolerable. 
Dose escalation of carboplatin is not to take place during the same cycle in which pevonedistat 
dose is escalated.
For patients with severe renal impairment
Renal clearance of pevonedistat is a minor route of elimination. Three patients with hematologic 
malignancies and severe renal impairment have been enrolled in Study Pevonedistat-1016 and 
received 10 mg/m2 pevonedistat in combination with azacitidine. No new safety signals were 
reported. The safety and preliminary PK data from these 3 patients support a starting dose of 
15 mg/m2 pevonedistat. Therefore, patients with severe renal impairment and hematologic 
malignancies or solid tumors will receive a starting dose of 15 mg/m2 pevonedistat in combination 
therapy in Part B.
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Starting in Cycle 1 of Part B, patients with hematologic malignancies and severe renal impairment 
will receive 15 mg/m2 pevonedistat on Days 1, 3, and 5 in combination with 75 mg/m2 azacitidine 
on Days 1 through 7 or Days 1 through 5, 8, and 9 in 28-day cycles.
Patients with advanced solid tumors and severe renal impairment who are considered to benefit 
from treatment with pevonedistat in combination with carboplatin plus paclitaxel will receive 
15 mg/m2 pevonedistat on Days 1, 3, and 5 in combination with paclitaxel 135 mg/m2 plus 
carboplatin AUC4 on Day 1 of each 21-day treatment cycle.
Patients with advanced solid tumors and severe renal impairment may receive pevonedistat in 
combination with docetaxel. For patients considered to benefit from treatment with pevonedistat 
plus docetaxel, the starting pevonedistat dose in Cycle 1 will be 15 mg/m2 in combination with 
docetaxel 75 mg/m2.
Following sponsor and investigator discussion of safety data from Cycle 1, patients with severe 
renal impairment who tolerate pevonedistat well at lower doses may be eligible for intrapatient 
pevonedistat dose escalation. Starting in Cycle 2 or in subsequent cycles, patients treated with 
pevonedistat in combination with azacitidine or carboplatin plus paclitaxel may be eligible for 
intrapatient pevonedistat dose escalation to a maximum dose of 20 mg/m2.
For patients receiving pevonedistat in combination with docetaxel who tolerate pevonedistat well 
at lower doses, intrapatient dose escalation of pevonedistat in dose increments of 5 mg/m2 per 
cycle is allowed starting in Cycle 2 (eg, pevonedistat may be increased to 15 mg/m2 on Days 1, 3, 
and 5 of Cycle 2) and in subsequent cycles, to a maximum dose of 25 mg/m2.
The dose of paclitaxel (135 mg/m2) is selected for patient safety, however, as paclitaxel is cleared 
through the hepatic route, patients with severe renal impairment may be eligible for intrapatient 
dose escalation to 175 mg/m2 paclitaxel in Cycle 2 or beyond if the lower dose is well-tolerated in 
Cycle 1.
The starting dose of carboplatin will be AUC4 to provide a window for patient safety. Starting in 
Cycle 2 or in subsequent cycles, intrapatient dose escalation of carboplatin to AUC5 will be 
allowed if treatment with AUC4 in Cycle 1 is judged to be safe and tolerable.
Dose escalation of any SOC agent is not permitted in the same cycle as dose escalation of other 
SOC agents or of pevonedistat.
5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objectives
The primary objectives (Part A) are as follows:

To characterize the PK of pevonedistat in patients with severe renal impairment.

To characterize the PK of pevonedistat in patients with mild hepatic impairment.

To characterize the PK of pevonedistat in patients with moderate hepatic impairment.
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5.1.2
Secondary Objectives
The secondary objectives (Part A and Part B) are as follows:

To evaluate disease response in patients with severe renal impairment or mild or moderate 
hepatic impairment that may be observed in the combination of pevonedistat with 
chemotherapy (azacitidine, docetaxel, or carboplatin plus paclitaxel).

To characterize the PK of pevonedistat and azacitidine in the combination setting in patients 
with hematologic malignancies and severe renal impairment or mild or moderate hepatic 
impairment.

To characterize the PK of pevonedistat in combination with docetaxel or carboplatin plus 
paclitaxel in patients with advanced solid tumors and severe renal impairment or mild or 
moderate hepatic impairment.
5.1.3
Safety Objective
The safety objective (Part A and Part B) is as follows:

To evaluate the safety of pevonedistat following a single dose, or in combination with 
chemotherapy (azacitidine, docetaxel, or carboplatin plus paclitaxel), in patients with normal 
organ function and in patients with organ impairment.
5.1.4
Exploratory Objectives
Not applicable.
5.2
Endpoints
5.2.1
Primary Endpoints
The primary endpoints are as follows:

Area under the plasma concentration-time curve from time zero to infinity (AUC∞) following a 
single dose of pevonedistat in patients with normal renal and hepatic function, severe renal 
impairment, or mild or moderate hepatic impairment.

Area under the plasma concentration-time curve from time zero to the time of the last 
quantifiable concentration (AUClast) following a single dose of pevonedistat in patients with 
normal renal and hepatic function, severe renal impairment, or mild or moderate hepatic 
impairment.

Maximum observed plasma concentration (Cmax) of pevonedistat following a single dose of 
pevonedistat in patients with normal renal and hepatic function, severe renal impairment, or 
mild or moderate hepatic impairment.
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5.2.2
Secondary Endpoints
The secondary endpoints are as follows:

t1/2z of pevonedistat following single- and multiple-dose administration.

Cmax of pevonedistat following multiple-dose administration.

Fraction of unbound drug in plasma (fu) of pevonedistat.

Cmax of azacitidine following multiple-dose administration.

Time of first occurrence of maximum observed concentration (Tmax) of azacitidine following 
multiple-dose administration.

t1/2z of azacitidine following multiple-dose administration.

Area under the concentration-time curve from time zero to the end of the dosing interval 
(AUCτ) of pevonedistat and azacitidine following multiple-dose administration.

CL of pevonedistat and apparent clearance (CL/F) of azacitidine.

Renal clearance (CLR) of pevonedistat and azacitidine.

Volume of distribution at steady-state (Vss) of pevonedistat and apparent Vss of azacitidine.

Measures of disease response, including response rate and duration of response, based on the 
investigator’s assessment (Part B only) using the following responses for each disease type:
–
CR, CRi, or PR for AML.
–
CR, PR, or hematologic improvement (HI) for MDS and CMML.
–
CR or PR in patients with solid tumors using the Response Evaluation Criteria in Solid 
Tumors (RECIST) version 1.1 criteria.
5.2.3
Exploratory Endpoints
None.
5.2.4
Safety Endpoints
The safety endpoints are:

AEs, SAEs, assessments of clinical laboratory values, vital signs measurements, and Eastern 
Cooperative Oncology Group (ECOG) performance status (PS).
6.0
STUDY DESIGN
6.1
Overview of Study Design
This study is an open-label, multicenter, phase 1/1b, 2-part study of pevonedistat plus select SOC 
agents in adult patients with hematologic malignancies (HR MDS, HR CMML, AML) or solid 
tumors with various degrees of renal or hepatic function. Eligible patients include those with 
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relapsed/refractory MDS, nonproliferative CMML, AML, and metastatic or advanced solid 
tumors for whom treatment with pevonedistat and SOC agents is appropriate. Patients with 
previously untreated hematologic malignancies not suitable for induction therapy will also be 
eligible for enrollment. The study has been designed to characterize the PK and assess the safety of 
pevonedistat in combination with SOC agents in patients with hematologic malignancies or solid 
tumors who also have severe renal impairment or mild or moderate hepatic impairment. As of 
Amendment 02, patients will be assigned to 1 of 4 arms based on their renal and/or hepatic
function: normal renal and hepatic function (Control Arm), severe renal impairment (Renal Arm), 
mild hepatic impairment (Mild Hepatic Arm), and moderate hepatic impairment (Moderate 
Hepatic Arm).
It is expected that approximately 42 patients will be enrolled in this study. As of Amendment 02, 
Part A of the study will be a single-agent pevonedistat PK assessment, followed by Part B 
treatment with pevonedistat in combination with SOC agents (azacitidine, docetaxel, or 
carboplatin plus paclitaxel).
Once enrolled into the study, all eligible patients will be administered a single dose of pevonedistat 
20 mg/m2 via approximately 1-hour IV infusion on Day 1 of Part A. Plasma PK samples will be 
collected at a series of predetermined time points up to 72 hours following the single dose of 
pevonedistat. There will be an approximate 4- to 7-day washout period before the start of Part B. 
The schedules of events and study schema for the study are provided in Appendix A and 
Appendix B, respectively.
After completion of Part A, all patients will have the opportunity to continue into Part B of the 
study.
In Part B, patients with hematologic malignancies may receive pevonedistat on Days 1, 3, and 5 in 
combination with azacitidine (75 mg/m2) on Days 1 through 7 or Days 1 through 5, 8, and 9 in 
28-day cycles. Patients will receive azacitidine SC in Cycle 1. Azacitidine will be given SC or IV 
during Cycle 2 and beyond. During Cycle 1 of Part B, plasma and urine PK samples for 
measurement of both pevonedistat and azacitidine will be collected at predetermined time points 
or intervals on Day 3. Plasma PK samples for measurement of pevonedistat will also be collected 
on Days 4 and 5 of Cycle 1.
Patients with advanced solid tumors may receive pevonedistat in combination with docetaxel or 
carboplatin plus paclitaxel on Day 1 and pevonedistat alone on Days 3 and 5 in 21-day cycles. 
During Cycle 1 of Part B, plasma PK samples for measurement of pevonedistat will be collected 
on Days 3, 4, and 5.
The schedule of sample collection for PK assessments is provided in Appendix A.
Following sponsor and investigator discussion of safety data from Cycle 1, patients in the organ 
impairment arms who tolerate pevonedistat well at a low starting dose may be eligible for 
intrapatient dose escalation of pevonedistat starting in Cycle 2 of Part B or soon thereafter. 
Patients who tolerate treatment well at low starting doses of SOC agents may also be eligible for 
intrapatient dose escalation of those agents, per USPI/SmPC recommendations.
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Details for dosing, study drug administration, and intrapatient dose escalation are provided in 
Section 8.1
Patients may continue to receive combination treatment with pevonedistat in 28-day cycles (in 
combination with azacitidine) or in 21-day cycles (in combination with docetaxel or carboplatin 
plus paclitaxel) in Part B until they experience symptomatic deterioration or disease progression, 
treatment is discontinued for another reason, or until the study is stopped by the sponsor.
Treatment with the study drug will be discontinued early if a patient experiences study 
drug-related toxicities. Patients may discontinue therapy at any time. Patients will attend the end of 
study (EOS)/early termination (ET) visit 30 (+10) days after receiving their last dose of study drug 
or before the start of subsequent antineoplastic therapy, if that occurs sooner.
AEs and ECOG PS will be assessed, and electrocardiograms (ECGs), clinical laboratory values 
(with select chemistry panel during Part B), and vital signs will be obtained, to evaluate the safety 
and tolerability of the study drug treatments. Toxicity will be evaluated according to National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 5.0, 
effective date 27 November 2017 [1]. Dose modification guidelines are presented in Section 8.3.
Measures of disease response (CR or PR for AML and solid tumors; CR, PR, or HI for MDS and 
CMML), including response rate and duration of response, will be based on the investigator’s 
assessment (Part B only).
6.2
Number of Patients
Approximately 42 patients will be enrolled at 25 to 30 study centers located in the United States 
(US) and EU. Enrollment is achieved when the first dose of any study drug has been administered.
Patients will be assigned to 1 of 4 arms based on their renal and/or hepatic function: normal renal 
and hepatic function (Control Arm), severe renal impairment (Renal Arm), mild hepatic 
impairment (Mild Hepatic Arm), and moderate hepatic impairment (Moderate Hepatic Arm). 
Patients who are withdrawn from treatment during Part A of the study, will be replaced. Patients 
who are nonevaluable for PK during Part A may also be replaced.
6.3
Duration of Study
6.3.1
Duration of an Individual Patient’s Study Participation
Part A: Patients will participate in the assessment of pevonedistat PK following a single-dose 
administration of pevonedistat (4 to 7 days).
Part B: Eligible patients who opt to continue into Part B of the study will receive pevonedistat in 
combination with SOC agents (azacitidine, docetaxel, or carboplatin plus paclitaxel). Patients may 
receive combination therapy until they experience symptomatic deterioration or PD, 
discontinuation for any other reason outlined in Section 9.7, or the study is stopped by the sponsor 
(eg, if a PTA study becomes available). The maximum duration of treatment is 12 cycles, unless 
the investigator and sponsor (or designee) agree that a patient would benefit from continued 
treatment. Patients who continue on treatment after 12 cycles will be permitted to take treatment 
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breaks, at the investigator’s discretion, that are no longer than 4 weeks in duration; treatment 
breaks may not be taken consecutively. The investigator will confirm patient eligibility for 
continued treatment upon return from a treatment break (Section 8.3). Patients with hematologic 
malignancies may be allowed to continue study treatment even if they meet the criteria for PD 
based only on bone marrow blast counts if, in the clinical judgment of the investigator, the patient 
is still receiving clinical benefit from this treatment, and the continuation is endorsed by the 
sponsor’s project clinician (or designee). Patients who continue on study under these conditions 
must be reconsented before continuing study treatment (see Section 9.4.1).
Patients with advanced solid tumors who have achieved clinical benefit from combination therapy 
(chemotherapy plus pevonedistat) and who have developed intolerance that is reasonably 
attributable to the chemotherapy after 2 or more cycles may continue on single-agent pevonedistat 
upon request by the investigator and agreement by the sponsor.
Patients will be followed for 30 (+10) days after the last dose of study drugs or the start of 
subsequent alternative anticancer therapy to permit detection of any delayed treatment-related 
AEs.
6.3.2
End of Study/Study Completion Definition and Planned Reporting
The final analyses for the CSR may be conducted when all patients have had the opportunity to 
complete Part A and Cycle 1 of Part B of the study. Patients will be followed until they are no 
longer receiving study drug or the study has been terminated by the sponsor.
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.
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Table 6.a
Primary and Secondary Endpoints for Disclosures
Endpoint
Maximum Time Frame Per Individual 
Patient

AUC∞following a single dose of pevonedistat in patients with 
normal renal and hepatic function, severe renal impairment, or 
mild or moderate hepatic impairment (Part A).
Up to 72 hours following single dose of 
pevonedistat.

AUClast following a single dose of pevonedistat in patients 
with normal renal and hepatic function, severe renal 
impairment, or mild or moderate hepatic impairment (Part A).
Up to 72 hours following single dose of 
pevonedistat.

Cmax of pevonedistat following a single dose of pevonedistat in 
patients with normal renal and hepatic function, severe renal 
impairment, or mild or moderate hepatic impairment (Part A).
Up to 72 hours following single dose of 
pevonedistat.

t1/2z of pevonedistat (Parts A and B).
Up to 72 hours following pevonedistat dosing.

fu of pevonedistat.
Up to 48 hours following pevonedistat dosing.

t1/2z of azacitidine (Part B).
Up to 8 hours following azacitidine dosing.

AUCτ of pevonedistat and azacitidine
(Part B).
Up to 48 hours following azacitidine and 
pevonedistat dosing.

CL of pevonedistat (Parts A and B).
Up to 72 hours following pevonedistat dosing.

CL/F of azacitidine.
Up to 8 hours following azacitidine dosing.

CLR, pevonedistat (Part B).
Up to 8 hours following pevonedistat dosing.

CLR, azacitidine (Part B).
Up to 8 hours following azacitidine dosing.

Vss of pevonedistat (Parts A and B).
Up to 72 hours following pevonedistat dosing.

Vss of azacitidine (Part B).
Up to 8 hours following azacitidine dosing.

Measures of disease response (CR or PR for AML and solid 
tumors; CR, PR, or HI for MDS and CMML); including 
response rate and duration of response, based on the 
investigator’s assessment (Part B).
Cycle 2, and then every 3rd cycle thereafter, or 
otherwise as clinically indicated per the 
discretion of the investigator. After completion 
of 11 cycles, disease response will be assessed 
every 6th cycle, or otherwise as clinically 
indicated. a
AML: acute myelogenous leukemia; AUC∞: area under the plasma concentration-time curve from time zero to 
infinity; AUClast: area under the plasma concentration-time curve from time zero to the time of the last quantifiable 
concentration; AUCτ : area under plasma concentration-time curve from time zero to the end of the dosing interval; 
CL: total clearance; CL/F: apparent clearance; CLR: renal clearance; Cmax: maximum observed plasma concentration; 
CMML: chronic myelomonocytic leukemia; CR: complete response/remission; fu: fraction of unbound drug in 
plasma; HI: hematologic improvement; MDS: myelodysplastic syndromes; PR: partial response/remission; t1/2z: 
terminal disposition phase half-life; Vss: volume of distribution at steady-state.
a The maximum duration of treatment will be 12 cycles; however, if it is determined after discussion between the 
investigator and the sponsor that a patient would derive benefit from continued treatment, the patient may remain on 
the current combination therapy.
6.3.4
Total Study Duration
It is anticipated that overall this study will last for approximately 3.5 years for Part A and Part B 
combined.
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6.3.5
PTA
6.3.5.1
PTA
If a PTA program should become an option for a patient, and if the responsible investigator and the 
sponsor agree that the patient would derive benefit from or would be harmed without continued 
treatment, then pevonedistat may be provided through the PTA program (where permitted by local 
regulations).
6.3.5.2
Duration of PTA
If a PTA program should become an option for a patient, as described in Section 6.3.5.1, the 
sponsor may continue to provide pevonedistat to that patient through the PTA program. Continued 
access to pevonedistat for participants will be terminated for those individuals who no longer 
benefit from treatment (eg, their disease has progressed or treatment is no longer tolerable), the 
benefit-risk no longer favors the individual, an appropriate alternative therapy becomes available, 
or pevonedistat becomes available either commercially or via another access mechanism. PTA 
may be terminated in a country or geographic region where the development of pevonedistat has 
been suspended or stopped by the sponsor or where pevonedistat can no longer be supplied.
7.0
STUDY POPULATION
7.1
Inclusion Criteria
7.1.1
All Patients
Each patient must meet all the following inclusion criteria to be enrolled in the study:
1. Male and female patients aged 18 years or older.
2. Expected survival of at least 3 months from the date of enrollment in the study.
3. ECOG PS of 0, 1, or 2 (Appendix D).
4. Recovered (ie, Grade ≤1 toxicity) from the reversible effects of prior anticancer therapy.
5. Prothrombin time (PT) and aPTT ≤1.5 × ULN at screening or within 7 days before the first 
dose of study drug.
6. Female patients who:

Are postmenopausal (see Appendix E) for at least 1 year before the screening visit, OR

Are surgically sterile, OR

Agree, if they are of childbearing potential, to practice 1 highly effective method of 
contraception and 1 additional effective (barrier) method (see Appendix F), at the same 
time, from the time of signing the informed consent through 6 months after the last dose of 
study drug, OR
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
Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle 
of the subject. Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation 
methods), withdrawal, spermicides only, and lactational amenorrhea are not acceptable 
methods of contraception. Female and male condoms should not be used together.
7. 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 subject. Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation 
methods), withdrawal, spermicides only, and lactational amenorrhea are not acceptable 
methods of contraception. Female and male condoms should not be used together.
8. Suitable venous access for the study-required blood sampling (ie, PK sampling).
9. Voluntary written consent must be given by the patient or the patient’s legally acceptable 
representative before performance of any study-related procedure not part of standard medical 
care, with the understanding that consent may be withdrawn by the patient or the patient’s 
legally acceptable representative at any time without prejudice to future medical care.
7.1.2
Patients With Hematologic Malignancies
In addition to the inclusion criteria in Section 7.1.1, each patient with hematologic malignancies 
must also meet the following inclusion criteria, as they apply to their specific malignancy, to be 
enrolled in the study:
10. Previously untreated hematologic malignancies not suitable for induction therapy.
11. Morphologically confirmed diagnosis of MDS or nonproliferative CMML (ie, with white 
blood cell [WBC] <13,000/µL) at study entry, based on one of the following:
French-American-British Classifications [2]:

Refractory anemia with excess blasts (RAEB), defined as having 5% to 20% myeloblasts 
in the bone marrow.

CMML with 10% to 19% myeloblasts in the bone marrow and/or 5% to 19% blasts in the 
blood.
OR
WHO Classifications [3]:

RAEB-1, defined as having 5% to 9% myeloblasts in the bone marrow.

RAEB-2, defined as having 10% to 19% myeloblasts in the bone marrow and/or 5% to 19% 
blasts in the blood.

CMML-2, defined as having 10% to 19% myeloblasts in the bone marrow and/or 5% to 19% 
blasts in the blood.
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
CMML-1 (although CMML-1 is defined as having <10% myeloblasts in the bone marrow 
and/or <5% blasts in the blood, these patients may enroll only if bone marrow blasts ≥5%).
12. All patients with MDS or CMML must also have one of the following Prognostic Risk 
Categories at study entry, based on the Revised International Prognostic Scoring System 
(IPSS-R) [4]:

Very high (>6 points).

High (>4.5-6 points).

Intermediate (>3-4.5 points): a patient determined to be in the Intermediate Prognostic 
Risk Category is only allowable in the setting of ≥5% bone marrow myeloblasts.
13. Patients with WHO-defined AML at study entry, including leukemia secondary to prior 
chemotherapy or resulting from an antecedent hematologic disorder, who have failed to 
achieve CR or who have relapsed after prior therapy and are not candidates for potentially 
curative treatment.
14. Patients with relapsed or refractory MDS at study entry, who have previously been treated with 
an hypomethylating agent.
15. For patients with hematologic malignancies, laboratory value requirements per study arms for 
eGFR, total bilirubin, and ALT are provided in the table below:
Treatment
Arm
eGFR
(mL/min/1.73 m2)
Total
Bilirubin
ALT
Control
≥90
≤ULN
≤ULN
Renal
<30
≤ULN
≤2.5 × ULN
Mild hepatic
≥60
ULN <bilirubin ≤1.5 × ULN
(not secondary to transfusions)
Any
Moderate hepatic
≥60
1.5 × ULN <bilirubin ≤3.0 × ULN
(not secondary to transfusions)
Any
ALT: alanine aminotransferase; eGFR: estimated glomerular filtration rate; ULN: upper limit of the normal range.
Refer to Section 9.4.16 for information regarding hepatic and renal function laboratory result requirements.
7.1.3
Patients With Advanced Solid Tumors
In addition to the inclusion criteria in Section 7.1.1, each patient with advanced solid tumors must 
also meet the following inclusion criteria to be enrolled in the study:
16. Adult patients who have a histologically or cytologically confirmed metastatic or locally 
advanced solid tumor that is appropriate for treatment with pevonedistat in combination with 
either docetaxel or carboplatin plus paclitaxel in Part B of this study, or have progressed 
despite standard therapy, or for whom conventional therapy is not considered effective.
17. For patients with advanced solid tumors, clinical laboratory values are specified below:

Hemoglobin ≥8 g/dL. Patients may be transfused to achieve this value.
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
For patients to be treated with pevonedistat plus docetaxel in Part B, total bilirubin must be 
≤ULN.

ALT, AST, and ALP ≤2.5 × ULN.
–
For patients to be treated with pevonedistat plus docetaxel in Part B, AST and ALT 
must be ≤1.5 × ULN. Only patients with severe renal impairment may be considered 
for this combination.

ANC ≥1500/mm3.

Platelet count ≥100,000/mm3.

Albumin ≥2.7 g/dL.
18. Computerized tomography (CT) scan or magnetic resonance imaging (MRI) of the chest, 
abdomen, and pelvis within 28 days of the first dose of study drug.
19. For patients with advanced solid tumors, laboratory value requirements per study arms for 
eGFR, total bilirubin, and ALT are provided in the table below:
Treatment
Arm
eGFR
(mL/min/1.73 m2)
Total
Bilirubin
ALT
Renal
<30
≤ULN
≤1.5 × ULN a
or
≤2.5 × ULN b
Mild hepatic c
≥60
ULN <bilirubin ≤1.5 × ULN
Any
Moderate hepatic c
≥60
1.5 × ULN <bilirubin ≤3.0 × ULN
Any
ALT: alanine aminotransferase; eGFR: estimated glomerular filtration rate; ULN: upper limit of the normal range.
Refer to Section 9.4.16 for information regarding hepatic and renal function laboratory result requirements.
a For patients who receive pevonedistat plus docetaxel only.
b For patients who receive pevonedistat plus carboplatin plus paclitaxel only.
c Patients with advanced solid tumors in the hepatic impairment arms will not receive combination treatment with 
pevonedistat and docetaxel.
7.2
Exclusion Criteria
7.2.1
All Patients
Patients meeting any of the following exclusion criteria are not to be enrolled in the study:
1. Any serious medical or psychiatric illness that could, in the investigator’s opinion, potentially 
interfere with the completion of study procedures or could limit expected patient survival to 
less than 6 months.
2. End-stage renal disease requiring hemodialysis at study entry.
3. Gilbert syndrome.
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4. Treatment with any investigational products or participation in any interventional studies 
within 21 days before the first dose of any study drug.
5. Known hypersensitivity to pevonedistat or its excipients.
6. Active uncontrolled infection or severe infectious disease, such as severe pneumonia, 
meningitis, or septicemia. Prophylactic treatment with antibiotics is allowed.
7. Major surgery within 14 days before first dose or a scheduled surgery during study period; 
insertion of a venous access device (eg, catheter, port) is not considered major surgery.
8. Life-threatening illness unrelated to cancer.
9. Known HIV seropositive.
10. Known hepatitis B surface antigen seropositive or known or suspected active hepatitis C 
infection. 
Note: Patients who have isolated positive hepatitis B core antibody (ie, in the setting of 
negative hepatitis B surface antigen and negative hepatitis B surface antibody) must have an 
undetectable hepatitis B viral load.
11. Known hepatic cirrhosis or severe pre-existing hepatic impairment.
12. Known cardiopulmonary disease defined as unstable angina, clinically significant arrhythmia, 
congestive heart failure (New York Heart Association Class III or IV; see Appendix G), and/or 
myocardial infarction within 6 months before first dose. However, patients with ischemic heart 
disease who have had acute coronary syndrome, myocardial infarction, or revascularization 
more than 6 months before screening and who are without cardiac symptoms may enroll. 
Patients with congestive heart failure (New York Heart Association Class III or IV) or New 
York Heart Association Class II with recent decompensation requiring hospitalization within 
4 weeks before screening are excluded.
13. Prolonged rate corrected QT interval ≥500 msec, calculated according to institutional 
guidelines.
14. Treatment with strong CYP3A inducers (see Appendix M) within 14 days before the first dose 
of pevonedistat.
15. Female patients who are lactating and breastfeeding or have a positive serum pregnancy test 
during the screening period or a positive urine pregnancy test on Day 1 of Part A, before first 
dose of study drug.
16. 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).
17. 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).
18. Diagnosed or treated for a different malignancy within 2 years before randomization or 
previously diagnosed with a different malignancy with any current evidence of residual 
disease. Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not 
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excluded if they have undergone resection. Patients with AML who have a history of MDS or 
CMML are not excluded, as MDS/CMML to AML is a natural progression for hematologic 
disease.
19. High blood pressure that cannot be controlled by standard treatments.
20. Left ventricular ejection fraction (LVEF) <50% within 6 months prior to study enrollment. If a 
result within this time frame is unavailable, LVEF must be determined by echocardiography or 
multigated acquisition scan at screening.
21. Severe uncontrolled ventricular arrhythmias or torsade de pointes; electrocardiographic 
evidence of acute ischemia or active conduction system abnormalities; or clinically significant 
arrhythmia (as an example, well-controlled atrial fibrillation would not be an exclusion 
whereas uncontrolled atrial fibrillation would be an exclusion).
22. Severe symptomatic pulmonary hypertension requiring pharmacologic therapy or patients 
with chronic respiratory disease that requires continuous oxygen.
7.2.2
Patients With Hematologic Malignancies
Patients with hematologic malignancies meeting any of the following additional exclusion criteria 
are not to be enrolled in the study:
23. Acute promyelocytic leukemia as diagnosed by morphologic examination of bone marrow, by 
fluorescent in situ hybridization or cytogenetics of peripheral blood or bone marrow, or by 
other accepted analysis.
24. Patients with AML with a WBC count ≥50,000/μL. Patients who are cytoreduced with 
leukapheresis or with hydroxyurea may be enrolled if they otherwise meet the eligibility 
criteria.
25. Patients with either clinical evidence of or history of central nervous system (CNS) 
involvement by AML.
26. Known hypersensitivity to azacitidine or its excipients.
27. For patients with hematologic malignancies, PT or aPTT >1.5 × ULN or active uncontrolled 
coagulopathy or bleeding disorder. Patients therapeutically anticoagulated with warfarin, 
direct thrombin inhibitors, direct factor Xa inhibitors, or heparin are excluded from enrollment.
7.2.3
Patients With Advanced Solid Tumors
Patients with advanced solid tumors meeting any of the following additional exclusion criteria are 
not to be enrolled in the study:
28. Prior treatment with radiation therapy involving ≥25% of the hematopoietically active bone 
marrow.
29. Known hypersensitivity or history of severe intolerance or toxicity to chemotherapeutic agents, 
including known history of severe hypersensitivity reactions to docetaxel (polysorbate 
80-based formulations) for patients to be treated with pevonedistat in combination with 
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docetaxel; history of hypersensitivity to carboplatin for patients to be treated with pevonedistat 
plus carboplatin plus paclitaxel; or history of severe hypersensitivity to paclitaxel 
(Cremophor-based formulations) for patients to be treated with pevonedistat with carboplatin 
plus paclitaxel.
30. CNS metastasis, except for patients who have received prior treatment (radiation or resection) 
and have stable CNS disease (eg, stable MRI, no steroid requirement).
8.0
STUDY DRUG
8.1
Study Drug Administration
All protocol-specific criteria for administration of study drug must be met and documented before 
drug administration. Study drug will be administered only to eligible patients under the 
supervision of the investigator or identified subinvestigator(s).
The amount of study drug (pevonedistat and/or azacitidine, docetaxel, or paclitaxel, as applicable) 
to be administered will be based on body surface area (BSA). BSA will be calculated using a 
standard formula (see example in Appendix H) on Day 1 of Part A and on Day 1 of each cycle in 
Part B if the patient experiences a >5% change in body weight from the weight used for the most 
recent BSA calculation.
On days when azacitidine is coadministered with pevonedistat, azacitidine is given first, followed 
by the pevonedistat IV infusion.
Part A:
All eligible patients will receive a single dose of 20 mg/m2 pevonedistat via a 1-hour IV infusion 
on Day 1. There will be no SOC agents administered or additional pevonedistat dosing during 
Part A.
Part B:
After completion of Part A, all patients will have the opportunity to continue into Part B.
Patients With Hematologic Malignancies
Patients with hematologic malignancies may receive pevonedistat on Days 1, 3, and 5 in 
combination with azacitidine (75 mg/m2) on Days 1 through 7 or Days 1 through 5, 8, and 9 in 
28-day cycles. Patients will receive azacitidine SC in Cycle 1. Azacitidine will be given SC or IV 
during Cycle 2 and beyond. On the days both study drugs are administered, azacitidine will be 
administered first, followed by pevonedistat. During Cycle 1 of Part B, plasma and urine PK 
samples for measurement of both pevonedistat and azacitidine will be collected at predetermined 
time points or intervals on Day 3. Plasma PK samples for measurement of pevonedistat will also 
be collected on Days 4 and 5 of Cycle 1. The schedule of PK sampling for patients with 
hematologic malignancies is provided in Appendix A, Table B.
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Patients With Advanced Solid Tumors
Patients with advanced solid tumors may receive pevonedistat in combination with docetaxel or 
with carboplatin plus paclitaxel on Day 1 and pevonedistat alone on Days 3 and 5 in 21-day cycles. 
During Cycle 1 of Part B, plasma PK samples for measurement of pevonedistat will be collected 
on Days 3, 4, and 5. The schedule of PK sampling for patients with solid tumors is provided in 
Table D of Appendix A.
For patients with solid tumors and severe renal impairment, the investigator will select which 
chemotherapy (docetaxel or carboplatin plus paclitaxel) each patient will receive in combination 
with pevonedistat based on his/her medical judgment and indication provided in package inserts 
(USPI/SmPC).
Starting Doses for Patients With Organ Impairment
Following sponsor and investigator discussion of safety data from Cycle 1, patients in the organ 
impairment arms who tolerate pevonedistat well at lower doses may be eligible for intrapatient 
dose escalation in Part B, starting in Cycle 2 or soon thereafter. The maximum dose of 
pevonedistat that may be administered in combination with azacitidine or carboplatin plus 
paclitaxel is 20 mg/m2. The maximum dose of pevonedistat that may be administered in 
combination with docetaxel is 25 mg/m2. Patients with advanced solid tumors may also be eligible 
for intrapatient dose escalation of SOC agents, depending on the study arm in which they are 
enrolled. Starting doses and intrapatient dose escalation guidelines for patients with organ 
impairment are described in Table 8.a, Table 8.b, and Table 8.c.
Table 8.a
Starting Doses for Patients With Mild Hepatic Impairment
Malignancy
Pevonedistat a
(mg/m2)
Azacitidine b
(mg/m2)
Paclitaxel c
(mg/m2)
Carboplatin d
Hematologic
20
75
-
-
Solid tumors
20
-
135
AUC4
AUC: area under the plasma concentration-time curve.
a The maximum dose of pevonedistat that may be administered in combination with azacitidine or carboplatin plus 
paclitaxel is 20 mg/m2.
b The maximum dose of azacitidine that may be administered in combination with pevonedistat is 75 mg/m2.
c The maximum dose of paclitaxel that may be administered in combination with pevonedistat and carboplatin is 
135 mg/m2.
d Following sponsor and investigator discussion of the available safety data, patients who tolerate treatment well at the 
initially assigned dose of carboplatin may be allowed to increase their dose to a maximum dose of AUC5 during 
Cycle 2 or in subsequent cycles of treatment.
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Table 8.b
Starting Doses for Patients With Moderate Hepatic Impairment
Malignancy
Pevonedistat a
(mg/m2)
Azacitidine b
(mg/m2)
Paclitaxel c
(mg/m2)
Carboplatin d
Hematologic
10
75
-
-
Solid tumors
10
-
90
AUC4
AUC: area under the plasma concentration-time curve.
a Following sponsor and investigator discussion of the available safety data, patients who tolerate treatment well at the 
initially assigned dose of pevonedistat may be allowed to increase their dose in increments of 5 mg/m2 per cycle 
starting in Cycle 2 (eg, pevonedistat at 15 mg/m2 on Days 1, 3, and 5 of Cycle 2). The maximum dose of pevonedistat 
that may be administered in combination with azacitidine or carboplatin plus paclitaxel is 20 mg/m2.
b The maximum dose of azacitidine that may be administered in combination with pevonedistat is 75 mg/m2.
c The maximum dose of paclitaxel that may be administered in combination with pevonedistat and carboplatin is 
90 mg/m2.
d Following sponsor and investigator discussion of the available safety data, patients who tolerate treatment well at the 
initially assigned dose of carboplatin may be allowed to increase their dose to a maximum dose of AUC5 during 
Cycle 2 or in subsequent cycles of treatment. Intrapatient dose escalation of carboplatin is not to take place during the 
same cycle in which pevonedistat dose is escalated.
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Table 8.c
Starting Doses for Patients With Severe Renal Impairment
Malignancy
Pevonedistat
(mg/m2)
Azacitidine a
(mg/m2)
Paclitaxel b
(mg/m2)
Carboplatin c
Docetaxel d
(mg/m2)
Hematologic
15 e
75
-
-
-
Solid tumors f
15 g
-
135
AUC4
Solid tumors f
15 g
75
AML: acute myelogenous leukemia; AUC: area under the plasma concentration-time curve; CMML: chronic 
myelomonocytic leukemia; MDS: myelodysplastic syndromes; SOC: standard of care.
Note: Dose escalation of any SOC agent is not permitted in the same cycle as dose escalation of other SOC 
agents or of pevonedistat. Only 1 study drug may be escalated in a cycle.
a The maximum dose of azacitidine that may be administered in combination with pevonedistat is 75 mg/m2.
b Following sponsor and investigator discussion of the available safety data, patients who tolerate treatment well at the 
initially assigned dose of paclitaxel may be allowed to increase their dose to a maximum dose of 175 mg/m2 in Cycle 2 
or in subsequent cycles.
c Patients who tolerate treatment well at the initially assigned dose of carboplatin may be allowed to increase their dose 
to a maximum dose of AUC5 in Cycle 2 or in subsequent cycles.
d The maximum dose of docetaxel that may be administered in combination with pevonedistat is 75 mg/m2. Patients 
receiving pevonedistat plus docetaxel may have a maximum of 2 docetaxel dose modifications, with dose reductions 
to 60 mg /m2 or 45 mg/m2 allowed.
e Patients with hematologic malignancies who tolerate treatment well at the initially assigned dose of pevonedistat 
may be allowed to increase their dose to a maximum of 20 mg/m2 starting in Cycle 2.
f For patients with solid tumors and severe renal impairment, the investigator will select which chemotherapy 
(docetaxel or carboplatin plus paclitaxel) that each patient will receive in combination with pevonedistat based on 
his/her medical judgment.
g Patients with advanced solid tumors who tolerate treatment well at the initially assigned dose of pevonedistat may be 
allowed to increase their dose in increments of 5 mg/m2 per cycle starting in Cycle 2 (eg, pevonedistat at 20 mg/m2 on 
Days 1, 3, and 5 of Cycle 2). The maximum dose of pevonedistat that may be administered in combination with 
carboplatin plus paclitaxel is 20 mg/m2. The maximum dose of pevonedistat that may be administered in combination 
with docetaxel is 25 mg/m2.
Study drugs will be administered per the instructions for dosing in Section 8.1.1, Section 8.1.2, 
and Section 8.1.3.
8.1.1
Instructions for Pevonedistat and Azacitidine Dosing
Patients will receive pevonedistat diluted with 5% dextrose or 0.9% saline solution in a 250 mL 
bag via a 60-minute IV infusion per the information provided in the Directions for Investigational 
Drug Use document located in the Pharmacy Manual. Pevonedistat should be administered 
through central or peripheral venous access. The infusion may be slowed or stopped and restarted 
for any associated infusion-related reactions. All infusion times must be recorded. The total time 
from drug reconstitution to end of infusion must not exceed 6 hours.
The entire content of the pevonedistat IV bag will be infused at a constant rate over 
60 (±10) minutes. The start and end time of IV infusion should be recorded accurately, particularly 
when PK assessments are performed. To ensure that all the pevonedistat is administered, the 
infusion line will be flushed with 0.9% saline solution or 5% dextrose immediately after 
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administration. The volume used for line flushing is not considered a part of the volume of the 
pevonedistat IV bag to be documented.
On Days 1, 3, and 5, when both study drugs are administered, azacitidine will be administered first 
followed by pevonedistat. The infusion of pevonedistat will begin between 15 and 60 minutes after 
completion of administration of azacitidine.
8.1.2
Instructions for Pevonedistat and Docetaxel Dosing
On Day 1 of each cycle in Part B, docetaxel 75 mg/m2 will be administered as a 1-hour IV infusion 
and pevonedistat will be administered as described in Section 8.1.1. On Days 3 and 5, only 
pevonedistat will be given. The duration of each cycle will be 21 days. Refer to the most recent 
USPI/SmPC for further details regarding docetaxel administration [13,20].
Premedication to prevent docetaxel-associated (hypersensitivity or other) reactions is 
recommended according to institutional guidelines or local practices. For example, patients may 
be treated with dexamethasone (4 mg twice daily for 3 days), which should start 24 hours before 
docetaxel administration.
8.1.3
Instructions for Pevonedistat and Carboplatin Plus Paclitaxel Dosing
On Day 1 of each cycle in Part B, paclitaxel will be given as an IV infusion over approximately 
3 hours, followed by carboplatin as an approximately 30-minute IV infusion. Pevonedistat will be 
administered as described in Section 8.1.1. On Days 3 and 5, only pevonedistat will be given. The 
duration of each cycle will be 21 days.

Refer to the most recent SmPC/USPI for further details regarding carboplatin administration 
[14,15].
If a patient’s GFR is estimated using serum creatinine measurements by the standardized 
isotope dilution mass spectrometry method, the US Food and Drug Administration (FDA) 
recommends that physicians consider capping the dose of carboplatin for desired exposure 
(AUC) to avoid potential toxicity due to overdosing. Using the Calvert formula described in 
the carboplatin label, the maximum doses can be calculated as follows:
Total carboplatin dose (mg) = (target AUC) (GFR + 25) [Calvert formula]
Maximum carboplatin dose (mg) = target AUC (mg min/mL) (150 mL/min)
The maximum dose is based on a GFR estimate that is capped at 125 mL/min for patients with 
normal renal function. No higher estimated GFR values should be used.
For a target AUC = 4, the maximum dose is 4 150 = 600 mg.
For a target AUC = 5, the maximum dose is 5 × 150 = 750 mg.
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
Refer to the most recent SmPC/USPI for further details regarding paclitaxel administration 
[17,19].
Premedication to prevent paclitaxel-associated (hypersensitivity or other) reactions is 
recommended according to institutional guidelines or local practices. For example, patients may 
be treated with either dexamethasone (10 mg) 24 hours before and on the day of paclitaxel dosing 
or methylprednisolone immediately before paclitaxel dosing.
8.2
Reference/Control Therapy
Not applicable.
8.3
Dose Modification Guidelines
8.3.1
Dose Modifications for Hematologic Toxicities
8.3.1.1
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 by 1 dose level (eg, from 20 mg/m2 to 15 mg/m2 or 10 mg/m2). 
The pevonedistat dose may be re-escalated to 15 mg/m2 or 20 mg/m2 at a subsequent cycle, if the 
toxicity has recovered to Grade ≤1 or the patient’s baseline.
Although leukostasis is not anticipated in this study, pevonedistat should be held for symptoms of 
leukostasis until the leukostasis is treated per institutional guidelines. Pevonedistat may be 
restarted when WBC count is <50,000/μL and following agreement by the sponsor’s project 
clinician (or designee).
8.3.1.2
Azacitidine
Dose reduction or delays of azacitidine for hematologic toxicities (including fever and neutropenia) 
should be strongly discouraged, as it may impact patient outcome.
In Part B, combination treatment with pevonedistat and azacitidine will be repeated every 28 days 
for patients with hematologic malignancies. For patients with Grade 4 neutropenia at risk of 
infection, particularly in a relapse/refractory setting, prophylactic administration of antibacterial or 
antifungal agents may be considered, as appropriate, per medical judgment of treating physician or 
per institutional guidelines. In addition, administration of granulocyte colony stimulating factor 
(G-CSF) prior to and during study may be considered as appropriate, per medical judgment of 
treating physician or per institutional guidelines.
For patients with Grade 4 neutropenia, particularly in a relapse/refractory setting, the start of a new 
treatment cycle may be delayed if failure to recover counts is thought to be related to marrow 
replacement with blasts. For patients with delays in the initiation of a new cycle of treatment due to 
toxicity, for therapy to resume, toxicity considered related to treatment must have resolved to the 
patient’s baseline values, or to a level considered acceptable by the investigator after discussion 
with the project clinician or designee.
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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. 
Should treatment need to be delayed for more than 2 weeks because of incomplete recovery from 
treatment-related toxicity, then the azacitidine dose will be decreased to 50 mg/m2 when treatment 
is resumed.
If the reduced dose is well tolerated and the toxicity leading to dose reduction was Grade ≤3, has 
resolved, and does not reoccur, the dose may resume at the original dose level in the next cycle 
after endorsement by the sponsor’s project clinician (or designee).
A delay in the initiation of a cycle by 4 weeks or greater because of lack of recovery from 
treatment-related hematologic toxicity to the patient’s baseline values, or to a level considered 
acceptable by the investigator after discussion with the project clinician (or designee) that is not 
related to leukemic infiltration, will trigger consideration for discontinuation of the patient from 
the study. If hematologic toxicity has not resolved by 6 weeks, the patient must be discontinued 
from the study.
If indicated, bone marrow evaluation will be performed to establish whether continued 
myelosuppression is related to persistent or progressing leukemic infiltration.
8.3.1.3
Docetaxel, Carboplatin, and Paclitaxel
Dose modification guidelines for specific hematologic toxicities in patients with advanced solid 
tumors receiving docetaxel or carboplatin/paclitaxel in Part B are presented in Table 8.d.
Patients with unresolved toxicities of Grade >1 lasting 3 weeks or longer from the date of the next 
scheduled treatment will be discontinued from the study. For detailed dose modification guidelines, 
see Section 8.3.2.3.
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Table 8.d
Dose Modification Guidelines for Specific Hematologic Toxicities in Patients 
With Advanced Solid Tumors
Pathologic Condition Severity
Action on Study Drug
Hematologic:
ANC
Febrile neutropenia
Hold dosing on Day 1 of Cycles ≥2 up to 3 weeks until febrile 
neutropenia is resolved, then resume dosing as appropriate. 
Consider use of growth factor or reduce chemotherapy by 1 dose 
level, as appropriate.
ANC <1500 cells/L on 
Day 1 of Cycles ≥2
Initiation (Day 1) of Cycles ≥2 should be delayed for up to 
3 weeks until ANC is ≥1500 cells/L. Consider use of growth 
factor or reduce chemotherapy by 1 dose level as appropriate.
Grade ≥3 neutropenia 
lasting >7 days
Initiation (Day 1) of Cycles ≥2 should be delayed until ANC is 
≥1500 cells/L. Consider use of growth factor or reduce 
chemotherapy by 1 dose level as appropriate.
Hematologic:
Platelets
Platelet count 
<100,000/L on any 
dosing day of Cycles ≥2
Dosing in Cycles ≥2 should be delayed for up to 3 weeks until 
platelet count is ≥100,000 cells/L. Dose of chemotherapy may 
be reduced by 1 dose level as appropriate.
Grade 4 
thrombocytopenia 
lasting >7 days or platelet 
count <25,000 cells/L at 
any time
Dosing in Cycles ≥2 should be delayed until platelet count is 
≥100,000 cells/L (see Section 8.3.2.3). Dose of chemotherapy 
may be reduced by 1 dose level as appropriate.
Hematologic:
Anemia
Grade ≥1 
No dose modification is allowed for anemia. Transfusion and/or 
erythropoietin may be given, as clinically indicated, for the 
treatment of anemia (see Section 8.7.1.1).
ANC: absolute neutrophil count.
8.3.2
Dose Modifications for Nonhematologic Toxicities
8.3.2.1
Pevonedistat
Pevonedistat Dose Adjustment Based on Serum Transaminases and Total Bilirubin
Transient ALT/AST elevations have been observed in some patients (approximately 5% to 8% in 
patients with AML/MDS and approximately 20% in patients with solid tumors) after pevonedistat 
dosing. For patients with increased liver function tests (compared to baseline) on Day 3 or Day 5, 
pevonedistat dosing should be held; once the elevated AST or ALT returns to the patient's baseline 
level or better, and/or elevated bilirubin returns to patient’s baseline level or better, pevonedistat 
dose may be resumed.
Pevonedistat Dose Adjustment Based on Hypophosphatemia
If hypophosphatemia is Grade ≥3, study drug treatment should not be resumed until the 
hypophosphatemia is Grade ≤2. Hypophosphatemia should be evaluated (including severity and 
etiology), monitored, and treated according to institutional guidelines.
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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 15 mg/m2 or 10 mg/m2 at the discretion of the investigator 
as clinically indicated. If the toxicity returns to Grade ≤1 or the patient’s baseline status, 
pevonedistat may be re-escalated to 15 mg/m2 or 20 mg/m2 at the next cycle.
8.3.2.2
Azacitidine
Azacitidine Dose Adjustment Based on Renal Function and Serum Electrolytes (Mild or 
Moderate Hepatic Impairment and Control Arms Only)
For renal toxicities, specifically elevated creatinine Grade >1, azacitidine should be reduced in 
accordance with the prescribing information [10] and/or institutional guidelines. Similarly, if 
unexplained elevations in serum creatinine or blood urea nitrogen occur, the next cycle should be 
delayed until values return to normal or baseline values, and the dose should be reduced by 50% on 
the next treatment course.
If unexplained reductions in serum bicarbonate levels to <20 mEq/L occur, the azacitidine dose 
should be reduced by 50% on the next course. The azacitidine dose may be re-escalated back to 
75 mg/m2 at the next cycle if the toxicity has recovered to Grade ≤1 or the patient’s baseline status.
8.3.2.3
Docetaxel, Carboplatin, and Paclitaxel
Criteria for Beginning or Delaying a Subsequent Treatment Cycle
For individual patients experiencing specific toxicities, treatment in each new cycle will be 
delayed until toxicity is reduced to Grade ≤1, patient’s baseline, or to a level considered acceptable 
by the investigator after discussion with the project clinician or designee.
If dosing with pevonedistat is held for toxicity during any given cycle, dosing may resume within 
that same cycle when toxicity is resolved. Alternatively, dosing may be held until the next cycle. 
The start of the next cycle may also be delayed for up to 3 weeks to allow patients to recover from 
any safety concerns, so that pevonedistat may be administered in combination with chemotherapy.
Day 1 dosing of any cycle in Part B may be delayed by up to 2 days to accommodate inclement 
weather, holidays, vacations, or other administrative reasons.
Criteria for Dose Interruption During a Cycle
During treatment with SOC agents, the infusion may be slowed or stopped and restarted for any 
associated infusion-related reactions. The exact date and time of each additional sample collection 
and the actual start and stop times of the infusion should be recorded accurately.
Criteria for Dose Reduction
Alopecia of any duration will not lead to dose modification or treatment delay.
Patients receiving pevonedistat plus docetaxel may have a maximum of 2 docetaxel dose 
modifications. Docetaxel is initially dosed at 75 mg/m2, dose reductions up to 60 mg /m2 and 
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45 mg/m2 may be considered (if applicable) or pevonedistat may be modified as described in 
Section 8.3.2.1.
The decision to treat at a reduced dose level of chemotherapy is at the discretion of the investigator. 
Discussions with the project clinician or designee are encouraged.
Criteria for Discontinuation of Study Drug
Patients receiving pevonedistat plus docetaxel who require more than 2 dose modifications of 
either docetaxel or pevonedistat will be discontinued from the study.
Patients receiving pevonedistat and carboplatin plus paclitaxel may have no more than 1 dose 
modification (if applicable) of chemotherapy agents or of pevonedistat (see above). Patients who 
require additional dose modifications will be discontinued from the study.
Dose modification guidelines for specific nonhematologic toxicities in patients with advanced 
solid tumors are presented in Table 8.e. Treatment cannot be withheld for longer than 3 weeks for 
any toxicity Grade >1.
Table 8.e
Dose Modification Guidelines for Specific Nonhematologic Toxicities in 
Patients With Advanced Solid Tumors
Pathologic Condition Severity
Action on Study Drug
Nausea, emesis, or 
diarrhea despite 
maximal prophylaxis
Grade 3
On days when both chemotherapy and pevonedistat are 
administered, hold dosing for up to 3 weeks or until the toxicity 
returns to Grade ≤1, then restart at the next lower dose of 
chemotherapy. On days when pevonedistat is given as a single 
agent, hold pevonedistat dosing for up to 3 weeks or until the 
toxicity returns to Grade ≤1 before dosing is resumed. Note: 
Ensure that optimal prophylaxis has been employed before dose 
reduction. Supportive care should be considered per local 
institutional guidelines, as clinically indicated.
Neurotoxicity
(paclitaxel or
docetaxel only)
Grade 2
Hold treatment until patient recovers to Grade 1 toxicity, then 
resume treatment at the next lower dose level. This will be a 
permanent dose reduction. Carboplatin or pevonedistat dose is 
not to be modified.
Allergic reaction
(paclitaxel or docetaxel 
only
Moderate symptoms
Stop infusion. Give IV diphenhydramine 25 to 50 mg, IV 
dexamethasone 10 mg, and/or treatment per institutional 
guidelines. After recovery of symptoms, resume infusion at a low 
infusion rate. If no further symptoms occur, resume full dose rate 
until infusion is complete. If symptoms recur, stop infusion and 
discontinue patient from the study.
IV: intravenous.
8.3.3
Intrapatient Dose Escalation (Part B)
In Part B, following sponsor and investigator discussion of the patient’s safety and tolerability data 
from Cycle 1, patients in the organ impairment arms who tolerate pevonedistat well at the initially 
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assigned dose may be allowed to increase their dose of pevonedistat in increments of 5 mg/m2 per 
cycle during Cycle 2 or in subsequent cycles of treatment. Patients with advanced solid tumors 
who tolerate initial doses of SOC agents may also be allowed to increase their dose of SOC agents, 
depending on the allowances of their study arm and only in cycles in which their dose of 
pevonedistat is not increased. Starting doses and intrapatient dose escalation plans for study drugs 
in each organ impairment arm are presented in Table 8.a, Table 8.b, and Table 8.c.
8.4
Excluded Concomitant Medications and Procedures
Prohibited concomitant therapies include investigational agents, androgens, supraphysiologic 
doses of corticosteroids, erythropoietin, thrombopoietin agonists (eg, eltrombopag and 
romiplostim), or chemotherapeutic agents active against hematologic malignancies or advanced 
solid tumors.
Results from Study C15011 indicated that itraconazole, a strong CYP3A/ P glycoprotein (P-gp) 
inhibitor, and fluconazole, a moderate CYP3A inhibitor, had no clinically meaningful effects on 
pevonedistat PK. The effect of rifampin, a strong CYP3A inducer, on pevonedistat PK was 
evaluated in Study P1015. The geometric mean AUC∞of pevonedistat in the presence of rifampin 
was 79% of that in the absence of rifampin (90% CI: 69.2%, 90.2%). The result indicated that 
coadministration of rifampin did not result in clinically meaningful alteration of pevonedistat 
systemic exposures in the context of 28% of inter-individual variability in pevonedistat clearance. 
In order to interpret the effects of organ impairment on pevonedistat PK without potential 
confounding factors, strong CYP3A inhibitors and inducers remain prohibited in this study.
A physiologically based PK (PBPK) model accounting for hepatic uptake and metabolism of 
pevonedistat was developed to describe the PK of pevonedistat and the observed low sensitivity to 
DDIs with strong CYP3A/P-gp inhibitor (itraconazole) and strong inducer (rifampin). The 
pevonedistat PBPK model indicates that the systemic exposure of pevonedistat was not sensitive 
to the perturbations of enzyme activity when the hepatic uptake becomes the rate-determining step 
of its clearance. Considering the minimum effect on P-gp inhibition and hepatic uptake being the 
rate-determining step of pevonedistat clearance, the effect of breast cancer resistance protein 
(BCRP) inhibition on pevonedistat systemic clearance is not expected to be clinically meaningful. 
Therefore, exclusion of BCRP inhibitors (eg, cyclosporine) is not deemed warranted in clinical 
studies of pevonedistat and, as of Amendment 02, BCRP inhibitors are no longer included in the 
list of excluded concomitant medications.
Medications that are generally excluded but are allowed with certain exceptions are listed in 
Table 8.f (for the combination pevonedistat plus SOC agents).
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Table 8.f
Concomitant Medications Excluded While Receiving Study Treatment: 
Combination Pevonedistat Plus SOC agents
Therapy
Comment/Exceptions
Acetaminophen and acetaminophen-containing products.
Acetaminophen and acetaminophen-containing 
compounds may be used judiciously and should not 
exceed a dose of 2 g of acetaminophen in a 24-hour 
period.
Systemic antineoplastic therapy, except for hydroxyurea.
Hydroxyurea dosing prior to and during the study 
treatment phase may be used and 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.
Strong CYP3A inhibitors and inducers
(see Appendix M)
Any investigational agent for MDS, CMML, or AML, or 
commercially available agents used in MDS, CMML, or 
AML, including androgens, supraphysiologic doses of 
corticosteroids, erythropoietin, eltrombopag [Promacta], 
or romiplostim [Nplate].
AML: acute myelogenous leukemia; CMML: chronic myelomonocytic leukemia; MDS: myelodysplastic syndromes; 
SmPC: Summary of Product Characteristics; USPI: United States Prescribing Information.
This list is not all-inclusive; consult the docetaxel, carboplatin, azacitidine, or paclitaxel USPIs or SmPCs, as 
applicable, for additional information regarding precautions, warnings, and contraindications.
8.5
Permitted Concomitant Medications and Procedures
Medications and procedures that are specifically permitted during the study are listed in Table 8.g.
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Table 8.g
Concomitant Medications and Procedures Permitted During the Study
Therapy
Comment
Antiplatelet agents (eg, aspirin, 
clopidogrel) and anticoagulants
May be used in patients who develop a thrombosis while on study. Note that 
patients with active uncontrolled coagulopathy or who are therapeutically 
anticoagulated with warfarin, direct thrombin inhibitors, direct Xa inhibitors or 
heparin are excluded from enrollment as per Section 7.2.
Antiemetics
May be administered according to institutional guidelines.
Antibacterial or antifungal agents
For patients with Grade 4 neutropenia, (defined as ANC ≤500/µL for 7 days or 
with fever), particularly in relapse/refractory setting, at risk of infection, 
prophylactic treatment with antibiotics (eg, fluoroquinolone, ciprofloxacin), 
antifungals (eg, voriconazole, fluconazole, parconazole), and antiviral agents 
(eg, acyclovir, entecavir, tenofovir) should be initiated, and continued at least 
through Cycle 1, or per institutional guidance.
Myeloid growth factors 
(eg, G-CSF, GM-CSF)
In general, the use of myeloid growth factors in patients with myeloid 
malignancies is discouraged and should be restricted. For patients with myeloid 
malignancy in CR, CRi, or marrow CR (MLFS), growth factors may be used in 
specific 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).
Nephrotoxic medications, 
including nonsteroidal 
anti-inflammatory drugs
Caution should be used with nephrotoxic concomitant medications (see 
Appendix K). Alternative concomitant nonnephrotoxic medications should be 
used whenever possible.
Platelet transfusion
Permitted as medically necessary per institutional guidelines (eg, for platelets 
<10,000/µL in the absence of clinical bleeding); see Section 8.7.
Red blood cell transfusion
To be considered for all patients with anemia, especially those with hemoglobin 
values ≤8 g/dL; see Section 8.7. When RBC transfusion is considered, it should 
be administered at least 1 day prior to dosing with pevonedistat. All incidences 
of transfusions (and units given) should be captured in the eCRF.
ANC: absolute neutrophil count; CR: complete response/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: morphologic leukemia-free state; RBC: red blood cell.
8.6
Precautions and Restrictions
Concomitant medications and procedures that are excluded or must be used with caution are 
described in Section 8.4 and Section 8.5, respectively.
Certain situations may warrant further caution, such as modifying the dose of study drug(s). Dose 
modification guidelines are provided in Section 8.3.
Refer to the package insert for VIDAZA USPI [10] or EU SmPC [11] for precautions and 
restrictions related to azacitidine use. Refer to the most recent SmPCs/USPIs for further details 
regarding administration of docetaxel, carboplatin, and paclitaxel.
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It is not known what effects pevonedistat has on human pregnancy or development of the embryo 
or fetus. Therefore, female patients participating in this study should avoid becoming pregnant, 
and male patients should avoid impregnating a female partner. Nonsterilized female patients of 
reproductive age group and male patients should use highly effective methods of contraception 
(see list provided in Appendix F) through defined periods during and after study treatment as 
specified below.
Female patients must meet one of the following criteria:

Be postmenopausal (see definition in Appendix E) for at least 1 year before the screening visit, 
OR

Be surgically sterile, OR

Agree, if they are of childbearing potential, to practice 1 highly effective method and 
1 additional effective (barrier) method of contraception at the same time, from the time of 
signing of the informed consent form (ICF) through 6 months after the last dose of study drug 
(whichever is longer), OR

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of 
the subject. Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation 
methods), withdrawal, spermicides only, and lactational amenorrhea are not acceptable 
methods of contraception. Female and male condoms should not be used together.

Agree to not donate eggs (ova) during the course of this study or for 6 months after receiving 
their last dose of study drug(s).
Female patients should be advised not to breastfeed while undergoing treatment with azacitidine.
Male patients, even if surgically sterilized (ie, status postvasectomy) must agree to one of the 
following:

Practice effective barrier contraception during the entire study treatment period and through 
4 months after the last dose of study drug, OR

Practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. 
Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods), 
withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of 
contraception. Female and male condoms should not be used together.
Male patients must agree to not donate sperm or father a child during the course of this study or for 
4 months after receiving their last dose of study drug(s).
Before starting treatment, male patients should be advised to seek counseling on sperm storage, 
and female patients should be advised to seek counseling on egg storage.
Nonclinical data suggest that male and female patients administered pevonedistat have a potential 
risk of infertility.
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8.7
Management of Clinical Events
Patients who experience an AE with pevonedistat should be followed closely for a recurrence of 
similar or other AEs upon subsequent dosing of pevonedistat.
8.7.1
Combination Pevonedistat Plus Standard of Care Agents
Common AEs reported for patients receiving the combination of pevonedistat with specific 
chemotherapeutic agents are provided in the most recent IB. For the combination of pevonedistat 
with SOC agents, follow the guidance in the following subsections of this protocol.
8.7.1.1
Guidance for Clinical Assessment and Management of Hemodynamic Compromise 
(All Patients)
It is essential that the patients receiving the combination of pevonedistat and SOC agents are 
carefully evaluated at screening and before each dose of study drug for early symptoms and signs 
of hemodynamic compromise and/or active infection. Particular attention should be given to fever, 
tachycardia, hypotension, orthostasis, tachypnea, recent nausea and vomiting, and clinical 
evidence of dehydration. Patients who experience an untoward reaction with the combination of 
pevonedistat and SOC agents 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/hr 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 electronic case report forms (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.
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8.7.1.2
Guidance for Management of Cytopenia and Infection (Patients with Hematologic 
Malignancies)
Cytopenia is common in patients with MDS, CMML, and AML. Patients with baseline 
neutropenia or those who have significant bone marrow involvement may be at particularly high 
risk. Patients receiving the combination of pevonedistat and azacitidine are carefully evaluated at 
screening and before each dose of study drug for neutropenia and risk of infection and provided 
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 
azacitidine first before modifications of pevonedistat. 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/µL for 7 days or with fever) who are therefore at 
high risk of infection, prophylactic treatment with antibiotics should be initiated as detailed in 
Table 8.g. Use of anti-infective agents are to be captured in the eCRF.

In general, the use of myeloid growth factors is discouraged and should be restricted. For 
patients in CR, CRi, or marrow CR (morphologic leukemia-free state), growth factors may be 
used in specific circumstances, as detailed in Table 8.g.
8.7.1.3
Guidance Management of Leukostasis (Patients with Hematologic Malignancies)
Pevonedistat treatment should be withheld for patients who develop symptoms of leukostasis. 
Treatment may include leukapheresis and hydroxyurea administration, per institutional guidelines. 
When the patient’s WBC count is <50,000/L and symptoms are improved, pevonedistat 
treatment may be restarted after consulting with the sponsor’s project clinician (or designee). 
Treatment with other chemotherapeutic agents may continue as clinically indicated.
8.7.1.4
Guidance for Management of Extravasation (All Patients)
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.
8.7.1.5
Guidance for Use of Granulocyte-Colony Stimulating Factor (Patients with Advanced 
Solid Tumors)
Use of growth factors such as G-CSF in patients with advanced solid tumors are permitted at the 
investigator’s discretion.
8.8
Blinding and Unblinding
This is an open-label study.
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8.9
Description of Investigational Agents
Upon receipt of drug supply, contents must be verified promptly and the proper contacts notified 
of any discrepancies or damages as described in the Study/Pharmacy Manual.
8.9.1
Azacitidine
Azacitidine may be supplied by the site from commercial sources, depending on regional 
availability. Commercially available azacitidine is supplied as lyophilized powder in 100 mg 
single-use vials. Refer to the Study/Pharmacy Manual and the VIDAZA USPI [10] or EU SmPC 
[11], as applicable, for additional information regarding azacitidine.
8.9.2
Pevonedistat
The drug product is labeled Pevonedistat (TAK-924/MLN4924) Injection for Solution for 
Infusion.
Pevonedistat Injection for Solution for Infusion will be supplied by the sponsor as detailed in the 
Study/Pharmacy Manual.
Each Pevonedistat Injection for Solution for Infusion vial contains 50 mg or 44 mg pevonedistat, 
as free base, formulated with the following excipients: citric acid (anhydrous), trisodium citrate 
dihydrate, betadex sulfobutyl ether sodium (Captisol), and water for injection.
Details are available in the IB.
8.9.3
Docetaxel, Carboplatin, and Paclitaxel
Docetaxel, carboplatin, and paclitaxel are each obtained from commercial sources according to 
local practice standards and are provided as commercially available dose formulations. Additional 
details are provided in the USPI/SmPC for each agent.
8.10
Preparation, Reconstitution, and Dispensation
Parenteral drug products should be inspected visually for particulate matter and discoloration 
before administration, whenever solution and container permit.
Before use, Pevonedistat Injection for Solution for Infusion vials should be brought to ambient 
conditions (15°C-30°C) by removing the vials from the refrigerator and placing them at room 
temperature. Accelerated warming methods, such as a water bath, must not be used. Pevonedistat 
Injection for Solution for Infusion is stable at ambient temperature for 6 hours before dilution. If 
the drug product vial is not to be used within the 6-hour timeframe, the vial should be returned to 
storage. Each vial is for single use only.
Each Pevonedistat Injection for Solution for Infusion vial contains nominally 5 mL (50 mg) or 
4.4 mL (44 mg) pevonedistat, as free base. Before injecting the drug product into the 250 mL IV 
bag containing a 5% dextrose or 0.9% saline solution, calculate the volume of drug product that 
will be administered and remove this volume from the 250 mL IV bag containing a 5% dextrose or 
0.9% saline solution (see Pharmacy Manual for details). Using sterile technique, withdraw the 
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appropriate volume of drug from the vial(s) and inject into the 250 mL IV bag containing a 5% 
dextrose or 0.9% saline solution. The bag must be gently inverted repeatedly to mix the contents. 
The prepared pevonedistat IV bag must be used within 6 hours if stored at room temperature or 
must be discarded. Alternatively, the prepared IV bag is chemically stable and may be stored for 
up to 18 hours at 2°C to 8°C. After 18 hours of storage at 2°C to 8°C, the prepared IV bag must be 
used within 3 hours upon coming to room temperature or must be discarded.
Discard bag, needle, and syringe in a proper biohazard container according to institutional 
guidelines.
Detailed reconstitution and dosage preparation instructions are provided in the Directions for Use
located in the Pharmacy Manual.
Instructions for the preparation, reconstitution, and dispensation of azacitidine are provided in the 
VIDAZA USPI [10] or EU SmPC [11]. For instructions and precautions regarding preparation of 
docetaxel, carboplatin, and paclitaxel, refer to the applicable USPI/SmPC for each agent.
Pevonedistat is an anticancer drug, and as with other potentially toxic compounds, caution should 
be exercised when handling pevonedistat.
8.11
Packaging and Labeling
Pevonedistat Injection for Solution for Infusion will be provided in United States Pharmacopeia 
(USP) Type I glass vials. Each USP Type I glass vial nominally contains 5 mL or 4.4 mL of 
compounded sterile solution, sealed with a chloro-butyl rubber stopper and oversealed with an 
aluminum seal and a plastic cap.
Azacitidine is available as lyophilized powder in 100 mg, single-use vials from commercial supply 
with commercial packaging and labeling. Azacitidine may be sourced locally by the clinical sites 
when regulations allow for clinical site sourcing with appropriate labeling.
Docetaxel, carboplatin, and paclitaxel may be sourced locally by the clinical site when 
arrangements have been made and agreed to by the sponsor and when regulations allow for clinical 
site sourcing, appropriate labeling, and compliance with local and regional regulations. As 
required by local regulations, any modifications to the plan for drug supply or storage will be 
communicated to the investigator and detailed in the Study Manual.
8.12
Storage, Handling, and Accountability
All investigational supplies are to be kept in a secure area with controlled access.
Vials of Pevonedistat Injection for Solution for Infusion are to be stored at 2°C to 8°C.
Details of the storage and handling of azacitidine are provided in the VIDAZA USPI [10] or EU 
SmPC [11]. For instructions and precautions regarding preparation of docetaxel, carboplatin, and 
paclitaxel, refer to the applicable USPI/SmPC for each agent.
8.13
Other Protocol-Specified Materials
Refer to the Pharmacy Manual.
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9.0
STUDY CONDUCT
This trial will be conducted in compliance with the protocol, Good Clinical Practice (GCP), 
applicable regulatory requirements, and International Council for Harmonisation (ICH) 
guidelines.
9.1
Study Personnel and Organizations
The contact information for the sponsor’s project clinician for this study, the central laboratory and 
any additional clinical laboratories or vendors participating on the study may be found in the Study 
Manual(s). A full list of investigators is available in the sponsor’s investigator database.
9.2
Arrangements for Recruitment of Patients
Recruitment and enrollment strategies for this study may include recruitment from the 
investigator’s local practice or referrals from other physicians. If advertisements become part of 
the recruitment strategy, they will be reviewed by the institutional review board 
(IRB)/independent ethics committee (IEC). It is not envisioned that prisoners (or other populations 
that might be subject to coercion or exploitation) will be enrolled into this study.
9.3
Treatment Group Assignments
No randomization or stratification will be performed in this study. Patients will be assigned on the 
basis of their renal and hepatic function.
Laboratory value requirements per treatment arm for eGFR, total bilirubin, and ALT are provided 
in Table 9.a and Table 9.b for patients with hematologic malignancies and advanced solid tumors, 
respectively.
Table 9.a
Laboratory Value Requirements per Treatment Arm for eGFR, Total 
Bilirubin, and ALT (Patients With Hematologic Malignancies Only)
Treatment
Arm
eGFR
(mL/min/1.73 m2)
Total
Bilirubin
ALT
Control
≥90
≤ULN
≤ULN
Renal
<30
≤ULN
≤2.5 × ULN
Mild hepatic
≥60
ULN <bilirubin ≤1.5 × ULN
(not secondary to transfusions)
Any
Moderate hepatic
≥60
1.5 × ULN <bilirubin ≤3.0 × ULN
(not secondary to transfusions)
Any
ALT: alanine aminotransferase; eGFR: estimated glomerular filtration rate; ULN: upper limit of the normal range.
Refer to Section 9.4.16 for information regarding hepatic and renal function laboratory result requirements.
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Table 9.b
Laboratory Value Requirements per Treatment Arm for eGFR, Total 
Bilirubin, and ALT (Patients With Advanced Solid Tumors Only)
Treatment
Arm
eGFR
(mL/min/1.73 m2)
Total
Bilirubin
ALT
Renal
<30
≤ULN
≤1.5 ×ULN a
or
≤2.5 × ULN b
Mild hepatic c
≥60
ULN <bilirubin ≤1.5 × ULN
Any
Moderate hepatic c
≥60
1.5 × ULN <bilirubin ≤3.0 × ULN
Any
ALT: alanine aminotransferase; eGFR: estimated glomerular filtration rate; ULN: upper limit of the normal range.
Refer to Section 9.4.16 for information regarding hepatic and renal function laboratory result requirements.
a For patients who receive pevonedistat plus docetaxel only.
b For patients who receive pevonedistat plus carboplatin plus paclitaxel only.
c Patients with advanced solid tumors in the hepatic impairment arms will not receive combination treatment with 
pevonedistat and docetaxel.
Part A (all patients):
Patients in all arms will receive pevonedistat 20 mg/m2 IV as a 1-hour infusion administered on 
Day 1.
Part B (patients with hematologic malignancies):
Starting in Cycle 1 of Part B, patients with hematologic malignancies and normal renal and hepatic 
function will receive 20 mg/m2 pevonedistat on Days 1, 3, and 5 in combination with 75 mg/m2
azacitidine on Days 1 through 5, 8, and 9 in 28-day cycles.
As of Amendment 02, the Control Arm of the study completed enrollment. Patients with advanced 
solid tumors with normal renal and hepatic function will not be enrolled in the Control Arm.
Starting in Cycle 1 of Part B, patients with hematologic malignancies and severe renal impairment 
or mild or moderate hepatic impairment will receive pevonedistat on Days 1, 3, and 5 in 
combination with azacitidine (75 mg/m2) on Days 1 through 7 or Days 1 through 5, 8, and 9 in 
28-day cycles. Patients will receive azacitidine SC in Cycle 1. Azacitidine will be given SC or IV 
during Cycle 2 and beyond. The starting doses for pevonedistat and azacitidine in patients with 
organ impairment are described in Section 8.1.
Part B (patients with advanced solid tumors):
For patients with solid tumors, the investigator will assign each patient to pevonedistat plus 
docetaxel or to pevonedistat plus carboplatin plus paclitaxel based on his/her medical judgment, 
and per information provided in the package inserts for the SOC agents (docetaxel, paclitaxel, or 
carboplatin) for indications for use.
Starting in Cycle 1 of Part B, patients with advanced solid tumors and severe renal impairment or 
mild or moderate hepatic impairment will receive docetaxel or carboplatin plus paclitaxel in 
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combination with pevonedistat on Day 1, and pevonedistat alone on Days 3 and 5 in 21-day 
cycles.
The starting doses for pevonedistat, docetaxel, carboplatin, and paclitaxel in patients with 
advanced solid tumors are described in Section 8.1.
9.4
Study Procedures
Refer to the schedule of events (SOE) tables (Appendix A) for timing of assessments. Additional 
details are provided as necessary in the sections that follow and in the Study and Laboratory 
Manuals. When applicable, specific visit windows for study procedures are provided in the 
footnotes to the study schedule tables.
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 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 
electronic data capture (EDC).
9.4.1
Informed Consent
Each patient, or the patient’s legally acceptable representative, must provide written informed 
consent before any study-required procedures are conducted, unless those procedures are 
performed as part of the patient’s SOC.
Reconsent of Patients With Hematologic Malignancies Who Meet the Criteria for PD and 
Continue Study Treatment
Patients with HR MDS or HR CMML may be allowed to continue study treatment if they meet the 
criteria for PD based only on bone marrow blast count (without AML transformation) if, in the 
clinical judgment of the investigator, the patient is still receiving clinical benefit from this 
treatment, and the continuation is endorsed by the sponsor’s project clinician (or designee). 
Patients with AML in this study may also be allowed to continue study treatment, even if they meet 
the criteria for PD based only on bone marrow blast counts if, in the clinical judgment of the 
investigator, the patient is still receiving clinical benefit from this treatment, and the continuation 
is endorsed by the sponsor’s project clinician (or designee). Patients who continue on study under 
these conditions must be reconsented before continuing study treatment.
9.4.2
Inclusion/Exclusion Confirmation
Confirmation of patient eligibility by the sponsor’s project clinician (or designee) is required prior 
to enrollment. During screening, a patient eligibility checklist must be completed and submitted by 
the investigator for review and approval by the sponsor or designee before the patient is enrolled. 
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, 
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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.
Refer to Section 9.4.16 for information regarding hepatic and renal function laboratory result 
requirements.
9.4.3
Patient Demographics
The date of birth, race, ethnicity, and sex of the patient are to be recorded during screening.
9.4.4
Medical History
During screening, a complete medical history will be compiled for each patient. The history will 
emphasize the background and progress of the patient’s malignancy. For patients with 
hematologic malignancies, see Section 7.1.2 for definitions relevant to medical history, including 
an assessment of bone marrow morphology (see Section 9.4.17.1 for additional details on bone 
marrow sample collection and evaluation). For patients with advanced solid tumors, see 
Section 7.1.3 for definitions relevant to medical history and Section 9.4.17.2 for details regarding 
evaluation of sites of disease by CT scan or MRI.
Information regarding any prior therapy for treatment of the patient’s malignancy, including start 
and stop dates of each therapeutic agent and response to therapy, will be collected in the eCRF. In 
addition, all blood transfusions related to the patient’s malignancy that the patient received within 
8 weeks before enrollment will be recorded to document baseline transfusion dependence.
9.4.5
Physical Examination
A complete physical examination will be performed per SOC at screening and at the EOS/ET visit. 
A symptom-directed physical examination will be completed per SOC at the times specified in the
SOE (Appendix A), and as clinically indicated at the discretion of the investigator.
9.4.6
Patient Height
Height will be measured only during screening.
9.4.7
Patient Weight
Weight will be measured during screening, within 3 days before Day 1 dosing in Part A, within 
3 days before Day 1 dosing in all cycles in Part B, and at the EOS/ET visit. If the screening 
assessment was done within 3 days before Day 1 in Part A, an assessment at Day 1 in Part A will 
not be necessary.
The amount of study drug (pevonedistat and/or azacitidine, docetaxel, or paclitaxel, as applicable) 
to be administered will be based on BSA. BSA will be calculated using a standard formula (see 
example in Appendix H) on Day 1 in Part A and on Day 1 of each cycle in Part B if the patient 
experiences a >5% change in body weight from the weight used for the most recent BSA 
calculation.
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The amount of carboplatin to be administered will be based on exposure (AUC) (refer to 
Section 8.1.3 for details of carboplatin dose calculations).
9.4.8
ECOG PS
ECOG PS will be assessed at the times specified in the SOE (Appendix A). Refer to Appendix D
for the PS grading scale.
9.4.9
Vital Signs
Vital signs, including diastolic and systolic blood pressure, heart rate, and body temperature will 
be collected as specified in the SOE (Appendix A) and as clinically indicated at the discretion of 
the investigator. When the timing of vital signs assessment coincides with the timing of a blood 
draw, vital signs will be completed before the collection of the blood sample, unless otherwise 
noted in the SOE (Appendix A).
9.4.10
Pregnancy Test
A serum pregnancy test will be performed locally for women of childbearing potential at screening 
and within 3 days before study drug dosing on Day 1 in Part A. The results from these tests must 
be available and negative before the first dose of study drug is administered.
In Part B, a serum pregnancy test will be performed for women of childbearing potential within 
3 days before Day 1 of each cycle and at EOS/ET. The results from these tests must be available 
and negative before the study drug is administered on Day 1. If the Day 1 serum pregnancy results 
will not be available before dosing, a urine pregnancy test may be performed. Pregnancy tests may 
also be repeated during the study if requested by an IEC/IRB or if required by local regulations.
Women of childbearing potential are defined as any sexually active female subjects who meet the 
following criteria:

Those who have not undergone hysterectomy or bilateral oophorectomy.

Those who have not had natural menopause for 12 consecutive months or longer 
(ie, follicle-stimulating hormone [FSH] >40 IU/L and no menopausal period for at least 
12 consecutive months; loss of menopausal periods following chemotherapy may not rule out 
childbearing potential).
9.4.11
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 (+10 days) after the last dose of any study 
drug(s). RBC and platelet transfusions will be recorded from 8 weeks before enrollment through 
30 days after the last dose of any study drug. See Section 8.4 and Section 8.5 for additional details 
regarding excluded and permitted concomitant medications and procedures.
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9.4.12
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.
9.4.13
Enrollment
Enrollment is achieved when the first dose of any study drug has been administered.
Procedures for completion of the enrollment information are described in the interactive web 
response system and Study Manual(s).
9.4.14
ECG
A 12-lead ECG will be performed at screening, within 3 days of Day 1 of each cycle in Part B, and 
at the EOS/ET visit, as specified in the SOE (Appendix A).
9.4.15
Clinical Laboratory Evaluations
Clinical laboratory evaluations will be performed locally. Clinical laboratory evaluations will be 
performed as outlined in the following sections.
9.4.15.1
Clinical Chemistry, Hematology, and Urinalysis
As specified in the SOE (Appendix A), the following samples will be obtained: blood samples for 
analysis of hematology and clinical chemistry parameters shown in Table 9.c, Table 9.d, Table 9.e, 
and for coagulation parameters in Table 9.f; and urine samples for analysis of the parameters 
shown in Table 9.g. Assessments may be performed more frequently if clinically indicated at the 
discretion of the investigator.
Table 9.c
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 I
Platelet (count)
ANC: absolute neutrophil count.
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Table 9.d
Complete Serum Chemistry Panel
Complete Serum Chemistry Panel
Albumin
ALP
ALT
AST
Bilirubin (total)
BUN
Calcium
CO2
Chloride 
Creatinine
Direct bilirubin
Glucose
Magnesium
Phosphate
Potassium
Sodium
Urate
ALP: alkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase; BUN: blood urea 
nitrogen; CO2: carbon dioxide.
Table 9.e
Select Serum Chemistry Panel
Select Serum Chemistry Panel
ALP
ALT
AST
Bilirubin (total)
BUN
Creatinine
ALP: alkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase; BUN: blood urea 
nitrogen.
Table 9.f
Coagulation Panel
Coagulation Panel
PT
INR
aPTT
aPTT: activated partial thromboplastin time; INR: international normalized ratio; PT: prothrombin time.
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Table 9.g
Urinalysis With Microscopic Analysis
Urinalysis
Bilirubin
Glucose
Ketones
Leukocytes
Nitrite
Occult blood
pH
Protein
Specific gravity
Turbidity and color
Microscopic assessment of leukocytes, erythrocytes, 
bacteria, casts, and crystals
The following Modification of Diet in Renal Disease Study (MDRD) equation will be used to 
calculate eGFR (mdrd.com):
eGFR (mL/min/1.73 m2) = 175 × (Scr, std)-1.154 × (Age)-0.203 × (0.742 if female) × (1.212 if African 
American).
9.4.16
Assessment of Hepatic and Renal Function for Treatment Group Assignment
Patients will be assigned to treatment arms on the basis of their renal and hepatic function.
For assessment of hepatic function (total bilirubin and ALT), 2 blood samples will be required 
before the start of pevonedistat dosing on Day 1 of Part A. These 2 samples should be obtained at 
least 48 hours apart, with the latest sample obtained no more than 48 hours before Day 1 and may 
be taken predose on Day 1. If the total bilirubin and ALT measurements from the 2 samples 
indicate the same liver function category for the patient (ie, normal, mild, or moderate hepatic 
impairment), pevonedistat can be administered as scheduled. If the results of the 2 samples 
indicate different liver function categories, a third sample must be obtained at least 48 hours after 
the second sample. If the results of the 2 most recent measurements (the second and third) denote 
the same liver function category, the patient may be enrolled and should receive a single dose of 
pevonedistat on Day 1 in Part A, within 48 hours of the third sample. If the second and third 
measurements indicate different liver function categories, the patient will not be eligible for 
inclusion in the study.
For assessment of renal function, at least 2 blood samples will be collected to determine spot 
serum creatinine for calculation of the eGFR according to the MDRD equation (see 
Section 9.4.15.1). The sampling for spot serum creatinine should be done within 14 days of 
starting treatment, with the most recent measurement performed within 7 days of starting 
treatment. The 2 measurements should both meet eligibility requirements based on the MDRD 
formula. If the 2 eGFR values do not both meet eligibility requirements, a third measurement will 
be taken and the 2 most recent measurements (the second and third) will be averaged to assess 
renal function status.
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9.4.17
Disease Assessment
9.4.17.1
Patients With Hematologic Malignancies
Disease assessments will be determined at time points indicated in the SOE based on local bone 
marrow aspirate blast counts and transfusions and laboratory data. The investigator’s assessment 
of disease status will be entered into the eCRF for each time point.
9.4.17.1.1
Bone Marrow Aspiration and Bone Marrow Biopsy
At screening and for study eligibility, a bone marrow aspiration and biopsy (performed locally) 
will be required to assess disease burden, cytogenetics, molecular characterizations, and cellular 
composition by flow cytometry. A bone marrow biopsy (in addition to bone marrow aspirate) is 
required only at screening to confirm the diagnosis. However, a bone marrow biopsy may be 
collected with bone marrow aspirate in accordance with institutional guidelines. If a biopsy was 
done within 28 days prior to enrollment, this archival biopsy may be used and does not need to be 
repeated. If bone marrow biopsy is not collected routinely per country/institutional guidelines, it is 
not required.
9.4.17.1.2
Assessment of Disease Response
Assessment of disease response will be conducted only in Part B of the study. Response criteria are 
provided in Appendix J. To determine disease response to pevonedistat treatment, the following 
procedures will be done (see Table C in Appendix A): bone marrow aspiration to assess disease 
response at Cycle 2 on Day 22 (+6 days) and then every third cycle afterward at any time between 
Day 15 and Day 28 until Cycle 11, provided that the disease assessment is available before Day 1 
of the following cycle. After completion of Cycle 11, bone marrow aspiration will be performed 
after completion of every sixth cycle (or otherwise as clinically indicated at the discretion of the 
investigator) after the patient’s previous scan at any time between Day 15 and Day 28, provided 
that the disease assessment is available before Day 1 of the following cycle.
Bone marrow samples will be analyzed locally at the clinical site to:

Determine blast count on aspirate samples: Samples will be evaluated locally for blast count 
per institutional standard practice to inform disease burden assessment.

Analyze cytogenetics for IPSS-R score determination and disease response assessment for 
patients with HR MDS and CMML. Chromosomal abnormalities and translocations that are 
routinely assessed for the diagnosis of MDS and AML are included in the IPSS-R.
Additional bone marrow aspiration(s) may be done if warranted by changes in peripheral blood 
counts, or otherwise as clinically indicated at the discretion of the investigator.
9.4.17.2
Patients with Advanced Solid Tumors
CT scans with IV contrast (unless medically contraindicated) or MRI of the chest, abdomen, and 
pelvis will be performed as entry criteria. If the patient has had appropriate imaging scans 
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performed within 28 days before the first dose of study drug in Part A, the results of those scans 
may be used.
CT scans with IV contrast encompassing the known sites of disease will also be performed during 
the study as specified in the SOE (Appendix A). A scan should be taken at the EOS visit if a scan 
has not been completed within 28 days prior to the EOS visit.
If a CT scan does not provide adequate imaging, MRI may be used to evaluate sites of disease. For 
each site of disease, the imaging modality (CT scan or MRI) used at entry must be used throughout 
the study. Tumor response will be assessed by the investigator at these times using the RECIST 
guidelines (version 1.1) as provided in Appendix J.
9.4.18
Biomarker, Pharmacodynamic, and PK Samples
9.4.18.1
Primary Specimen Collection
The primary specimen collection is displayed in Table 9.h.
Table 9.h
Primary Specimen Collection
Specimen Name in Procedure in SOE 
(Appendix A)
Primary 
Specimen
Description of Intended Use
Sample 
Collection
Plasma samples for pevonedistat protein 
binding a
Plasma
Unbound pevonedistat PK 
parameters
Mandatory
Plasma samples for pevonedistat PK
Plasma
PK measurements
Mandatory
Plasma samples for azacitidine PK
Plasma
PK measurements
Mandatory
Urine samples for pevonedistat PK
Urine
PK measurements
Mandatory
Urine samples for azacitidine PK
Urine
PK measurements
Mandatory
PK: pharmacokinetic(s); SOE: schedule of events.
a Samples for pevonedistat plasma protein binding measurement should be collected predose and at the end of 
infusion. The end of infusion sample will be used if bioanalytically feasible. If not feasible, the predose sample will 
also be used for pevonedistat plasma protein binding measurement.
9.4.19
PK Measurements
9.4.19.1
Blood Sampling
Blood samples for the determination of plasma concentrations of pevonedistat will be collected 
from all patients during Part A and Part B (Cycle 1) of the study at the timepoints specified in 
Appendix A, Table A, Table B, and Table D. Blood samples for the determination of plasma 
concentrations of azacitidine will be collected from patients with hematologic malignancies during 
Part B (Cycle 1) at the timepoints specified in Appendix A, Table B. The timing, but not the 
number, of PK blood samples may be changed if emerging data indicate that an alteration in the 
sampling scheme is needed to better characterize the PK of pevonedistat or azacitidine.
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The exact date and time of each sample collection and the actual start and stop times of the infusion 
should be recorded accurately, with particular care given to the recording of blood sampling times 
for pevonedistat that occur close to the infusion.
To ensure that the measurements are representative of plasma exposure for pevonedistat, blood 
draws will be conducted in the arm opposite a patient’s IV infusion. In the case that only a single 
arm is available, blood may be drawn as distal to the site for IV infusion as feasible, and the site of 
blood draw should be documented.
Details regarding the preparation, handling, and shipping of samples are provided in the Study 
Manual.
If deemed appropriate, the blood samples collected in this study may be additionally analyzed to 
determine the plasma concentrations of pevonedistat major metabolites in humans.
The primary objective of PK sampling in this study is to measure pevonedistat concentrations in 
plasma. In addition, the end of infusion sample on Day 1 of Part A will be used for protein binding 
measurement to calculate unbound exposure of pevonedistat based on the measured total plasma 
concentrations and fu. If the end of pevonedistat infusion sample during Part A is not 
bioanalytically feasible for protein binding measurement, the predose sample taken on Day 1 of 
Part A, spiked with pevonedistat concentrations, will be used for pevonedistat plasma protein 
binding. These PK samples may also be used for the exploratory measurement of plasma 
concentrations of metabolites of pevonedistat, if technically feasible and considered necessary for 
further understanding the metabolism of pevonedistat in patients with cancer.
9.4.19.2
Urine Sampling
Urine output will be collected from all patients during Part B (Cycle 1) of the study at the 
timepoints specified in Appendix A, Table B. Urine samples will be analyzed for estimate of urine 
PK parameters of pevonedistat and (in patients with hematologic malignancies) azacitidine. The 
exact date and time of each sample collection, and the volume of urine collected, should be 
recorded accurately.
Detailed instructions on the procedure for collection, processing, storage, and shipment of the 
urine samples will be provided in the Study Manual.
9.4.20
Pharmacodynamic Measurements
Not applicable to this study.
9.4.21
DNA Measurements
Not applicable to this study.
9.4.22
Banked Tumor Specimen Measurements
Not applicable to this study.
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9.5
Completion of Study Treatment (for Individual Patients)
Part A:
Patients will be considered to have completed the protocol-specified treatment in Part A if they 
receive the single dose of pevonedistat.
Patients who have completed treatment in Part A and do not opt to continue into Part B will be 
considered to have completed study treatment.
Part B:
Patients who continue to Part B will be considered to have completed study treatment if they 
complete at least 12 cycles of treatment, discontinue treatment due to PD, or discontinue for any 
reason.
9.6
Completion of Study (for Individual Patients)
Part A:
Patients will be considered to have completed the study if they receive the Part A single dose of 
pevonedistat, provide samples for PK measurements (that will be used to provide data necessary 
for assessment of the effects of severe renal impairment or mild or moderate hepatic impairment 
on pevonedistat PK), and complete the EOS visit. Note an EOS visit is needed in Part A only if the 
patient does not continue into Part B for any reason (see SOE for Part A in Appendix A).
Part B:
Patients who opt to continue into Part B will be considered to have completed the study if they 
have completed study treatment and the EOS visit or until the sponsor terminates the study.
9.7
Discontinuation of Treatment With Study Drug and Patient Replacement
Patients who do not complete the protocol-specified dosing, PK, and safety assessment in Part A 
may be considered nonevaluable and replaced.
Treatment with study drug may be discontinued for any of the following reasons:

AE (see Section 10.1.2).

Protocol deviation.

PD.
Note: Patients with hematologic malignancies may be allowed to continue study treatment if 
they meet the criteria for PD on the basis of only bone marrow blast count (without AML 
transformation in patients with HR MDS or HR CMML) if, in the clinical judgment of the 
investigator, the patient is still receiving clinical benefit from this treatment and the 
continuation is endorsed by the sponsor’s project clinician (or designee). Patients who meet the 
criteria for PD and continue on study under these conditions must be reconsented before 
continuing study treatment.
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
Symptomatic deterioration.

Unsatisfactory therapeutic response.

Initiation of hematopoietic stem cell transplant.

Pregnancy (patient must be discontinued).

Study terminated by sponsor.

Withdrawal by the patient.

Lost to follow-up.

Other.
Once study drug has been discontinued, all study procedures outlined for the EOS visit will be 
completed as specified in the SOE. The primary reason for study drug discontinuation will be 
recorded on the eCRF.
Patients who have achieved objective clinical benefit from combination therapy 
(chemotherapy plus pevonedistat) and who have developed intolerance that is reasonably 
attributable to the chemotherapy after 2 or more cycles may continue on single-agent pevonedistat 
at the same dose and schedule upon request by the investigator and agreement with the sponsor. 
The dose of single-agent pevonedistat may be escalated to the maximum dose specified for the 
patient’s treatment arm, as described in Section 8.1.
Patients who are eligible may be able to continue to receive study drug; see Section 6.3.5 for PTA.
9.8
Withdrawal of Patients From Study
A patient may be withdrawn from the study for any of the following reasons:

Lost to follow-up.

Study terminated by sponsor.

Withdrawal by patient.

Completed study.

Death.

Other.

PD.

Initiation of hematopoietic stem cell transplant.
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.
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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.
10.0
ADVERSE EVENTS
10.1
Definitions
10.1.1
Pretreatment Event Definition
A PTE is any untoward medical occurrence in a patient or subject who has signed informed 
consent to participate in a study but before administration of any study medication; it does not 
necessarily have to have a causal relationship with study participation.
10.1.2
AE Definition
AE means any untoward medical occurrence in a patient or subject administered a pharmaceutical 
product; the untoward medical occurrence does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product whether or not it is related to the medicinal product. This includes any 
newly occurring event, or a previous condition that has increased in severity or frequency since the 
administration of study drug.
An abnormal laboratory value will not be assessed as an AE unless that value leads to 
discontinuation or delay in treatment, dose modification, therapeutic intervention, or is considered 
by the investigator to be a clinically significant change from baseline.
10.1.3
SAE Definition
SAE means any untoward medical occurrence that at any dose:

Results in death.

Is life-threatening (refers to an AE in which the patient was at risk of death at the time of the 
event. It does not refer to an event 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, 
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based on appropriate medical judgment, 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 [1]. Clarification should be made between 
an SAE and an AE that is considered severe in intensity (Grade 3 or 4) because the terms serious
and severe are NOT synonymous. The general term severe is often used to describe the intensity 
(severity) of a specific event; the event itself, however, may be of relatively minor medical 
significance (such as a Grade 3 headache). This is NOT the same as serious, which is based on 
patient/event outcome or action criteria described above and is usually associated with events that 
pose a threat to a patient’s life or ability to function. A severe AE (Grade 3 or 4) does not 
necessarily need to be considered serious. For example, a WBC count of 1000/mm3 to less than 
2000/mm3 is considered Grade 3 (severe) but may not be considered serious. Seriousness (not 
intensity) serves as a guide for defining regulatory reporting obligations.
10.2
Procedures for Recording and Reporting AEs and SAEs
All AEs spontaneously reported by the patient 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 and serious PTEs (as defined in Section 10.1) must be reported (see 
Section 10.3 for the period of observation) by the investigator to the Takeda Global 
Pharmacovigilance department or designee within 24 hours of becoming aware of the event. This 
will be done by transmitting an 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 and serious PTEs should be followed up until resolution or permanent outcome of the 
event. The timelines and procedure for follow-up reports are the same as those for the initial report.
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Planned hospital admissions or surgical procedures for an illness or disease that existed before the 
patient was enrolled in the trial or before study drug was given are not to be considered AEs unless 
the condition deteriorated in an unexpected manner during the trial (eg, surgery was performed 
earlier or later than planned).
For both serious and nonserious AEs, the investigator must determine both the severity (toxicity 
grade) of the event and the relationship of the event to study drug administration. For serious PTEs, 
the investigator must determine both the severity (toxicity grade) of the event and the causality of 
the event in relation to study procedures.
Severity (toxicity grade) for each AE, including any lab abnormality, will be determined using the 
NCI CTCAE, version 5.0, effective 27 November 2017 [1]. The criteria are provided in the Study 
Manual.
Relationship of the event to study drug administration (ie, its causality) will be determined by the 
investigator responding yes (related) or no (unrelated) to this question: Is there a reasonable 
possibility that the AE is associated with the study drug?
10.3
Monitoring of AEs and Period of Observation
AEs, both nonserious and serious, will be monitored throughout the study as follows:

AEs will be reported from the start of study drug administration through 30 days (+10 days) 
after administration of the last dose of study drug and recorded in the eCRFs. AEs 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 will be reported as follows:
–
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 and serious PTEs will be reported to the 
Takeda Global Pharmacovigilance department or designee from the signing of the ICF in 
Part A through 30 days (+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 caused by 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.
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If a female partner of a male patient becomes pregnant during the male patient’s participation in 
this study, the sponsor must also be contacted immediately by 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 below.
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 below.
Call Center
Phone Number
Email
Fax
Dohmen Life 
Science Services
1-844-662-8532
Non–toll-free number: 1-510-740-1273 
GlobalOncologyMedinfo
@takeda.com 
1-800-881-6092
Product complaints 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, 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
Sponsor Safety Assessment
Safety data will be reviewed and assessed periodically by a global pharmacovigilance team and a 
cross-functional safety management team throughout the conduct of the study. These 
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cross-functional reviews will include a global safety lead from the study team, and other 
representation from other departments at Takeda such as Clinical Research, Pharmacovigilance, 
Biostatistics, Clinical Pharmacology, and Clinical Operations.
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.
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 such items as 
inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site.
Any change of, modification of, or addition to the data on the eCRFs should be made by the 
investigator or appropriate site personnel. Corrections to eCRFs are recorded in an audit trail that 
captures the old information, the new information, identification of the person making the 
correction, the date the correction was made, and the reason for the change.
The principal investigator must review the eCRFs for completeness and accuracy and must sign 
and date the appropriate eCRFs as indicated. Furthermore, the principal investigator must retain 
full responsibility for the accuracy and authenticity of all data entered on the eCRFs.
eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The sponsor (or designee) will be permitted to review the subject’s medical and 
hospital records pertinent to the study to ensure accuracy of the eCRFs. The completed eCRFs are 
the sole property of the sponsor and should not be made available in any form to third parties, 
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 subjects, medical records, temporary media such as thermal-sensitive paper, source 
worksheets, all original signed and dated ICFs, subject authorization forms regarding the use of 
personal health information (if separate from the ICFs), electronic copies of eCRFs including the 
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audit trail, and detailed records of drug disposition to enable evaluations or audits from regulatory 
authorities and the sponsor or its designees. Any source documentation printed on degradable 
thermal-sensitive paper should be photocopied by the site and filed with the original in the 
subject’s chart to ensure long-term legibility. Furthermore, ICH E6 Section 4.9.5 requires the 
investigator to retain essential documents specified in ICH E6 (Section 8) until at least 2 years 
after the last approval of a marketing application for a specified drug indication being investigated 
or, if an application is not approved, until at least 2 years after the investigation is discontinued and 
regulatory authorities are notified. In addition, ICH E6 Section 4.9.5 states that the study records 
should be retained until an amount of time specified by applicable regulatory requirements or for a 
time specified in the clinical study site agreement between the investigator and sponsor.
Refer to the clinical study site agreement for the sponsor’s requirements for record retention. The 
investigator should contact and receive written approval from the sponsor before disposing of any 
such documents.
13.0
STATISTICAL METHODS
13.1
Statistical and Analytical Plans
Analyses will be primarily descriptive in nature. No formal statistical hypothesis testing will be 
performed. A statistical analysis plan will be prepared and finalized before database lock. This 
document will provide further details regarding the definition of analysis variables and analysis 
methodology to address all study objectives.
Summary tabulations will be presented to display the number of observations, mean, standard 
deviation, median, minimum, and maximum for continuous variables along with the number and 
percentage (calculated using nonmissing values) per category for categorical data, unless specified 
otherwise.
13.1.1
Analysis Sets

Safety population will include patients who receive at least 1 dose of study drug. The safety 
population will be used for all safety analyses.

PK population will include patients who:
–
Complete the protocol-specified pevonedistat dosing and PK assessment in Part A and/or 
protocol-specified pevonedistat and/or azacitidine dosing and PK assessment in Cycle 1 of 
Part B.
–
Do not receive any excluded concomitant medications through the completion of Part A.
–
Have sufficient concentration-time data to permit reliable estimation of PK parameters.

Response-evaluable population: patients who receive at least 1 dose of study drug, have a 
baseline disease assessment, and have at least 1 postbaseline disease assessment will be used 
for analyses of response.
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13.1.2
Demographics and Other Baseline Characteristics
Demographic and baseline characteristics will be summarized in a descriptive fashion, including 
sex, age, race, ethnicity, weight, height, BSA, organ function category (ie, normal, severe renal 
impairment, or mild or moderate hepatic impairment), baseline disease characteristics, and other 
parameters as appropriate.
13.1.3
Efficacy Analysis
Efficacy measures will include disease response and duration of disease response. Analysis of all 
efficacy measures will be descriptive. Disease response in AML will be based on the ORR 
(CR + PR) using the Revised Recommendations of the International Working Group (IWG) for 
Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards 
for Therapeutic Trials in AML [5].
For AML patients, all CR includes both CR and CRi.
Disease response in patients with MDS or CMML will be based on the best overall response 
(CR + PR + HI) as determined by the investigator using the revised IWG response criteria for 
MDS (detailed in Appendix J) [6].
Disease response to pevonedistat in combination with docetaxel or carboplatin plus paclitaxel will 
be based on the best overall response as determined by the investigator using RECIST version 1.1 
guidelines (Appendix J).
The duration of response will be defined in all patients with disease response as the time between 
the first documentation of response and the first documentation of PD or death if no prior PD is 
documented. Responders without disease progression will be censored at the last clinical 
assessment of response.
13.1.4
PK Analysis
Individual and mean pevonedistat plasma concentration-time data following a single dose of 
pevonedistat during the PK assessment in Part A will be plotted and listed by organ function group. 
Individual and mean pevonedistat and/or azacitidine plasma concentration-time data following 
multiple-dose administration during Cycle 1 of Part B will be plotted and listed by organ function 
group and by dose levels. Plasma pevonedistat and/or azacitidine PK parameters for each patient 
will be calculated using noncompartmental analysis methods. Unbound values of pevonedistat 
Cmax, AUClast, AUC∞and AUCin individual patients will be calculated as the product of the 
patient’s pevonedistat fu and the total values of Cmax, AUClast, AUC∞and AUC, respectively. 
Descriptive statistics will be presented for pevonedistat PK parameters (Cmax, AUClast, AUC∞, 
AUC, CL, t1/2z, CLR, fu, and unbound values of Cmax, AUClast, AUC∞and AUC) by organ 
function and dose levels. Descriptive statistics will be presented for azacitidine PK parameters 
(Cmax, Tmax, AUC, CL/F, t1/2z, and CLR by organ function and dose levels.
The analysis for the effects of organ impairment on pevonedistat PK will be based on unbound 
pevonedistat plasma exposure (AUC) following a single dose of pevonedistat in Part A. To assess 
the effects of severe renal impairment or mild or moderate hepatic impairment on pevonedistat PK 
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(unbound AUClast and AUC∞), an analysis of variance (ANOVA) on the natural log-transformed 
PK parameters will be performed for severe renal impairment (Renal Arm) versus the normal 
group (Control Arm), mild hepatic impairment (Mild Hepatic Arm) versus the normal group 
(Control Arm), and moderate hepatic impairment (Moderate Hepatic Arm) versus the normal 
group (Control Arm). The ANOVA results will be used to estimate the ratios of least-squares 
geometric means (severe renal impairment vs normal, mild hepatic impairment vs normal, and 
moderate hepatic impairment vs normal) and corresponding 90% CIs for pevonedistat unbound 
AUC. The PK-evaluable population will be used for these analyses.
13.1.5
Pharmacodynamic Analysis
Not applicable.
13.1.6
PK/Pharmacodynamic Analysis
Not applicable.
13.1.7
Immunogenicity Analyses
Not applicable.
13.1.8
Safety Analysis
A safety analysis will be conducted separately for Part A and Part B. The safety population will be 
used for the safety analysis. Safety will be evaluated on the basis of the incidence of AEs, severity 
and type of AEs, and by changes from baseline in the patient’s vital signs, weight, and clinical 
laboratory values using the safety population. Exposure to the study drugs and reasons for 
discontinuation will be tabulated.
A treatment-emergent adverse event (TEAE) in Part A is defined as any AE that occurs after 
administration of the single dose of study treatment in Part A and up through 30 days after the 
single dose of study drug in Part A for patients who do not continue into Part B; or up through 
Part B Cycle 1 Day 1 (predose) for patients who continue into Part B.
A TEAE in Part B is defined as any AE that occurs after administration of the first dose of study 
treatment in Part B and up through 30 days after the last dose of study drug in Part B.
AEs will be tabulated according to MedDRA by System Organ Class, High-Level Term, and 
Preferred Term 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).

The most commonly reported TEAEs (ie, those events reported by ≥10% of all patients).

SAEs.
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
Drug-related SAEs.
A listing of TEAEs resulting in study drug discontinuation will be provided.
The most commonly reported TEAEs (ie, those events reported by ≥10% of all patients) will be 
tabulated by System Organ Class and Preferred Term. Tabulation also will be provided that 
enumerates AEs by maximum intensity. Deaths, SAEs, and AEs resulting in study drug 
discontinuation will be tabulated.
Descriptive statistics for the actual values of clinical laboratory parameters (and 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.
Shift tables for laboratory parameters will be generated to show 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 
pevonedistat safety profile.
Graphical displays will be used to show vital sign parameters over time separately for Part A and 
for Part B.
All concomitant medications collected from screening throughout the study period will be 
classified to Preferred Terms according to the WHO Drug Dictionary.
Additional safety analyses may be performed to enumerate rates of toxicities and to further define 
the safety profile of pevonedistat.
13.2
Interim Analysis
No interim analysis is planned.
13.3
Determination of Sample Size
The sample size calculation is based on the number of patients required to adequately characterize 
the PK of pevonedistat in the impaired organ function groups (severe renal impairment or mild or 
moderate hepatic impairment) in comparison to the control group. Based on these considerations, 
the expected sample size is approximately 9 for the control group (normal renal and hepatic 
function) and 9 to 12 patients in each of the 3 organ impairment arms. Patients who are considered 
nonevaluable may be replaced. The sample size of approximately 9 patients specified as being 
required for the PK-evaluable population in each group in Part A is based on typical sample sizes 
utilized in organ impairment PK studies in cancer patients, rather than on specific statistical 
considerations. With a sample size of 9 patients per group, if the ratio of geometric means 
(impaired organ function vs control) of AUC∞is X, the associated 90% CI is expected to be 
(0.688X, 1.45X) based on the %CV in pevonedistat AUC∞ of 43.8% (Study C15011).
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14.0
QUALITY CONTROL AND QUALITY ASSURANCE
14.1
Study Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and institution guarantee access to source documents by the sponsor or its 
designee (CRO) and by the IRB or IEC.
All aspects of the study and its documentation will be subject to review by the sponsor or designee 
(as long as blinding is not jeopardized) including, but not limited to, the investigator’s binder, 
study medication, subject medical records, informed consent documentation, documentation of 
subject authorization to use personal health information (if separate from the ICFs), and review of 
eCRFs and associated source documents. It is important that the investigator and other study 
personnel are available during the monitoring visits and that sufficient time is devoted to the 
process.
In the event a monitor cannot visit the site in a timely manner due to the COVID-19 pandemic, 
alternative monitoring approaches, such as remote source data verification (SDV) and remote 
source data review (SDR), 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 and privacy laws and where permitted by the IRB/IEC.
14.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will require 
deviation from protocol-specified procedures, the investigator should consult with the sponsor or 
designee (and IRB or IEC, as required) to determine the appropriate course of action. There will be 
no exemptions (a prospectively approved deviation) from the inclusion or exclusion criteria.
The site should document all protocol deviations in the subject’s source documents. In the event of 
a significant deviation, the site should notify the sponsor or its designee (and IRB or EC, as 
required). Significant deviations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the subject, or confound interpretation of 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 subject or the reliability and robustness of the data generated, it may be 
reported to regulatory authorities as a serious breach of GCP and the protocol.
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, 
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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, 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.
15.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of Helsinki, 
and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will conduct the study 
according to applicable local or regional regulatory requirements and align his or her conduct in 
accordance with the responsibilities of the investigator that are listed in Appendix 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 IB, a copy of the ICF, and, if 
applicable, subject 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 subject informed consent must be 
obtained and submitted to the sponsor or designee before commencement of the study, ie, before 
shipment of the sponsor-supplied drug or study-specific screening activity. The IRB or IEC 
approval must refer to the study by 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 notify the site of activation status once the sponsor has confirmed the adequacy of site 
regulatory documentation and, when applicable, the sponsor has received permission from the 
competent authority to begin the trial. Until the site receives notification of activation status, no 
protocol activities, including screening, may occur.
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Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the ICF, recruitment 
materials intended for viewing by subjects, local safety reporting requirements, reports and 
updates regarding the ongoing review of the study at intervals specified by the respective IRB or 
IEC, and submission of the investigator’s final status report to the IRB or IEC. All IRB and IEC 
approvals and relevant documentation for these items must be provided to the sponsor (or 
designee).
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and sponsor.
15.2
Subject Information, Informed Consent, and Subject Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The ICF, subject authorization form (if applicable), and subject 
information sheet (if applicable) describe the planned and permitted uses, transfers, and 
disclosures of the subject’s personal and personal health information for purposes of conducting 
the study. The ICF and the subject information sheet (if applicable) further explain the nature of 
the study, its objectives, and potential risks and benefits, 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 subject authorization form. The ICF, subject authorization form (if 
applicable), and subject information sheet (if applicable) must be approved by both the IRB or IEC 
and the sponsor before use.
The ICF, subject authorization form (if applicable), and subject information sheet (if applicable) 
must be written in a language fully comprehensible to the prospective subject. It is the 
responsibility of the investigator to explain the detailed elements of the ICF, subject authorization 
form (if applicable), and subject information sheet (if applicable) to the subject. Information 
should be given in both oral and written form whenever possible and in the manner deemed 
appropriate by the IRB or IEC. If the subject is not capable of rendering adequate written informed 
consent, then the subject’s legally acceptable representative may provide such consent for the 
subject in accordance with applicable laws and regulations.
The subject, or the subject’s legally acceptable representative, must be given ample opportunity to 
(1) inquire about details of the study and (2) decide whether to participate in the study. If the 
subject, or the subject’s legally acceptable representative, determines that he or she will participate 
in the study, then the ICF and subject authorization form (if applicable) must be signed and dated 
by the subject, or the subject’s legally acceptable representative, at the time of consent and before 
the subject enters into the study. The subject or the subject’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 subject authorization 
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(if applicable) at the time of consent and before the subject 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, subject authorization form (if applicable), and subject information 
sheet (if applicable) will be stored in the investigator’s site file. The investigator must document 
the date the subject signs the informed consent in the subject’s medical record. Copies of the 
signed ICF, the signed subject authorization form (if applicable), and subject information sheet (if 
applicable) shall be given to the subject.
All revised ICFs must be reviewed and signed by relevant subjects or the relevant subject’s legally 
acceptable representative in the same manner as the original informed consent. The date the 
revised consent was obtained should be recorded in the subject’s medical record, and the subject 
should receive a copy of the revised ICF.
Patients with PD based only on bone marrow blasts counts may be allowed to remain on study, 
after discussion between the investigator and project clinician or designee, if it is judged that they 
are deriving clinical benefit from doing so. Patients who meet the criteria for PD and continue on 
study under these conditions must be reconsented before continuing study treatment.
15.3
Subject Confidentiality
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will 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 subject attributes, such as sex, age, or date 
of birth, and subject initials may be used to verify the subject and accuracy of the subject’s unique 
identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the sponsor 
requires the investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (eg, US FDA, UK MHRA, Japan PMDA), the sponsor’s designated auditors, 
and the appropriate IRBs and IECs to review the subject’s original medical records (source data or 
documents) including, but not limited to, laboratory test result reports, ECG reports, admission and 
discharge summaries for hospital admissions occurring during a subject’s study participation, and 
autopsy reports. Access to a subject’s original medical records requires the specific authorization 
of the subject as part of the informed consent process (see Section 15.2).
Copies of any subject source documents that are provided to the sponsor must have certain 
identifying personal information removed, eg, subject name, address, and other identifier fields 
not collected on the subject’s eCRF.
15.4
Publication, Disclosure, and Clinical Trial Registration Policy
15.4.1
Publication
The investigator is obliged to provide the sponsor with complete test results and all data derived by 
the investigator from the study. During and after the study, only the sponsor may make study 
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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.
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 subjects 
receive investigator contact information, they may call the site requesting enrollment into the trial. 
The investigative sites are encouraged to handle the trial inquiries according to their established 
subject screening process. If the caller asks additional questions beyond the topic of trial 
enrollment, they should be referred to the sponsor.
Any investigator who objects to Takeda providing this information to callers must provide Takeda 
with a written notice requesting that their information not be listed on the registry site.
15.4.3
Clinical Trial Results Disclosure
Takeda will post the results of clinical trials on ClinicalTrials.gov for the US and 
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.
15.4.3.1
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 
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may be unrelated to the study drug or the patient’s disease. The data provided to external 
researchers will not include information that identifies patients personally.
15.5
Insurance and Compensation for Injury
Each subject in the study must be insured in accordance with the regulations applicable to the site 
where the subject is participating. If a local underwriter is required, then the sponsor or sponsor’s 
designee will obtain clinical study insurance against the risk of injury to clinical study subjects. 
Refer to the clinical study site agreement regarding the sponsor’s policy on subject compensation 
and treatment for injury. If the investigator has questions regarding this policy, he or she should 
contact the sponsor or sponsor’s designee.
16.0
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of cisplatin/paclitaxel versus carboplatin/paclitaxel as first-line treatment of ovarian cancer. J 
Natl Cancer Inst 2003;95(17):1320-9.
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Appendix A
SOE
SOE for Part A: Single-Agent Pevonedistat and PK (All Patients)
Procedure
Screening a
PK Period
EOS/
ET
Days
Day 1
Day 2
Day 3
Day 4 b
Window
(+10 days)
Informed consent
x
Inclusion/exclusion criteria c
x
Demographics
x
Medical history
x
Complete physical examination
x
x
Symptom-directed physical examination d
x e
Height
x
Weight f
x
x e
x
Vital signs g
x
x
x
ECOG PS
x
x e
x
12-lead ECG
x
x
Pregnancy test h
x
x e
x
Hematology i
x
x e
x
Coagulation
x
Complete chemistry panel j
x
x e
x
Urinalysis k
x
x
Pevonedistat IV infusion
x l
Plasma sample for pevonedistat PK (see Table A)
x
x
x
x
Plasma sample for pevonedistat protein binding (see Table A)
x
Bone marrow aspiration/biopsy and investigator disease 
assessment for patients with hematologic malignancies only m
x
Tumor assessment for solid tumors by RECIST, version 1.1 n
x
x o
Monitoring of concomitant medications and procedures
Recorded from the first dose of any study drug through 30 days (+10) days after the last dose of any study drug.
RBC and platelet transfusion documentation
Recorded from 8 weeks before enrollment through 30 days after the last dose of any study drug.
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Procedure
Screening a
PK Period
EOS/
ET
Days
Day 1
Day 2
Day 3
Day 4 b
Window
(+10 days)
AE/SAE reporting
Recorded from the first dose of any study drug through 30 days (+10) days after the last dose of any study drug.
AEs 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 will be reported from signing of the ICF through 30 days after the last dose of any study drug.
AE: adverse event; ALP: alkaline phosphatase; ALT: alanine aminotransferase; AML: acute myelogenous leukemia; AST: aspartate aminotransferase; BSA: body surface area; 
BUN: blood urea nitrogen; CT: computerized tomography; ECG: electrocardiogram; ECOG PS: Eastern Cooperative Oncology Group performance status; eGFR: estimated 
glomerular filtration rate; EOS: end of study; ET: early termination; ICF: informed consent form; IV: intravenous(ly); LVEF: left ventricular ejection fraction; MDRD: Modification 
of Diet in Renal Disease; PK: pharmacokinetic(s); RBC: red blood cells; RECIST: Response Evaluation Criteria in Solid Tumors; SAE: serious adverse event; SC: subcutaneous(ly); 
SOE: schedule of events; WBC: white blood cell.
An EOS visit is needed in Part A only if for any reason the patient does not continue into Part B.
a Unless otherwise noted, the screening visit must occur within 28 days before the day of the first dose of study drug on Day 1.
b Patients may start Part B 4 to 7 days after the pevonedistat dose in Part A.
c Confirmation of patient eligibility by the sponsor’s project clinician (or designee) is required prior to enrollment. A patient eligibility checklist must be completed and submitted by 
the investigator for review and approval by the sponsor or designee prior to patient enrollment. For assessment of hepatic function, 2 blood samples (total bilirubin and ALT), will be 
required before the start of pevonedistat dosing on Day 1. These 2 samples should be obtained at least 48 hours apart, with the latest sample obtained no more than 48 hours before 
Day 1 and may be taken predose on Day 1. If the total bilirubin and ALT measurements from the 2 samples indicate the same liver function category for the patient (ie, normal, mild, 
or moderate hepatic impairment), pevonedistat can be administered as scheduled. If the results of the 2 samples indicate different liver function categories, a third sample must be 
obtained at least 48 hours after the second sample. If the results of the 2 most recent measurements (the second and third) denote the same liver function category, the patient may be 
enrolled and should receive a single dose of pevonedistat on Day 1 within 48 hours of the third sample. If the second and third measurements indicate different liver function 
categories, the patient will not be eligible for inclusion in the study. For assessment of renal function, at least 2 blood samples will be collected to determine spot serum creatinine for 
calculation of the eGFR according to the MDRD equation (see Section 9.4.15.1). The sampling for spot serum creatinine should be done within 14 days of starting treatment, with the 
most recent measurement performed within 7 days of starting treatment. The 2 measurements should both meet eligibility requirements based on the MDRD formula. If the 2 eGFR 
values do not both meet eligibility requirements, a third measurement will be taken and the 2 most recent measurements (the second and third) will be averaged to assess renal function 
status. LVEF must be <50% within 6 months prior to study enrollment. If a result within this time frame is unavailable, LVEF must be determined by echocardiography or multigated 
acquisition scan at screening.
d The symptom-directed physical examination will be conducted within 3 days before dosing on Day 1. The symptom-directed physical examination may be performed at other visits 
during Part A of the study at the discretion of the investigator.
e Except for measurement of WBC count, procedures conducted during the screening period that are performed within 24 hours of Day 1 can also be used as the predose Day 1 
evaluation and do not need to be repeated. If dosing falls on a Monday, the collection window may be extended to collect samples on a previous Friday, with the exception of the 
hepatic and renal function assessments.
f Weight will be measured during screening and within 3 days before Day 1 dosing for calculating BSA. BSA will be calculated using a standard formula (see example in Appendix H) 
on Day 1.
g Vital signs, including diastolic and systolic blood pressure, heart rate, and body temperature will be obtained at screening. On Day 1, vital signs are to be measured predose 
(20 minutes [±10 minutes]) before the infusion of pevonedistat, 30 minutes (±10 minutes) after the start of the pevonedistat infusion, and 30 min (±10 minutes) after the completion 
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of the pevonedistat infusion. When the timing of vital signs assessment coincides with the timing of a blood draw, vital signs will be measured before blood sample collection. Vital 
sign measurements will be taken with the patient in the supine (after 3-5 minutes in this position) or sitting position (after 3-5 minutes in this position). Either oral or axial body 
temperature may be used, but the same method for measuring body temperature (oral or axial) should be used consistently for the same patient throughout the study.
h A serum pregnancy test will be performed for women of childbearing potential at screening and within 3 days before study drug dosing on Day 1. The results from these tests must 
be available and negative before the first dose of study drug is administered.
i Hematology samples will be collected during screening and within 3 days before infusion/administration with study drug on Day 1. Please note: The sample for WBC count must be 
drawn before dosing on Day 1. For patients with hematologic disease, WBC count must be <50,000/μL before administration of pevonedistat; hydroxyurea maybe used to control the 
level of WBCs to no lower than 10,000/μL while on pevonedistat. An additional sample will be taken on Day 1 at 4 hours after the completion of pevonedistat infusion.
j Samples for the full clinical chemistry panel will be collected predose on Day 1. In addition, samples will be taken on Day 1 at 4 hours after the completion of pevonedistat infusion 
(see Table 9.d).
k Urinalysis will be analyzed locally. See Section 9.4.15.1. for additional details.
l All eligible patients will receive a single dose of 20 mg/m2 pevonedistat via a 1-hour IV infusion on Day 1. Plasma PK samples will be collected at a series of predetermined time 
points up to 72 hours (Day 4) following the single dose of pevonedistat. There will be no SOC agents or additional pevonedistat dosing in Part A.
m At screening and for study eligibility, a bone marrow aspiration and biopsy (performed locally) will be required to assess disease burden, cytogenetics, molecular characterizations, 
and cellular composition by flow cytometry. A bone marrow biopsy (in addition to bone marrow aspirate) is required only at screening to confirm the diagnosis. However, a bone 
marrow biopsy may be collected with bone marrow aspirate in accordance with institutional guidelines. If a biopsy was done within 28 days before enrollment, this archival biopsy 
may be used and does not need to be repeated. If a bone marrow biopsy is not collected routinely per country/institutional guidelines, it is not required.
n Radiological imaging (CT scan or magnetic resonance imaging) of chest, abdomen, and pelvis are required as entry criteria for this study to assess the status of the patient’s 
underlying disease. If the patient has had appropriate imaging scans performed within 28 days before the first dose of study drug in Part A, the results of those scans may be used.
o An EOS/ET CT scan does not need to be completed/repeated if a scan was performed within the previous 28 days.
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Table A
Part A: Pevonedistat Plasma PK Sampling Schedule – Pevonedistat Single-Dose PK (All Patients)
Pevonedistat Plasma PK Sample
Day 1
Day 2
Day 3
Day 4
Predose
x a,c
End of pevonedistat infusion
x b,c
30 minutes (± 5 minutes) postinfusion of pevonedistat
x d
1 hour (± 15 minutes) postinfusion of pevonedistat
x d
2 hours (±20 minutes) postinfusion of pevonedistat
x d
3 hours (±20 minutes) postinfusion of pevonedistat
x d
4 hours (±30 minutes) postinfusion of pevonedistat
x d
6 hours (±30 minutes) postinfusion of pevonedistat
x d
8 hours (±30 minutes) postinfusion of pevonedistat
x d
24 hours (±1 hour) postdose of pevonedistat
x e
48 hours (±1 hour) postdose of pevonedistat
x e
72 hours (±1 hour) postdose of pevonedistat
x e
IV: intravenous(ly); PK: pharmacokinetics.
a The predose sample is to be collected within 1 hour before pevonedistat infusion.
b The sample is to be collected at the end of pevonedistat infusion (immediately before stopping the IV infusion). The infusion takes approximately 1 hour.
c Samples for pevonedistat plasma protein binding measurement should be collected predose and at the end of infusion. The end of infusion sample will be used if bioanalytically 
feasible. If not feasible, the predose sample will also be used for pevonedistat plasma protein binding measurement.
d The time of sample collection is to be based on the time of completion of pevonedistat infusion.
e The time of sample collection is to be based on the time of initiation of pevonedistat infusion.
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SOE for Part B: Treatment Cycle 1 (28-Day Cycle) Through EOS (Patients With Hematologic Malignancies Only)
Day
Cycle 1 and Subsequent Cycles (28 days)
EOS/ET
Day 1
Day 3
Day 4
Day 5
Day 8 a
Day 15 a
Day 22
Procedure
Window
(±1 day)
(±3 day)
(±3 days)
(+10 days) b
Symptom-directed physical 
examination c
x
Complete physical examination
x
Weight
x d
x
Vital signs e
x
x
x
x
ECOG PS f
x
x
12-lead ECG g
x
x
Pregnancy test h
x
x
Hematology i
x
x
x
x
x
x
x
Complete chemistry panel
x
x
Select chemistry panel j
x
x
x
x
x
Urinalysis k
x
x
Plasma sample for pevonedistat PK 
(Cycle 1 only, see Table B)
x
x
x
Plasma sample for azacitidine PK 
(Cycle 1 only, see Table B)
x
Urine sample for pevonedistat PK 
(Cycle 1 only, see Table B)
x
Urine sample for azacitidine PK 
(Cycle 1 only, see Table B)
x
Bone marrow aspiration/biopsy and 
investigator disease assessment
See the Bone Marrow Collection and Assessment Schedule (Table C).
Pevonedistat IV infusion l
Days 1, 3, and 5 of each cycle.
Azacitidine IV or SC administration l
Days 1-7 or Days 1-5, 8, and 9 of each cycle.
Monitoring of concomitant 
medications and procedures
Recorded from the first dose of any study drug through 30 days (+10) days after the last dose of any study drug.
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Day
Cycle 1 and Subsequent Cycles (28 days)
EOS/ET
Day 1
Day 3
Day 4
Day 5
Day 8 a
Day 15 a
Day 22
Procedure
Window
(±1 day)
(±3 day)
(±3 days)
(+10 days) b
RBC and platelet transfusion 
documentation
Recorded from 8 weeks before enrollment through 30 days after the last dose of any study drug.
AE/SAE reporting
Recorded from the first dose of any study drug through 30 days (+10) days after the last dose of any study drug.
AEs 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 will be reported from signing of the ICF through 30 days after the last dose of any study drug.
AE: adverse event; ALP: alkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase; BSA: body surface area; BUN: blood urea nitrogen; COVID-19: 
coronavirus disease 2019; ECG: electrocardiogram; ECOG PS: Eastern Cooperative Oncology Group performance status; EOS: end of study; ET: early termination; IV: 
intravenous(ly); PK: pharmacokinetic(s); RBC: red blood cells; SAE: serious adverse event; SC: subcutaneous(ly); SOE: schedule of events; WBC: white blood cell.
Study completion is defined as completion of study treatment and the EOS visit.
Nonessential protocol visits in Part B 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 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 for the assessments performed are to be captured in the electronic data capture.
a Hematology samples and select chemistry panels will be collected on Days 8 (±1 day) and 15 (±1 day) in Cycle 1 and in any cycle in which intrapatient dose escalation of any study 
drug occurs.
b The EOS/ET visit will occur 30 days (+10 days) after the last dose of study drugs or before the start of subsequent antineoplastic therapy, if that occurs sooner.
c The symptom-directed physical examination will be conducted within 3 days before dosing on Day 1 of each treatment cycle. The symptom-directed physical examination may be 
performed at other visits during the treatment cycle at the discretion of the investigator.
d 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 H) 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.
e Vital signs, including diastolic and systolic blood pressure, heart rate, and body temperature will be collected predose (30 minutes [±10 minutes]) before the infusion of pevonedistat 
and 30 minutes (±10 minutes) after the start of the pevonedistat infusion on Days 1, 3, and 5 of each cycle, at EOS/ET, and as clinically indicated at the discretion of the investigator. 
On Cycle 1 Day 1, vital signs are to be measured predose (20 minutes [±10 minutes]) before the infusion of pevonedistat, 30 minutes (±10 minutes) after the start of the pevonedistat 
infusion, and 30 min (±10 minutes) after the completion of the pevonedistat infusion. Vital sign measurements will be taken with the patient in the supine (after 3-5 minutes in this 
position) or sitting position (after 3-5 minutes in this position). Either oral or axial body temperature may be used, but the same method for measuring body temperature (oral or axial) 
should be used consistently for the same patient throughout the study.
f ECOG PS will be performed within 3 days before the beginning (Day 1) of each treatment cycle and at the EOS/ET visit.
g A 12-lead ECG will be performed Day 1 predose of every cycle and at EOS/ET. Predose assessment may be performed up to 3 days in advance if necessary. ECGs may be obtained 
as clinically indicated at the discretion of the investigator. ECG assessments are to be performed with the patient supine and rested for 5 minutes.
h A serum pregnancy test will be performed for women of childbearing potential within 3 days before Day 1 of each cycle and at EOS/ET. The results from these tests must be 
available and negative before the study drug is administered on Day 1. If the Day 1 serum pregnancy results will not be available before dosing, a urine pregnancy test may be 
performed.
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i Hematology samples will be collected before infusion with study drug(s) on Days 1, 3, and 5, and on Day 22 of each cycle, and at EOS/ET. Samples may be drawn up to 1 day before 
dosing. If dosing falls on a Monday, the collection window may be extended to collect samples on the previous Friday. Additional collections on Days 8 (±1 day) and 15 (±1 day) will 
be performed in Cycle 1 or in any cycle in which study drug dose is escalated. Please note: The sample for WBC count must be drawn before each dose on Days 1, 3, and 5. WBC 
count must be <50,000/μL before administration of pevonedistat; hydroxyurea may be used to control the level of WBCs to no lower than 10,000/μL while on pevonedistat.
j The select chemistry panel will be collected predose on Days 3 and 5 and on Day 22 of each cycle. For Days 3 and 5, samples may be drawn up to 1 day before dosing. If dosing falls 
on a Monday, the collection window may be extended to collect samples on the previous Friday. Additional collections on Days 8 (±1 day) and 15 (±1 day) will be performed in 
Cycle 1 or in any cycle in which study drug dose is escalated. The select chemistry panel will include the following: BUN, creatinine, total bilirubin, ALP, AST, and ALT.
k Urinalysis will be analyzed locally. See Section 9.4.15.1. for additional details.
l Following a 4- to 7-day washout period after single-dose pevonedistat administration in Part A, starting on Day 1 patients will receive pevonedistat on Days 1, 3, and 5 in 
combination with azacitidine (75 mg/m2) on Days 1 through 7 or Days 1 through 5, 8, and 9 in 28-day cycles. Patients will receive azacitidine SC in Cycle 1. Azacitidine will be given 
SC or IV during Cycle 2 and beyond. On Days 1, 3, and 5, when both study drugs are administered, azacitidine will be administered first, followed by pevonedistat. The pevonedistat 
infusion may be slowed or stopped and restarted for any associated infusion-related reactions. Following sponsor and investigator discussion of the available safety data, patients who 
tolerate treatment well at the initially assigned dose of pevonedistat may be allowed to increase their dose during Cycle 2 or in subsequent cycles of treatment. Eligible patients may 
continue to receive treatment in Part B until they experience symptomatic deterioration or disease progression, treatment is discontinued for another reason, or until the study is 
stopped by the sponsor. See Section 8.0 for details of study drug administration.
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Table B
Part B: Azacitidine and Pevonedistat Plasma and Urine PK Sampling Schedule in Cycle 1 (Patients With 
Hematologic Malignancies Only)
Day
Dosing a
Azacitidine Plasma PK
Pevonedistat Plasma PK
Urine PK for Azacitidine and 
Pevonedistat
Azacitidine
Pevonedistat
Timepoint
Sample
Timepoint
Sample
Timepoint
3
x
Predose
x b
Predose b
x b
Predose c
x (start infusion)
5 minutes (±5 minutes)
x d
0–2 hours postdose interval g
15 minutes (±5 minutes)
x d
30 minutes (±10 minutes)
x d
45 minutes (±10 minutes)
x d
x (end infusion)
1 hour (±10 minutes)
x d,e
End of pevonedistat infusion
x e,f
1.5 hours (±10 minutes)
x d,e
30 minutes (±5 minutes)
x e,h
2 hours (±20 minutes)
x d,e
1 hour (±15 minutes)
x e,h
3 hours (±20 minutes)
x d,e
2 hours (±20 minutes)
x e,h
4 hours (±30 minutes)
x d,e
3 hours (±30 minutes)
x e,h
2-4 hours postdose interval g
5 hours (±30 minutes)
x d,e
4 hours (±30 minutes)
x e,h
7 hours (±30 minutes)
x d,e
6 hours (±30 minutes)
x e,h
4-6 hours postdose interval g
8 hours (±30 minutes)
x h
6–8 hours postdose interval g
4
24 hours (±1 hour)
x i
5
48 hours (±1 hour)
x i, j
IV: intravenous; PK: pharmacokinetic(s); SC: subcutaneous(ly).
a For days when azacitidine is coadministered with pevonedistat, azacitidine will be given first, followed by pevonedistat infusion.
b The predose plasma sample is to be collected within 10 minutes before the start of azacitidine administration.
c Patients should be asked to void completely in a container approximately 30 minutes before administration of the first dose of study drug. An aliquot of this spot urine specimen will
be a predose urine sample. Detailed instructions on the procedure for collection, processing, storage, and shipment of the urine samples will be provided in the Study Manual.
d Samples should be collected after azacitidine SC administration.
e These samples are collected to measure both azacitidine and pevonedistat plasma concentrations.
f The sample is to be collected at the end of pevonedistat infusion (immediately before stopping the IV infusion). The pevonedistat infusion takes approximately 1 hour.
g Postdose intervals are based on completion of azacitidine SC administration.
h The time of sample collection is to be based on the time of completion of pevonedistat IV infusion on Day 3.
i The time of sample collection is to be based on the time of initiation of pevonedistat IV infusion on Day 3.
j The sample is to be collected before the combination dose administration on Day 5.
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Table C
Bone Marrow Collection and Assessment Schedule (Patients with Hematologic Malignancies Only)
Assessment
Screening
Cycle 2
Day 22
(+6 Days)
Cycle 5
(Between
Days 15-28)
Cycle 8
(Between
Days 15-28)
Cycle 11
(Between
Days 15-28)
Subsequent Cycles
(Between Days 15-28);
Every 6 Cycles Thereafter
Relapse
Bone marrow blast count
x a
x b
x b
x b
x b
x b
x
Cytogenetics c
x
x
x 
x 
x 
x 
x
eCRF: electronic case report form; FISH: fluorescence in situ hybridization.
All samples will be collected and analyzed locally.
a At screening and for study eligibility, a bone marrow aspiration and biopsy (performed locally) will be required to assess disease burden, cytogenetics, molecular characterizations, 
and cellular composition by flow cytometry. A bone marrow biopsy (in addition to bone marrow aspirate) is required only at screening to confirm the diagnosis. However, a bone 
marrow biopsy may be collected with bone marrow aspirate in accordance with institutional guidelines. If a biopsy was done within 28 days before enrollment, this archival biopsy 
may be used and does not need to be repeated. If bone marrow biopsy is not collected routinely per country/institutional guidelines, it is not required.
b A bone marrow aspirate for blast count (to determine disease response) will be performed on Day 22 (+6 days) of Cycle 2, and between Days 15 and 28 of Cycle 5, Cycle 8, 
Cycle 11, and then every 6 cycles afterward or otherwise as clinically indicated at the discretion of the investigator. Results must be available before dosing starts in the next cycle.
c Cytogenetics analysis will be done at the clinical site: a bone marrow aspirate sample will be tested according to institutional guidelines in a cytogenetics laboratory routinely used 
by the site. Analyses should be done by karyotype, and by FISH if possible. Results will be collected in the eCRF.
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SOE for Part B: Treatment Cycle 1 (21-Day Cycle) Through EOS (Patients with Advanced Solid Tumors Only)
Day
Cycle 1 and Subsequent Cycles (21 days)
EOS/ET
Day 1
Day 3
Day 4
Day 5
Day 8 a
Day 15 a
Procedure
Window
(±3 day)
(±3 day)
(+10 days) b
Symptom-directed physical 
examination c
x
Complete physical examination
x
Weight
x d
x
Vital signs e
x
x
x
x
ECOG PS f
x
x
12-lead ECG g
x
x
Pregnancy test h
x
x
Hematology i
x
x
x
x
x
x
Complete chemistry panel
x
x
Select chemistry panel j
x
x
x
x
Urinalysis k
x
x
Plasma sample for pevonedistat 
PK (Cycle 1 only, see Table D)
x
x
x
Tumor assessment for solid 
tumors by RECIST, version 1.1 l
To be completed within 28 days before dosing in Part B, end of Cycle 2, Cycle 5, and every 6 cycles thereafter.
x
Pevonedistat IV infusion m
Days 1, 3, and 5 of each cycle.
Chemotherapy IV infusion m
Day 1 of each cycle.
Monitoring of concomitant 
medications and procedures
Recorded from the first dose of any study drug through 30 days (+10) days after the last dose of any study drug.
RBC and platelet transfusion 
documentation
Recorded from 8 weeks before enrollment through 30 days after the last dose of any study drug.
AE/SAE reporting
Recorded from the first dose of any study drug through 30 days (+10) days after the last dose of any study drug.
AEs 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 will be reported from signing of the ICF through 30 days after the last dose of any study drug.
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AE: adverse event; ALP: alkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase; BSA: body surface area; BUN: blood urea nitrogen; 
CT: computerized tomography; ECG: electrocardiogram; ECOG PS: Eastern Cooperative Oncology Group performance status; EOS: end of study; ET: early termination; 
ICF: informed consent form; IV: intravenous(ly); MRI: magnetic resonance imaging; PK: pharmacokinetic(s); RBC: red blood cells; RECIST: Response Evaluation Criteria in Solid 
Tumors; SAE: serious adverse event; SOE: schedule of events
Study completion is defined as completion of study treatment and the EOS visit.
Nonessential protocol visits in Part B 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 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 for the assessments performed are to be captured in the electronic data capture (EDC).
a Hematology samples and select chemistry panels will be collected on Days 8 (±1 day) and 15 (±1 day) in Cycle 1 and in any cycle in which intrapatient dose escalation of any study 
drug occurs.
b The EOS/ET visit will occur 30 days (+10 days) after the last dose of study drugs or before the start of subsequent antineoplastic therapy, if that occurs sooner.
c The symptom-directed physical examination will be conducted within 3 days before dosing on Day 1 of each treatment cycle. The symptom-directed physical examination may be 
performed at other visits during the treatment cycle at the discretion of the investigator.
d 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 H) 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.
e Vital signs, including diastolic and systolic blood pressure, heart rate, and body temperature will be collected predose (30 minutes [±10 minutes]) before the infusion of pevonedistat 
and 30 minutes (±10 minutes) after the start of the pevonedistat infusion on Days 1, 3, and 5 of each cycle, at EOS/ET, and as clinically indicated at the discretion of the investigator. 
On Cycle 1 Day 1, vital signs are to be measured predose (20 minutes [±10 minutes]) before the infusion of pevonedistat, 30 minutes (±10 minutes) after the start of the pevonedistat 
infusion, and 30 min (±10 minutes) after the completion of the pevonedistat infusion. Vital sign measurements will be taken with the patient in the supine (after 3-5 minutes in this 
position) or sitting position (after 3-5 minutes in this position). Either oral or axial body temperature may be used, but the same method for measuring body temperature (oral or axial) 
should be used consistently for the same patient throughout the study.
f ECOG PS will be performed within 3 days before the beginning (Day 1) of each treatment cycle and at the EOS/ET visit.
g A 12-lead ECG will be performed Day 1 predose of every cycle and at EOS/ET. Predose assessment may be performed up to 3 days in advance if necessary. Additional ECGs may 
be obtained as clinically indicated at the discretion of the investigator. ECG assessments are to be performed with the patient supine and rested for 5 minutes.
h A serum pregnancy test will be performed for women of childbearing potential within 3 days before Day 1 of each cycle and at EOS/ET. The results from these tests must be 
available and negative before the study drug is administered on Day 1. If the Day 1 serum pregnancy results will not be available before dosing, a urine pregnancy test may be 
performed.
i Hematology samples will be collected before infusion with study drug(s) on Days 1, 3, and 5, and EOS/ET. Samples may be drawn up to 1 day before dosing. If dosing falls on a 
Monday, the collection window may be extended to collect samples on the previous Friday. Additional collections on Days 8 (±1 day) and 15 (±1 day) will be performed in Cycle 1 
or in any cycle in which study drug dose is escalated.
j The select chemistry panel will be collected predose on Days 3 and 5 and will include the following: BUN, creatinine, total bilirubin, ALP, AST, and ALT. On Days 3 and 5 samples 
may be drawn up to 1 day before dosing. If dosing falls on a Monday, the collection window may be extended to collect samples on the previous Friday. Additional collections on 
Days 8 (±1 day) and 15 (±1 day) will be performed in Cycle 1 or in any cycle in which study drug dose is escalated.
k Urinalysis will be analyzed locally. See Section 9.4.15.1. for additional details.
l Tumor assessment will be performed before the start of the study and at the completion of Cycle 2, Cycle 5, and every 6 cycles thereafter in Part B. Patients will undergo CT (with 
IV contrast, except for patients with an allergy to contrast agents), MRI, x-ray, and/or bone scanning to monitor and assess disease progression. If the anatomic region cannot be 
adequately imaged by CT, MRI may be used instead; see Section 9.4.17.2. An EOS/ET CT scan does not need to be completed/repeated if a scan was performed within the previous 
28 days. Response will be determined according to RECIST version 1.1.
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m The investigator will select which chemotherapy (docetaxel or carboplatin plus paclitaxel) that each patient will receive in combination with pevonedistat. Following a 4- to 7-day 
washout period after single-dose pevonedistat administration in Part A, starting on Cycle 1 Day 1, patients will receive pevonedistat and chemotherapy agents on Day 1 and 
pevonedistat alone on Days 3 and 5 in 21-day cycles. The infusion of pevonedistat may be slowed or stopped and restarted for any associated infusion-related reactions. Following 
sponsor and investigator discussion of the available safety data, patients who tolerate treatment well at the initially assigned dose of pevonedistat may be allowed to increase their dose 
during Cycle 2 or in subsequent cycles of treatment. The chemotherapeutic agent may be dose reduced because of toxicities in accordance with Section 8.3.2.3. See Section 8.0 for the 
details of study drug administration.
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Table D
Part B: Pevonedistat Plasma PK Sampling Schedule in Cycle 1 (Patients with Advanced Solid Tumors)
Day
Dosing
Pevonedistat Plasma PK
Pevonedistat
Timepoint
Sample
3
Predose a
x a
x (start infusion)
x (end infusion)
End of pevonedistat infusion
x b
30 minutes (±5 minutes)
x c
1 hour (±15 minutes)
x c
2 hours (±20 minutes)
x c
3 hours (±30 minutes)
x c
4 hours (±30 minutes)
x c
6 hours (±30 minutes)
x c
8 hours (±30 minutes)
x c
4
24 hours (±1 hour)
x d
5
48 hours (±1 hour)
x d
IV: intravenous; PK: pharmacokinetic(s).
a The predose plasma sample is to be collected within 10 minutes before the start of pevonedistat infusion.
b The sample is to be collected at the end of pevonedistat infusion (immediately before stopping the IV infusion). The pevonedistat infusion takes approximately 1 hour.
c The time of sample collection is to be based on the time of completion of pevonedistat IV infusion on Day 3.
d The time of sample collection is to be based on the time of initiation of pevonedistat IV infusion on Day 3.
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Appendix B
Study Diagrams
D: Day; IV: intravenous; PK: pharmacokinetic; SC: subcutaneous
In Part A, patients will receive a singe IV dose of pevonedistat for PK assessment. In Part B, patients with hematologic 
malignancies will receive an IV infusion of pevonedistat on Days 1, 3, and 5 in combination with 75 mg/m2 
azacitidine on Days 1-7 or Days 1–5, 8, and 9 in a 28 -day treatment period. Patients will receive azacitidine SC during 
Cycle 1 of Part B (PK assessment period). Azacitidine will be administered SC or IV during Cycle 2 and beyond. Part 
B may start 4–7 days after the dose of pevonedistat administered in Part A. Intrapatient dose escalation may start in 
Cycle 2 or in subsequent cycles.
See Section 8.1 for details of study drug administration.
0- 8hr 24hr
48hr
72hr
0- 8hr 24hr
48hr
D1
D2
D3
D 4
D1
D2
D3
D4
D5
D6
D7
D8
D9
D10
D 28
urine*
Pevonedistat dose
Azacitidine dose
sample collection for PK 
*
Urine collection for PK
Part B
[4-7 days]
Part A
[WASHOUT]
PEVONEDISTAT
Days 1 through 5, 8 and 9 
AZACITIDINE
OR
Days 1 through 7 
PEVONEDISTAT
20 mg/m2
SCREENING 
(28 days)
PEVONEDISTAT-1016   PART A: SINGLE DOSE PEVONEDISTAT AND PART B: PEVONEDISTAT IN 
COMBINATION WITH AZACITIDINE (PATIENTS WITH HEMATOLOGIC MALIGNANCIES)
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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 subjects before the receipt of written 
approval from relevant governing bodies/authorities.
5. Ensure that all colleagues and employees assisting in the conduct of the study are informed of 
these obligations.
6. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform to 
21 CFR Part 56, ICH and local regulatory requirements.
7. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and approval 
of the protocol. Promptly report to the IRB/IEC all changes in research activity and all 
anticipated risks to subjects. Make at least yearly reports on the progress of the study to the 
IRB/IEC, and issue a final report within 3 months of study completion.
8. Ensure that requirements for informed consent, as outlined in 21 CFR Part 50, ICH and local 
regulations, are met.
9. Obtain valid informed consent from each subject who participates in the study, and document 
the date of consent in the subject’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each ICF should contain a subject authorization section that 
describes the uses and disclosures of a subject’s personal information (including personal 
health information) that will take place in connection with the study. If an ICF does not include 
such a subject authorization, then the investigator must obtain a separate subject authorization 
form from each subject or the subject’s legally acceptable representative.
10. Prepare and maintain adequate case histories of all persons entered into the study, including 
eCRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
2 years following notification by the sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
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contact and receive written approval from the sponsor before disposing of any such 
documents.
11. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
12. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor.
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
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, 1982 [21].
ECOG: Eastern Cooperative Oncology Group.
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Appendix E
Definition of Postmenopausal
A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause. A high FSH level in the postmenopausal range may be used to confirm a postmenopausal 
state in women not using hormonal contraception or hormonal replacement therapy. However, in 
the absence of 12 months of amenorrhea, a single FSH measurement is insufficient. Please refer to 
the following source for additional information: European Heads of Medicines Agencies Clinical 
Trial Facilitation Group; see 
hma.eu/fileadmin/dateien/Human_Medicines/01-About_HMA/Working_Groups/CTFG/2014_09
_HMA_ CTFG_Contraception.pdf.
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Appendix F
Acceptable Methods of Contraception Considered Highly Effective
Birth control methods that can achieve a failure rate of less than 1% per year when used 
consistently and correctly are considered to be highly effective. Such methods include the 
following:

Combined (estrogen and progestogen–containing) hormonal contraception associated with 
inhibition of ovulation a:
–
Oral.
–
Intravaginal.
–
Transdermal.

Progestogen-only hormonal contraception associated with inhibition of ovulation a:
–
Oral.
–
Injectable.
–
Implantable. b

Intrauterine device. b

Intrauterine hormone-releasing system. b

Bilateral tubal occlusion. b

Vasectomized partner. b,c

Sexual abstinence. d
Methods Considered Less Highly Effective
Acceptable birth control methods that result in a failure rate of more than 1% per year include the 
following:

Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mode of action.

Male or female condom with or without spermicide. e

Cap, diaphragm, or sponge with spermicide. e
a Hormonal contraception may be susceptible to interaction with the investigational medicinal product, which may 
reduce the efficacy of the contraception method.
b Contraception methods that, in the context of this guidance, are considered to have low user dependency.
c Vasectomized partner is a highly effective birth control method provided that partner is the sole sexual partner of the 
woman of childbearing potential participant of the study and that the vasectomized partner has received medical 
assessment of the surgical success.
d In the context of this guidance, sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of 
sexual abstinence needs to be evaluated in relation to the duration of the clinical study and the preferred and usual 
lifestyle of the subject.
e A combination of male condom with either cap, diaphragm, or sponge with spermicide (double-barrier methods) is 
also considered an acceptable, but not a highly effective, birth control method.
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Appendix G
New York Heart Association Classification of Cardiac Disease
The following table presents the New York Heart Association classification of cardiac disease 
[22].
Class
Functional Capacity
Objective Assessment
I
Patients with cardiac disease but without resulting limitations of physical 
activity. Ordinary physical activity does not cause undue fatigue, palpitation, 
dyspnea, or anginal pain.
No objective evidence of 
cardiovascular disease
II
Patients with cardiac disease resulting in slight limitation of physical activity. 
They are comfortable at rest. Ordinary physical activity results in fatigue, 
palpitation, dyspnea, or anginal pain.
Objective evidence of 
minimal cardiovascular 
disease
III
Patients with cardiac disease resulting in marked limitation of physical 
activity. They are comfortable at rest. Less than ordinary activity causes 
fatigue, palpitation, dyspnea, or anginal pain.
Objective evidence of 
moderately severe 
cardiovascular disease
IV
Patients with cardiac disease resulting in inability to carry on any physical 
activity without discomfort. Symptoms of heart failure or the anginal 
syndrome may be present even at rest. If any physical activity is undertaken, 
discomfort is increased.
Objective evidence of 
severe cardiovascular 
disease
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Appendix H
BSA Calculation
BSA should be calculated using a standard formula. An example formula follows:
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Appendix I
Formula for ANC Calculation
ANC = total leukocyte count × total percentage of neutrophils (segmented neutrophils + band 
neutrophils)
Example:
If total leukocyte count = 4.3 × 103/L; segmented neutrophils = 48%; band neutrophils = 2%
Then:
ANC = 4300 × (0.48 + 0.02) = 4300 × 0.5 = ANC of 2150
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Appendix J
Response Criteria for MDS, CMML, AML, and Solid Tumors
Response Criteria for Altering Natural History of MDS and CMML
Category
Response Criteria
CR
Bone marrow: ≤5% myeloblasts with normal maturation of all cell lines a
Persistent dysplasia will be noted a
Peripheral blood b
Hgb ≥11 g/dL
Platelets ≥100 109/L
Neutrophils ≥1.0 109/L
Blasts 0%
PR
All CR criteria if abnormal before treatment except:
Bone marrow blasts decreased by ≥50% over pretreatment but still >5%
Cellularity and morphology not relevant
Marrow CR
Bone marrow: ≤5% myeloblasts and decrease by ≥50% over pretreatment
Peripheral blood: any HI responses (see Table, below) will be noted separately, in addition to 
marrow CR
Stable disease
Failure to achieve at least PR, but no evidence of progression for >8 weeks
If a patient has <50% increase in blast count from pretreatment, then this is stable disease and 
the patient should remain on study
Failure
Death during treatment or PD (as defined below), or progression to AML or a more advanced 
MDS or CMML FAB/WHO subtype than pretreatment
Relapse after CR or 
PR
At least one of the following:
Return to pretreatment bone marrow blast percentage
Decrement of ≥50% from maximum remission/response levels in granulocytes or platelets
Note: Transient cytopenias during chemotherapy courses should not be considered relapse, 
as long as they recover to the previous levels
Reduction in Hgb concentration by ≥1.5 g/dL or transfusion dependence
Cytogenic response
Complete
Disappearance of the chromosomal abnormality without appearance of new ones
Partial
At least 50% reduction of the chromosomal abnormality 
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Category
Response Criteria
Progressive disease 
(PD)
Note: Transient cytopenias during chemotherapy courses should not be considered PD, as 
long as they recover to the previous levels; progression based on blood values should not be 
considered at all until after the post-Cycle 4 marrow draw
If a patient has ≥50% increase in blast count from pretreatment (without AML 
transformation) but is still deriving benefit from this treatment (eg, improvement in 
peripheral blood counts), the patient may continue on study as agreed by the investigator and 
the sponsor’s project clinician (or designee)
For patients with:

Less than 5% blasts: ≥50% increase in blasts to >5% blasts.

5%-9% blasts: ≥50% increase to >10% blasts.

10%-19% blasts: ≥50% increase to >20% blasts.

20%-30% blasts.
Any of the following:

At least 50% decrement from maximum remission/response in granulocytes or platelets.

Reduction in Hgb by ≥2 g/dL.

New transfusion dependence.
To convert hemoglobin from grams per deciliter to grams per liter, multiply grams per deciliter by 10.
AML: acute myelogenous leukemia; CMML: chronic myelomonocytic leukemia; CR: complete response/remission; 
DFS: disease-free survival; FAB: French-American-British; Hgb: hemoglobin; HI: hematologic improvement; MDS: 
myelodysplastic syndromes; PFS: progression-free survival; PR: partial response/remission; WHO: World Health 
Organization.
a Dysplastic changes should consider the normal range of dysplastic changes.
b Transient cytopenias during repeated chemotherapy courses should not be considered as interrupting durability of 
response, as long as they recover to the improved counts of the previous course.
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Response Criteria for HI for MDS and CMML
HI a
Response Criteria (Responses Must be At Least 8 Weeks in Duration)
Erythroid response (pretreatment, <11 
g/dL)
Hgb increase by ≥1.5 g/dL
Relevant reduction of units of RBC transfusions by an absolute number of at 
least 4 RBC transfusions/8 weeks compared with the pretreatment 
transfusion number in the previous 8 weeks. Only RBC transfusions given 
for a Hgb of ≤9.0 g/dL pretreatment will count in the RBC transfusion 
response evaluation.
Platelet response (pretreatment, 
<100 109/L)
Absolute increase of ≥30 109/L for patients starting with >20 109/L 
platelets
Increase from <20 109/L to >20 109/L and by at least 100% 
Neutrophil response (pretreatment, 
<1.0 109/L)
At least 100% increase and an absolute increase >0.5 109/L
Progression or relapse after HI b
At least one of the following:

At least 50% decrement from maximum response levels in granulocytes 
or platelets.

Reduction in Hgb by ≥1.5 g/dL.

Transfusion dependence.
To convert hemoglobin levels from grams per deciliter to grams per liter, multiply grams per deciliter by 10.
CMML: chronic myelomonocytic leukemia; Hgb: hemoglobin; HI: hematologic improvement; 
MDS: myelodysplastic syndromes; RBC: red blood cell.
a Pretreatment counts will be the average of screening and Cycle 1 Day 1 predose samples.
b In the absence of another explanation, such as acute infection, a course of chemotherapy, gastrointestinal bleeding, 
hemolysis, and so forth. The 2 kinds of erythroid and platelet responses should be reported overall as well as by the 
individual response pattern.
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Response Criteria for AML
Category
Response Criteria
Morphologic complete 
remission (CR)
A CR designation requires that the patient achieve the morphologic leukemia-free state and 
have an ANC of more than 1000/µL and platelets of ≥100,000/µL. A morphologic 
leukemia-free state requires less than 5% blasts in an aspirate sample with marrow spicules 
and with a count of at least 200 nucleated cells. Hemoglobin concentration or hematocrit has 
no bearing on remission status, although the patient must be independent of transfusions. 
There should be no residual evidence of extramedullary leukemia.
Morphologic complete 
remission with 
incomplete blood 
count recovery (CRi)
After chemotherapy, some patients fulfill all of the criteria for CR except for residual 
neutropenia (<1000/µL) or thrombocytopenia (<100,000/µL).
Cytogenetic CR
Reversion to a normal karyotype at CR or CRi.
Partial remission (PR)
This designation requires all of the hematologic values for a CR but with a decrease of at 
least 50% in the percentage of blasts to 5% to 25% in the bone marrow aspirate. Thus, if the 
pretreatment bone marrow blast percentage was 50% to 100%, the percentage of blasts must 
decrease to a value between 5% and 25%; if the pretreatment blast percentage was 20% to 
less than 49%, they must decrease by at least half to a value of more than 5%. A repeat bone 
marrow aspiration after several weeks may be required to distinguish between a PR and 
increased blasts caused by bone marrow regeneration. A value of ≤5% blasts may also be 
considered a PR if Auer rods are present.
Progressive disease 
(PD)
Because the IWG criteria for AML do not provide a standardized definition for PD [5], PD is 
defined in this protocol as one of the following:

>50% increase in bone marrow blasts from baseline value to >30% blasts.

>50% increase in circulating blasts from baseline value to >30% blasts in peripheral 
blood (in the exceptional case when bone marrow examination is not possible).

Development of biopsy-proven extramedullary disease, or new sites of extramedullary 
leukemia.
Relapse after CR
Relapse after CR is defined as a reappearance of leukemic blasts in the peripheral blood 
or >5% blasts in the bone marrow not attributable to any other cause (eg, bone marrow 
regeneration after consolidation therapy). In the setting of recent treatment, if there are no 
circulating blasts and the bone marrow contains 5% to 20% blasts, a repeat bone marrow 
performed at least a week later is necessary to distinguish relapse from bone marrow 
regeneration.
AML: acute myelogenous leukemia; ANC: absolute neutrophil count; IWG: International Working Group.
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Response Criteria for Target and Nontarget Lesions in Solid Tumors
Evaluation of Target Lesions
CR
Disappearance of all target lesions. Any pathological lymph nodes (whether target or nontarget) must 
have reduction in short axis to <10 mm.
Partial 
response
At least a 30% decrease from baseline in the sum of diameters of target lesions, taking as reference the 
baseline sum of diameters.
PD
At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on 
study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase 
of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of 1 or 
more new lesions is also considered progression.
SD
Neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for PD, 
taking as reference the smallest sum of diameters while on study.
Evaluation of Nontarget Lesions
CR
Disappearance of all nontarget lesions and normalization of tumor marker level. All lymph nodes must 
be nonpathological in size (<10 mm short axis). 
Non-CR/ 
Non-PD 
Persistence of one or more nontarget lesion(s) or/and maintenance of tumor marker level above the 
normal limits.
PD
Appearance of one or more new lesions and/or unequivocal progression of existing nontarget lesions.
Source: Eisenhauer, 2009 [23].
CR: complete response/remission; PD: progressive disease; SD: stable disease.
Overall Disease Response Criteria for Target and Nontarget Lesions in Solid Tumors
Target Lesions
Nontarget Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/Non-PD
No
Partial response
CR
Not evaluated
No
Partial response
PR
Non-PD or not all evaluated
No
Partial response
SD
Non-PD or not all evaluated
No
SD
Not all evaluated
Non-PD
No
Inevaluable
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
Source: Eisenhauer, 2009 [23].
CR: complete response/remission; PD: progressive disease; SD: stable disease.
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Appendix K
Drugs Associated With Nephrotoxicity
The drugs listed in the table below are permitted to be used during the conduct of this study but 
should be used with caution.
Drugs Associated With Nephrotoxicity
Analgesics
Cardiovascular agents
Nonsteroidal anti-inflammatory drugs
Angiotensin-converting enzyme inhibitors, angiotensin 
receptor blockers
Antidepressants/mood stabilizers
Clopidogrel (Plavix), ticlopidine (Ticlid)
Lithium
Contrast dye
Antimicrobials
Diuretics
Acyclovir (Zovirax)
Loops, thiazides
Aminoglycosides
Triamterene (Dyrenium)
Amphotericin B (Fungizone; deoxycholic acid 
formulation more so than the lipid formulation)
Herbals
Beta lactams (penicillins, cephalosporins)
Chinese herbals with aristolochic acid
Foscarnet (Foscavir)
Others
Ganciclovir (Cytovene)
Allopurinol (Zyloprim)
Pentamidine (Pentam)
Gold therapy
Quinolones
Haloperidol (Haldol)
Rifampin (Rifadin)
Pamidronate (Aredia)
Sulfonamides
Phenytoin (Dilantin)
Vancomycin (Vancocin)
Quinine (Qualaquin)
Antiretrovirals
Zoledronate (Zometa)
Adefovir (Hepsera), cidofovir (Vistide), tenofovir 
(Viread)
Indinavir (Crixivan)
Calcineurin inhibitors
Cyclosporine (Neoral)
Tacrolimus (Prograf)
Source: Modified from Naughton, 2008 [16].
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Pevonedistat (TAK-924/MLN4924)
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Page 127 of 134
Protocol Incorporating Amendment 4
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CONFIDENTIAL
Appendix L
Hematologic Toxicity of Carboplatin Alone and in Combination With 
Paclitaxel
In 2 prospectively randomized, controlled studies conducted by the National Cancer Institute of 
Canada Clinical Trials Group and the Southwest Oncology Group, 789 chemotherapy-naïve 
patients with advanced ovarian cancer were treated with carboplatin or cisplatin in combination 
with cyclophosphamide every 28 days for 6 courses before surgical re-evaluation. See the table 
below for the hematologic adverse experiences of patients treated with carboplatin in combination 
with cyclophosphamide.
Hematologic Adverse Experiences of Patients With Ovarian Cancer Treated With 
Carboplatin in Combination With Cyclophosphamide
Adverse Experience
Laboratory Value
NCIC CTG Study
% Patients
(N=447)
SWOG Study
% Patients
(N=342)
Bone marrow
Thrombocytopenia
<100,000/mm3
70
59
<50,000/mm3
41
22
Neutropenia
<2000 cells/mm3
97
95
<1000 cells/mm3
81
84
Leukopenia
<4000 cells/mm3
98
97
<2000 cells/mm3
68
76
Anemia
<11 g/dL
91
88
<8 g/dL
18
8
Infections
14
18
Bleeding
10
6
Transfusions
42
25
Source: Carboplatin US Package Insert 2011 [14].
NCIC CTG: National Cancer Institute of Canada Clinical Trials Group; SWOG: Southwest Oncology Group.
In a randomized clinical study, 798 patients with ovarian cancer were treated with either cisplatin 
plus paclitaxel or paclitaxel plus carboplatin therapy at 3-week intervals for 6 courses. See the 
table below for the hematologic adverse experiences of patients treated with 
paclitaxel/carboplatin.
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Protocol Incorporating Amendment 4
27 May 2021
CONFIDENTIAL
Hematologic Toxicities and Associated Supportive Care in Patients With Advanced Ovarian Cancer Stratified by Treatment 
Arm and Toxicity Grade
NCI CTC Grade, %
Difference a in the Proportions 
of Patients With Grades 3/4 
Toxicity, %
Paclitaxel+Carboplatin Arm
Cisplatin+Paclitaxel Arm
Toxicity
Set
N
0
1
2
3
4
N
0
1
2
3
4
E
95% CI
Hemoglobin
C
2209
29.1
49.4
20.1
1.3
0.1
2095
33.6
49.5
16.1
0.8
0.0
-0.6
-1.3 to 0.0
P
388
9.0
40.7
44.3
5.4
0.5
382
14.7
44.2
37.2
3.9
0.0
-2.0
-5.1 to 1.1
Platelets
C
2193
71.9
19.9
5.2
2.5
0.5
2082
93.4
6.2
0.2
0.2
0.0
-2.9
-3.6 to -2.1
P
388
43.3
31.2
12.6
10.1
2.8
382
78.3
19.4
1.3
1.0
0.0
-11.8
-15.3 to -8.4
Transfusions pRBCs 
a
C
1868
94.3
--
--
5.7
--
1766
97.2
--
--
2.8
--
-2.9
-4.2 to -1.6
P
383
81.7
--
--
18.3
--
370
89.5
--
--
10.5
--
-7.7
-12.7 to -2.8
Leukocytes (WBC)
C
2200
37.0
22.6
29.3
10.8
0.3
2073
56.4
23.3
17.3
2.9
0.0
-8.1
-9.6 to -6.6
P
388
13.4
16.0
38.7
30.4
1.5
382
31.4
35.1
32.7
10.5
0.3
-21.2
-26.8 to -15.6
Neutrophils
C
1842
56.9
12.9
12.8
12.4
5.0
1864
70.9
10.6
9.8
6.4
2.3
-8.7
-10.8 to -6.5
P
371
31.3
12.9
18.9
21.6
15.4
373
48.0
13.1
16.9
15.0
7.0
-14.9
-21.4 to -8.5
Febrile neutropenia
C
2228
98.3
--
--
1.7
0.0
2110
99.3
--
--
0.7
0.0
-0.9
-1.6 to -0.3
P
388
92.0
--
--
8.0
0.0
384
96.4
--
--
3.6
0.0
-4.3
-7.6 to -1.1
Supportive care: 
antibiotics b
C
1868
98.3
--
--
1.7
--
1768
97.9
--
--
2.1
--
0.4
-0.5 to 1.3
P
383
93.2
--
--
6.8
--
370
90.5
--
--
9.5
--
2.7
-1.2 to 6.6
Supportive care: 
G-CSF b
C
1868
94.0
--
--
6.0
--
1767
98.2
--
--
1.8
--
-4.2
-5.5 to -3.0
P
383
85.6
--
--
14.4
--
370
95.4
--
--
4.6
--
-9.8
-13.9 to -5.7
Source: du Bois, 2003 [24].
The symbol “--” denotes “not defined.”
C: maximum grade over all courses; G-CSF: granulocyte colony stimulating factor; E: estimate; N: number of courses in set C and number of patients in set P; NCI CTC: National 
Cancer Institute Common Toxicity Criteria; P: maximum grade over all courses within a patient; pRBCs: packed red blood cells; WBC: white blood cell.
a Differences are calculated by subtracting the paclitaxel+carboplatin arm proportion from the cisplatin+paclitaxel arm proportion; statistically significant differences in proportions 
between the 2 treatment arms are in bold font. All percentages are rounded to 1 decimal place; therefore, the estimates may differ by ±1 from the difference of the percentages of the 
treatment arm columns.
b Transfusion of pRBCs and use of antibiotics and G-CSF were not assessed for the last treatment cycle within a patient. Use of antibiotics and use of G-CSF are graded in the same 
fashion as transfusion of pRBCs. Use of antibiotics/application of G-CSF is coded as a toxicity of Grade 3; a Grade 0 is applied otherwise.
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Protocol Incorporating Amendment 4
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CONFIDENTIAL
Appendix M Excluded Strong CYP3A Inhibitors and Inducers
Use of strong CYP3A inhibitors and inducers listed in the table below should be avoided during 
pevonedistat therapy unless otherwise noted in the protocol.
In Vivo Inhibitors and Inducers of CYP3A
Strong Inhibitors
Strong Inducers
Clarithromycin
Carbamazepine
Idelalisib
Phenytoin
Itraconazole
Phenobarbital
Ketoconazole
Primidone
Nefazodone 
Rifabutin
Posaconazole 
Rifampin
Telithromycin 
Rifapentine
Voriconazole
St. John’s wort
CYP: cytochrome P450.
Strong CYP3A inhibitors and inducers should only be excluded during the Part A and Cycle 1 of Part B of the study 
where the pevonedistat pharmacokinetic measurements are conducted.
This is not an exhaustive list; refer to the following source: 
https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhi
bitors-and-inducers.
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Protocol Incorporating Amendment 4
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CONFIDENTIAL
Appendix N
Protocol History
Amendment History:
Date
Amendment No.
Amendment Type
Region
27 May 2021
4
Substantial
Global
04 November 2020
3
Substantial
Global
29 June 2020
2
Substantial
Global
25 February 2019
1
Substantial
Global
07 November 2018
Initial protocol
Not applicable
Global
Rationale for Amendment 3
This document describes the changes in reference to the protocol incorporating Amendment 3 The 
primary reason for this amendment is to incorporate changes requested by global health authorities. 
In addition, this amendment permits alternative clinical site monitoring approaches, if needed, and 
where allowed by the local health authority, privacy laws, and permitted by the institutional review 
board/ethics committee (IRB/IEC). These changes to alternative monitoring procedures are 
intended to minimize the impact of the coronavirus disease-2019 (COVID-19) pandemic while 
ensuring data quality and integrity.
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 3
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.
Add use of strong cytochrome 
P450 (CYP)3A inducers within 
14 days of baseline to the list of 
exclusion criteria.
2.
Add strong CYP3A inducers 
and inhibitors to the list of 
excluded concomitant 
medications.
Although strong CYP3A inhibitors 
and inducers did not have clinically 
meaningful impact on pevonedistat 
systemic exposures based on results 
from Studies C15011 and 
Pevonedistat-1015, strong CYP3A 
inhibitors and inducers remain 
prohibited in this study in order to 
interpret the effects of organ 
impairment on pevonedistat PK 
without potential confounding 
factors.
Change made in response to 
protocol review by global health 
authorities.
Section 2.0 STUDY SUMMARY
Section 4.1.3.1 Clinical 
Pharmacokinetics
Section 4.1.5 Potential for DDIs
Section 7.2 Exclusion Criteria
Section 8.4 Excluded Concomitant 
Medications and Procedures, 
including Table 8.f Concomitant 
Medications Excluded While 
Receiving Study Treatment: 
Combination Pevonedistat Plus 
SOC agents
Appendix M Excluded Strong 
CYP3A Inhibitors and Inducers
3.
Provide alternative clinical site 
monitoring approaches due to 
the COVID-19 pandemic.
To ensure data quality and integrity 
and maintain patient safety during 
the COVID-19 pandemic.
Section 14.1 Study Site Monitoring 
Visits
Appendix A SOE Table B 
Footnotes
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Protocol Incorporating Amendment 4
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CONFIDENTIAL
Protocol Amendment 3
Summary of Changes Since the Last Version of the Approved Protocol
Description of Each Change and Rationale
Sections Affected by Change
Description
Rationale
Location
4.
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 2.0 STUDY SUMMARY
Section 7.1 Inclusion Criteria
Section 7.2 Exclusion Criteria
Section 8.6 Precautions and 
Restrictions
5.
Added patients with previously 
untreated hematologic 
malignancies not suitable for 
induction therapy to inclusion 
criteria.
Clarified to make Inclusion Criteria 
section consistent with Overview of 
Study Design section.
Section 2.0 STUDY SUMMARY
Section 7.1 Inclusion Criteria
6.
Updated azacitidine dosing to 
permit subcutaneous (SC) or 
intravenous (IV) dosing during 
Cycle 2 and beyond in Part B.
7.
Updated azacitidine dosing 
schedule to permit dosing on 
Days 1 through 7 or Days 1 
through 5, 8, and 9 in 28-day 
cycles in Part B.
Clarified that azacitidine 
administration by SC and IV routes 
is permissible as per the United 
States Prescribing Information 
(USPI) and Summary of Product 
Characteristics (SmPC) and has 
been studied in Study C15009.
Section 2.0 STUDY SUMMARY
Section 6.1 Overview of Study 
Design
Section 8.1 Study Drug 
Administration
Section 8.1.1 Instructions for 
Pevonedistat and Azacitidine 
Dosing
Section 9.3 Treatment Group 
Assignments
Appendix A SOE Table A 
Footnote l
Appendix A SOE Table B 
Footnote a
Appendix B Study Diagrams
8.
Updated eligibility criterion to 
emphasize the role of patient’s 
legally acceptable 
representative for voluntary 
written consent.
Clarified potential role of the 
patient’s legally acceptable 
representative for consistency with 
existing language in 
Section 15.2 Subject Information, 
Informed Consent, and Subject 
Authorization.
Section 2.0 STUDY SUMMARY
Section 7.1 Inclusion Criteria, #9
Section 9.4.1 Informed Consent
9.
Updated protocol amendment 
history sections.
Change made to reflect the current 
format being used by the sponsor.
Section 1.3 Protocol Amendment 3 
Summary of Changes
Appendix N Protocol History
RATIONALE FOR AMENDMENT 2
The primary reasons for Amendment 2 were to include patients with moderate hepatic impairment 
in the study and to allow enrollment of patients with advanced solid tumors with severe renal 
impairment or mild or moderate hepatic impairment. These changes expanded participation in the 
organ impairment arms of the study without compromising the safety of the study participants or 
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Protocol Incorporating Amendment 4
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CONFIDENTIAL
the primary objectives of the study. For patients with solid tumors to be enrolled in this study, they 
must have had histologically or cytologically confirmed metastatic or locally advanced solid 
tumor(s), appropriate for treatment with one of the 2 combination therapies in Part B (docetaxel or 
carboplatin/paclitaxel), that had progressed despite standard therapy. Patients with solid tumors 
for whom conventional therapy was not considered effective were also eligible for enrollment. As 
patients with combined abnormalities of transaminases and alkaline phosphatase should not be 
treated with docetaxel [20], it was to only be administered to patients in the severe renal 
impairment arm.
Other modifications to the study design included removing the determination of the maximum 
tolerated dose (MTD) and recommended phase 2 dose (RP2D) of pevonedistat in combination 
with azacitidine in patients with organ impairment in Part A and adding assessment of the 
pharmacokinetics (PK) and safety of pevonedistat in combination with azacitidine in these specific 
patient populations in Part B. In addition, an evaluation of the safety of pevonedistat in 
combination with carboplatin plus paclitaxel in patients with mild or moderate hepatic impairment, 
or in combination with carboplatin plus paclitaxel or with docetaxel in patients with severe renal 
impairment, was to be performed in Part B of the study.
Minor grammatical, editorial, formatting, and administrative changes not affecting the conduct of 
the study were included for clarification and administrative purposes only.
Changes in Amendment 2
1. Include patients with advanced solid tumors in the single-dose pevonedistat PK assessment in 
Part A and, if eligible, continue treatment with pevonedistat in combination with standard of 
care (SOC) chemotherapy (docetaxel or carboplatin plus paclitaxel) in Part B.
2. Include patients with moderate hepatic impairment in the assessment of pevonedistat PK in 
patients with organ impairment.
3. Remove dose escalation phase and determination of MTD/RP2D for pevonedistat in 
combination with azacitidine in patients with hematologic malignancies (myelodysplastic 
syndromes [MDS], chronic myelomonocytic leukemia [CMML], and acute myelogenous 
leukemia) from Part A.
4. Add secondary objectives to assess the PK of pevonedistat and azacitidine in combination 
treatment in patients with hematologic malignancies/organ impairment and to assess the PK of 
pevonedistat in patients with advanced solid tumors/organ impairment receiving combination 
treatment with SOC agents.
5. Revise starting dose, maximum dose, and intrapatient dose escalation rules for each of the 
organ impairment arms in the study.
6. Add dose modification guidelines for patients with advanced solid tumors treated with 
pevonedistat in combination with SOC agents.
7. Revise guidelines for pevonedistat dose adjustment based on serum transaminases, total 
bilirubin, and other toxicities.
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Protocol Incorporating Amendment 4
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CONFIDENTIAL
8. Add guidance for management of cytopenia and infection for patients with hematologic 
malignancies and for use of granulocyte-colony stimulating factor in patients with advanced 
solid tumors.
9. Add inclusion and exclusion criteria for patients with advanced solid tumors.
10. Revise laboratory values required for enrollment to include patients with moderate hepatic 
impairment.
11. Add inclusion criterion to indicate that all patients should have an expected survival of at least 
3 months from the date of enrollment in the study.
12. Clarify that medical history and diagnosis-related inclusion criteria for patients with 
hematologic malignancies must be met at study entry.
13. Add exclusion criterion for patients diagnosed or treated for a different malignancy within 
2 years before enrollment or previously diagnosed with a different malignancy with any 
current evidence of residual disease (excluding prior MDS or CMML).
14. Add exclusion criterion for patients with end-stage renal disease requiring hemodialysis.
15. Add exclusion criterion for patients with Gilbert syndrome.
16. Remove use of strong cytochrome P450 (CYP)3A inducers within 14 days of baseline from 
list of exclusion criteria and remove strong CYP3A inducers and known breast cancer 
resistance protein inhibitors from the list of excluded concomitant medications.
17. Clarify and add exclusion criteria for patients with cardiovascular conditions.
18. Update the number of patients to be enrolled in the study and increase the number of study sites 
to approximately 25 to 30 sites.
19. Update vial volume and dilution instructions for pevonedistat to include a vial volume of 
4.4 mL and a diluent of 0.9% saline solution.
20. Increase study duration to 3.5 years.
21. Clarify timing for collection of plasma samples for measuring pevonedistat protein binding.
22. Specify that adverse events 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).
23. Specify that nonessential protocol visits that do not require on-site sample collection and
assessment may be completed via telemedicine.
RATIONALE FOR AMENDMENT 1
The primary reason for Amendment 1 was to remove eligibility criteria relevant to the absolute 
neutrophil count (ANC), platelets, and hemoglobin to be consistent with other studies in the 
pevonedistat program. Patients with hematologic malignancy (acute myeloid leukemia [AML] and 
myelodysplastic syndromes [MDS]) suffer from cytopenia and/or anemia related to their 
underlying illness, particularly in a relapse/refractory setting. The sponsor had also considered 
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Protocol Incorporating Amendment 4
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CONFIDENTIAL
feedback from the study investigators indicating that certain eligibility criteria may represent 
major hurdles for enrolling patients with underlying hematologic disease (AML and MDS) in 
urgent need of treatment. Therefore, changes were made to the original protocol to modify these 
restrictions without compromising patient safety and to make further clarifications regarding study 
execution. Sections relating to the definition of dose-limiting toxicities (DLTs) and dose 
modification guidelines were also revised to correlate with the aforementioned changes.
Minor grammatical, editorial, formatting, and administrative changes not affecting the conduct of 
the study are included for clarification and administrative purposes only.
Changes in Amendment 1
1. Correct the study title to remove “relapsed/refractory” (also remove wording elsewhere in the 
protocol as appropriate to the study) and clarify study phase as 1/1b.
2. Delete requirements for ANC ≥1000/mm3, platelet count ≥75,000/mm3, and hemoglobin 
≥8 g/dL from the inclusion criteria.
3. Delete Grade 4 neutropenia and Grade 4 thrombocytopenia from DLTs for hematologic 
toxicity.
4. Revise dose modifications.
5. Revise the table of Concomitant Medications and Procedures Permitted During the Study.
6. Clarify treatment group assignments by adding the laboratory value requirements per 
treatment arm.
7. Correct header in laboratory table by adding “Complete” to Serum Chemistry.
8. Correct header in laboratory table from “Select Serum Chemistry” to “Coagulation Panel.”
9. Clarify the assessment of hepatic and renal function prior to enrollment.
10. Increase the number of study sites to support patient enrollment.
11. Update footnotes in Schedule of Events tables for clarification.
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ELECTRONIC SIGNATURES 
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm ‘UTC’) 
 
 
 
 
090101d6810bb995
Amendment 4 to A Phase 1/1b Study of Pevonedistat in Combination With Select Standard of Care Agents in
Patients With Higher-Risk Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, Acute Myelogenous
Leukemia, or Advanced Solid Tumors With Severe Renal Impairment or Mild or Moderate Hepatic Impairment
Clinical Science Approval
01-Jun-2021 15:31 UTC
Clinical Pharmacology Approval
01-Jun-2021 16:23 UTC
Clinical Science Approval
01-Jun-2021 16:26 UTC
Biostatistics Approval
01-Jun-2021 16:43 UTC
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SAP_001.pdf: 
STATISTICAL ANAYSIS PLAN
NCT Number: 
Study Title: 
Study Number: 
NCT03814005 
A Phase 1/1b Study of Pevonedistat in Combination With Select 
Standard of Care Agents in Patients With Higher-Risk 
Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, 
Acute Myelogenous Leukemia, or Advanced Solid Tumors With 
Severe Renal Impairment or Mild or Moderate Hepatic Impairment 
Pevonedistat-1016
SAP Version and Date:    
Version 4.0: 23-February-2022
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1.0
TITLE PAGE
STATISTICAL ANALYSIS PLAN
STUDY NUMBER: Pevonedistat-1016
A Phase 1/1b Study of Pevonedistat in Combination With Select Standard of Care Agents
in Patients With Higher-Risk Myelodysplastic Syndromes, Chronic Myelomonocytic
Leukemia, Acute Myelogenous Leukemia, or Advanced Solid Tumors With Severe Renal
Impairment or Mild or Moderate Hepatic Impairment
Pevonedistat Plus Select Standard of Care Agents Administered in Cancer Patients With 
Renal or Hepatic Impairment
PHASE 1/1b
Version: 4.0
Date: 21 February 2022
Prepared by:
, Statistical and Quantitative Sciences
Based on:
Protocol Version: Amendment 4
Protocol Date: 27 May 2021
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.
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Statistical Analysis Plan 
31 January 2022
CONFIDENTIAL
1.1
Approval Signatures
Study Title:
A Phase 1/1b Study of Pevonedistat in Combination With Select Standard 
of Care Agents in Patients With Higher-Risk Myelodysplastic Syndromes, 
Chronic Myelomonocytic Leukemia, Acute Myelogenous Leukemia, or 
Advanced Solid Tumors With Severe Renal Impairment or Mild or 
Moderate Hepatic Impairment
Approvals:
 PhD
 Statistical and Quantitative Sciences
Date
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Statistical Analysis Plan 
31 January 2022
CONFIDENTIAL
2.0
TABLE OF CONTENTS
1.0
TITLE PAGE ..................................................................................................................1
1.1
Approval Signatures ..................................................................................................2
2.0
TABLE OF CONTENTS.................................................................................................3
3.0
LIST OF ABBREVIATIONS..........................................................................................5
4.0
OBJECTIVES .................................................................................................................8
4.1
Primary Objectives ....................................................................................................8
4.2
Secondary Objectives.................................................................................................8
4.3
Additional Objectives ................................................................................................8
4.4
Study Design .............................................................................................................8
5.0
ANALYSIS ENDPOINTS.............................................................................................10
5.1
Primary Endpoints ...................................................................................................10
5.2
Secondary Endpoints ...............................................................................................10
5.3
Exploratory Endpoints .............................................................................................11
5.4
Safety Endpoints......................................................................................................11
6.0
DETERMINATION OF SAMPLE SIZE.......................................................................11
7.0
METHODS OF ANALYSIS AND PRESENTATION...................................................12
7.1
General Principles....................................................................................................12
7.1.1
Study Definition ..............................................................................................12
7.1.2
Definition of Study Days .................................................................................13
7.1.3
Definition of Baseline Values ..........................................................................13
7.1.4
Definition of Study Visit Windows..................................................................13
7.1.5
Conventions for Missing Adverse Event Dates ................................................13
7.1.6
Conventions for Missing Concomitant Medication Dates.................................14
7.2
Analysis Sets ...........................................................................................................15
7.3
Disposition of Patients .............................................................................................16
7.4
Demographic and Other Baseline Characteristics.....................................................16
7.4.1
Demographics..................................................................................................16
7.4.2
Baseline Characteristics...................................................................................16
7.5
Medical History.......................................................................................................17
7.6
Concomitant Medications ........................................................................................17
7.7
Study Drug Exposure and Compliance.....................................................................17
7.8
Efficacy Analysis.....................................................................................................19
7.8.1
Primary Efficacy Endpoint(s)...........................................................................19
7.8.2
Secondary Efficacy Endpoint(s).......................................................................19
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Statistical Analysis Plan 
31 January 2022
CONFIDENTIAL
7.8.3
Additional Efficacy Endpoint(s).......................................................................19
7.9
Pharmacokinetic/Pharmacodynamic Analysis ..........................................................19
7.9.1
Pharmacokinetic Analysis................................................................................19
7.9.2
Pharmacodynamic Analysis.............................................................................21
7.10
Other Outcomes.......................................................................................................21
7.11
Safety Analysis........................................................................................................21
7.11.1
Adverse Events................................................................................................22
7.11.2
Dose Limiting Toxicities (DLTs).....................................................................26
7.11.3
Clinical Laboratory Evaluations.......................................................................26
7.11.4
Vital Signs.......................................................................................................29
7.11.5
12-Lead ECGs .................................................................................................29
7.11.6
Safety Eastern Cooperative Oncology Group (ECOG) Performance Status......29
7.11.7
Protocol Deviations .........................................................................................30
7.12
Interim Analysis ......................................................................................................30
7.13
Changes in the Statistical Analysis Plan...................................................................30
8.0
REFERENCES..............................................................................................................30
9.0
APPENDICES...............................................................................................................32
LIST OF APPENDICES
Appendix A
Schedule of Events (SOE)..................................................................................32
Appendix B
Study Diagrams .................................................................................................45
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3.0
LIST OF ABBREVIATIONS
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AML
acute myeloid leukemia
ANC
absolute neutrophil count
ANOVA
analysis of variance
AST
aspartate aminotransferase
AUClast
area under the plasma concentration-time curve from time zero to the time of the 
last quantifiable concentration
AUC∞
area under the plasma concentration-time curve from time 0 to infinity
AUCτ
area under plasma concentration-time curve over dosing interval
BDC
bile in bile duct–cannulated
BSA
body surface area
BUN
blood urea nitrogen
CDLs
cullin-dependent ubiquitin E3 ligases
CL
total clearance
CMML
chronic myelomonocytic leukemia
Cmax
maximum observed plasma concentration
COVID-19
coronavirus disease 2019
eCRF
electronic case report form
CR
complete response/remission
CrCL
creatinine clearance
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
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EDC
electronic data capture
eGFR
estimated glomerular filtration rate
ELN
European Leukemia Net
EOS
end of study
ET
early termination
FDA
[United States] Food and Drug Administration
fu
fraction of unbound drug in plasma
FSH
follicle stimulating hormone
GFR
glomerular filtration rate
HI
hematologic improvement
HLT
High level term
HLGT
High level group term
HMA
hypomethylating agents
HR MDS
higher-risk myelodysplastic syndrome
ICF
informed consent form
IPSS-R
Revised International Prognostic Scoring System
IRT
interactive response technology
IV
Intravenous (ly)
LLQ
lower limit of quantification
MDRD
Modification of Diet in Renal Disease
MRT
mean residence time
MTD
Maximum tolerated dose
MedDRA
Medical Dictionary for Regulatory Activities
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NGS
next-generation sequencing
NYHA
New York Heart Association
ORR
overall response rate
OS
overall survival
PCR
polymerase chain reaction
PD
progressive disease
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PFS
progression-free survival
PK
pharmacokinetic(s)
PR
partial remission
PS
performance status
PT
preferred term
PTE
pretreatment events
QTc
prolonged rate corrected
RAEB-
refractory anemia with excess blasts
RBC
red blood cells
RP2D
recommended phase 2 dose
SAE
serious adverse event
SAP
statistical analysis plan
SmPC
Summary of Product Characteristics
SOE
schedule of events
SC
Subcutaneous(ly)
SOC
system organ class
std dev
standard deviation
t1/2z
terminal disposition phase half-life
TAD
time after dosing
TEAE
treatment-emergent adverse event
tmax
time of first occurrence of maximum observed concentration
TRM
treatment-related mortality
ULN
upper limit of the normal range
US
United States
USPI
US Prescribing Information
Vss
volume of distribution at steady-state
WBC
white blood cell
WHO
World Health Organization
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4.0
OBJECTIVES
4.1
Primary Objectives
The primary objectives (Part A) are as follows:

To characterize the PK of pevonedistat in patients with severe renal impairment.

To characterize the PK of pevonedistat in patients with mild hepatic impairment.

To characterize the PK of pevonedistat in patients with moderate hepatic impairment.
4.2
Secondary Objectives
The secondary objectives (Part A and Part B) are as follows:

To evaluate disease response in patients with severe renal impairment or mild or 
moderate hepatic impairment that may be observed in the combination of pevonedistat 
with chemotherapy (azacitidine, docetaxel, or carboplatin plus paclitaxel).

To characterize the PK of pevonedistat and azacitidine in the combination setting in 
patients with hematologic malignancies and severe renal impairment or mild or moderate 
hepatic impairment.

To characterize the PK of pevonedistat in combination with docetaxel or carboplatin plus 
paclitaxel in patients with advanced solid tumors and severe renal impairment or mild or 
moderate hepatic impairment.
4.3
Additional Objectives
The safety objectives (Part A and Part B) are as follows:

To evaluate the safety of pevonedistat following a single dose, or in combination with 
chemotherapy (azacitidine, docetaxel, or carboplatin plus paclitaxel), in patients with 
normal organ function and in patients with organ impairment.
4.4
Study Design
This study is an open-label, multicenter, phase 1/1b, 2-part study of pevonedistat plus select
standard of care (SOC) agents in adult patients with hematologic malignancies (higher-risk 
myelodysplastic syndromes [HR MDS], higher-risk chronic myelomonocytic leukemia [HR 
CMML], acute myelogenous leukemia [AML]) or solid tumors with various degrees of renal or 
hepatic function. Eligible patients will include those with relapsed/refractory MDS, non-
proliferative CMML, AML, and metastatic or advanced solid tumors for whom treatment with 
pevonedistat and SOC agents is appropriate. Patients with previously untreated hematologic 
malignancies not suitable for induction therapy will also be eligible for enrollment. The study 
has been designed to characterize the PK and assess the safety of pevonedistat in combination 
with SOC agents in patients with hematologic malignancies or solid tumors who also have severe 
renal impairment or mild or moderate hepatic impairment. Patients will be assigned to 1 of the 4 
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study arms based on their renal and/or hepatic function: normal renal and hepatic function 
(Control Arm), severe renal impairment (Renal Arm), mild hepatic impairment (Mild Hepatic 
Arm), and moderate hepatic impairment (Moderate Hepatic Arm).
It is expected that approximately 42 patients will be enrolled in this study. Part A of the study 
will be a single-agent pevonedistat PK assessment, followed by Part B treatment with 
pevonedistat in combination with SOC agents (azacitidine, docetaxel, or carboplatin plus 
paclitaxel).
Once enrolled into the study, all eligible patients will be administered a single dose of 
pevonedistat 20 mg/m2 via approximately 1-hour intravenous (IV) infusion on Day 1 of Part A. 
Plasma PK samples will be collected at a series of predetermined time points up to 72 hours 
following the single dose of pevonedistat. There will be an approximate 4- to 7-day washout 
period before the start of Part B. The schedules of events and study schema for the study are 
provided in Appendix A and Appendix B, respectively.
After completion of Part A, all patients will have the opportunity to continue into Part B of the 
study.
In Part B, patients with hematologic malignancies may receive pevonedistat on Days 1, 3, and 5 
in combination with azacitidine on Days 1 through 5, 8, and 9 in 28-day cycles. During Cycle 1 
of Part B, plasma and urine PK samples for measurement of both pevonedistat and azacitidine 
will be collected at predetermined time points or intervals on Day 3. Plasma PK samples for 
measurement of pevonedistat will also be collected on Days 4 and 5 of Cycle 1.
Patients with advanced solid tumors may receive pevonedistat in combination with docetaxel or 
carboplatin plus paclitaxel on Day 1 and pevonedistat alone on Days 3 and 5 in 21-day cycles. 
During Cycle 1 of Part B, plasma PK samples for measurement of pevonedistat will be collected 
on Days 3, 4, and 5.
The schedule of sample collection for PK assessments is provided in Appendix A.
Following sponsor and investigator discussion of safety data from Cycle 1, patients in the organ 
impairment arms who tolerate pevonedistat well at a low starting dose may be eligible for 
intrapatient dose escalation of pevonedistat starting in Cycle 2 of Part B or soon thereafter. 
Patients who tolerate treatment well at low starting doses of SOC agents may also be eligible for 
intrapatient dose escalation of those agents, per USPI/SmPC recommendations.
Details for dosing, study drug administration, and intrapatient dose escalation are provided in 
Section 8.1 of the protocol.
Patients may continue to receive a combination treatment with pevonedistat in 28-day cycles (in 
combination with azacitidine) or in 21-day cycles (in combination with docetaxel or carboplatin 
plus paclitaxel) in Part B until they experience symptomatic deterioration or disease progression, 
treatment is discontinued for another reason, or until the study is stopped by the sponsor.
Treatment with the study drug will be discontinued early if a patient experiences study drug-
related toxicity. Patients may discontinue therapy at any time. Patients will attend the end of 
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study (EOS)/early termination (ET) visit 30 (+10) days after receiving their last dose of study 
drug or before the start of subsequent antineoplastic therapy, if that occurs sooner.
Adverse events (AEs) and Eastern Cooperative Oncology Group (ECOG) performance status
(PS) will be assessed, and electrocardiograms (ECGs), clinical laboratory values (with select 
chemistry panel during Part B), and vital signs will be obtained, to evaluate the safety and 
tolerability of the study drug treatments. Toxicity will be evaluated according to National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 5.0, 
effective date 27 November 2017 [1]. Dose modification guidelines are presented in Section 8.3
of the protocol.
Measures of disease response (complete response [CR] or partial response [PR] for AML and 
solid tumors; CR, PR, or hepatic improvement [HI] for MDS and CMML), including response 
rate and duration of response, will be based on the investigator’s assessment (Part B only).
5.0
ANALYSIS ENDPOINTS
5.1
Primary Endpoints
The primary endpoints are as follows:

Area under the plasma concentration-time curve from time zero to infinity (AUC∞) 
following a single dose of pevonedistat in patients with normal renal and hepatic 
function, severe renal impairment, or mild or moderate hepatic impairment.

Area under the plasma concentration-time curve from time zero to the time of the last 
quantifiable concentration (AUClast) following a single dose of pevonedistat in patients 
with normal renal and hepatic function, severe renal impairment, or mild or moderate
hepatic impairment.

Maximum observed plasma concentration (Cmax) of pevonedistat following a single dose 
of pevonedistat in patients with normal renal and hepatic function, severe renal 
impairment, or mild or moderate hepatic impairment.
5.2
Secondary Endpoints
The secondary endpoints are as follows:

t1/2z of pevonedistat following single- and multiple-dose administration.

Cmax of pevonedistat and Cmax of azacitidine following multiple-dose administration.

Fraction of unbound drug in plasma (fu) of pevonedistat.

Time of first occurrence of maximum observed concentration (Tmax) of azacitidine 
following multiple-dose administration.

t1/2z of azacitidine following multiple-dose administration.
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
Area under the concentration-time curve from time zero to the end of the dosing interval
(AUCτ) of pevonedistat and azacitidine following multiple-dose administration.

Clearance (CL) of pevonedistat and apparent clearance (CL/F) of azacitidine.

Renal clearance (CLR) of pevonedistat and azacitidine.

Volume of distribution at steady-state (Vss) of pevonedistat and apparent Vss/F of 
azacitidine.

Measures of disease response, including response rate and duration of response, based on 
the investigator’s assessment (Part B only) using the following responses for each disease 
type:
–
CR, CRi, or PR for AML.
–
CR, PR, or HI for MDS and CMML.
–
CR or PR in patients with solid tumors using the Response Evaluation Criteria in 
Solid Tumors (RECIST) version 1.1 criteria.
5.3
Exploratory Endpoints
None.
5.4
Safety Endpoints
The safety endpoints are:

AEs, SAEs, assessments of clinical laboratory values, vital signs measurements, and 
ECOG PS.
6.0
DETERMINATION OF SAMPLE SIZE
The sample size calculation is based on the number of patients required to adequately 
characterize the PK of pevonedistat in the impaired organ function groups (severe renal 
impairment or mild or moderate hepatic impairment) in comparison to the control group. Based 
on these considerations, the expected sample size is approximately 9 for the control group 
(normal renal and hepatic function) and 9 to 12 patients in each of the 3 organ impairment arms. 
Patients who are considered non-evaluable may be replaced. The sample size of approximately 
9 patients specified as being required for the PK population in each group in Part A is based on 
typical sample sizes utilized in organ impairment PK studies in cancer patients, rather than on 
specific statistical considerations. With a sample size of 9 patients per group, if the ratio of 
geometric means (impaired organ function vs control) of AUC∞is X, the associated 90% CI is 
expected to be (0.688X, 1.45X) based on the %CV in pevonedistat AUC∞of 43.8% 
(Study C15011).
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7.0
METHODS OF ANALYSIS AND PRESENTATION
7.1
General Principles 
This study is largely descriptive, in that no formal statistical hypothesis testing will be performed 
for the primary endpoints, i.e., AUC∞, AUClast, Cmax. Summary tabulations will present the 
number of observations, mean, standard deviation, median, minimum, and maximum for 
continuous variables, and the number and percent (calculated using non-missing values) per 
category for categorical data, unless specified otherwise. 
Based on the topline results of the Study Pevonedistat-3001 (Pevo-3001), where the primary 
endpoint of event-free survival (EFS) was not met, Takeda will not pursue further development 
of pevonedistat in any indication. Thus, enrollment into this study was discontinued (see Section 
7.13).
All the tables that display non-PK information from Part A of the study will be presented by 
study arm (Control Arm, Renal Impairment Arm and Mild Hepatic Arm), and total, unless 
specified otherwise. The Moderate Hepatic Arm was planned in the study protocol, but no 
subject was enrolled. As a result, the moderate hepatic arm will not be presented. In addition, 
inclusion of patients with solid tumors was planned in the study protocol, but no subject was 
enrolled. As a result, no solid tumor data will be presented either. Due to the small target sample 
size in this study, the presentation of the non-PK information in Part B will depend on the 
characteristics of the patients who continue into Part B. By study arm presentation, similarly to 
Part A will be displayed. 
All the tables that display PK information will be presented by Part A and Part B of the study, 
study arm, dose level (for Part B only), and total, unless specified otherwise. 
All available efficacy and safety data will be included in data listings and tables as needed. Data 
that are potentially spurious or erroneous will be examined under the auspices of standard data 
management operating procedures.  
All statistical analyses will be conducted using SAS® Version 9.2, or higher.
Means and medians will be presented to 1 more decimal place than the recorded data. The 
standard deviations will be presented to 2 more decimal places than the recorded data. 
Confidence intervals about a parameter estimate will be presented using the same number of 
decimal places as the parameter estimate.
Screen failure patients will be grouped and listed.
7.1.1
Study Definition
A patient is considered to be enrolled when the first dose of study drug has been administered. 
Study start date is defined as the date of first dose of study drug for Part A. 
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7.1.2
Definition of Study Days
Part A
Study Day 1 is defined as the date on which a patient is administered their first dose of study
drug. Other study days are defined relative to Study Day 1, with ‘Day 1’ being Study Day 1 and 
‘Day -1’ being the day prior to Study Day 1.
Part B
Study Day 1 is defined as the date on which a patient is administered their first dose of the study 
drug in Cycle 1.
7.1.3
Definition of Baseline Values
Part A
Unless otherwise specified, the baseline value is defined as the value collected at the time closest 
to, but prior to, the start of study drug administration during Part A. For analysis of ECG data, 
the baseline value is the average of the screening and Part A Day 1 predose value if ECG is 
collected at both screening and Part A Day 1 predose. If ECG is collected at only one of these 
two time points, the baseline value takes the value of the one that is collected.
Part B
Similarly, the baseline value is defined as the value collected at the time closest to, but prior to, 
the start of study drug administration during Part B. Since there is no screening visit for Part B, 
the baseline value for ECG is also the one collected at the time closest to, but prior to, the start of 
study drug administration during Part B.
7.1.4
Definition of Study Visit Windows
All data will be categorized based on the scheduled visit at which they are collected. These visit 
designators are predefined values that appear as part of the visit tab in the electronic case report 
form (eCRF). The analysis of PK data will be based on the actual elapsed time post-dose.
7.1.5
Conventions for Missing Adverse Event Dates
Every effort will be made to avoid missing/partial dates in on-study data. 
Adverse events with stop dates that are completely or partially missing will be imputed as
follows:

If the stop date has a year and month, but the day is missing, the last day of the month
will be imputed.

If the stop date has a year, but the day and month are missing, the 31st of December
will be imputed.
After the imputation, the imputed dates will be compared against the date of death, if available. If
the date is later than the date of death, the date of death will be used as the imputed date stead.
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Adverse events with start dates that are completely or partially missing will be imputed
as follows:

If the start date has a month and year but the day is missing, the 1st day of the month 
will be imputed.
•
If this imputed date is earlier than the 1st dose date, then the 1st dose date will
be used instead.
•
If this imputed date is later than the stop date (possibly imputed), then the 
stop date will be used instead.

If the start date has a year, but the day and month are missing, the 15th of June will be
imputed.
•
If this imputed date is earlier than the 1st dose date, then the 1st dose date will
be used instead.
•
If this imputed date is later than the stop date (possibly imputed), then the 
stop date will be used instead.
If the start date of an event is completely missing, then it is imputed with the first dose date.
7.1.6
Conventions for Missing Concomitant Medication Dates
Concomitant medications in the category of general medication are not imputed for the missing 
start dates. Other concomitant medications, such as anti-cancer therapies with start dates that are 
completely or partially missing will be analyzed and imputed as follows:
1. If the start date has a month and year but the day is missing, the event will be considered 
concomitant if the month and year of the start date of the event are: 

On or after the month and year of the date of the 1st dose of study drug
and 

on or before the month and year of the date of the last dose of any study drug plus 
28 days for patients with hematologic disease, or the start date of subsequent 
anticancer therapy, whichever occurs first.

For the category of prior anti-cancer therapy, the day is imputed to the 15. 

For the category of alternate therapy, if year and month are the same as those of 
treatment end date, the day is imputed as the treatment end date plus one; 
otherwise, the day is imputed as the 1st day of non-missing concomitant 
medication start month.
2. If the start date has a year, but the day and month are missing, the event will be 
considered concomitant if the year of the start date of the event is:

On or after the year of the date of the 1st dose of study drug
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and 

on or before the year of the date of the last dose of any study drug plus 28 days
for patients with hematologic disease, or the start date of subsequent anticancer 
therapy, whichever occurs first.

For the category of prior anti-cancer therapy, if the year is the same as that of the 
1st dose of study drug, the 15th of January will be used unless it is later than the 1st
dose date, in which case the 1st of January will be used; if the year is not the same 
as that of the 1st dose of study drug, the 15th of June will be used unless other data 
indicate that the date is earlier.

For the category of alternate therapy, if year is the same as that of treatment end 
date, the treatment end date plus one is imputed; otherwise, the month and day is 
imputed as the 1st of January of non-missing concomitant medication start month.
3. If the start date of an event is completely missing, then the event is assumed to be 
concomitant and no imputation is applied. 
However, if the end date is complete or partially missing, but it is clear that the end date is before 
the first dose of study drug, the event will not be considered concomitant. 
When the start date is complete and is before the first dose, and the concomitant medication is 
not ongoing but the end date is missing completely or partially, a similar algorithm should be 
used to assess whether the end date is before the last dose of study drug plus 28 days for patients 
with hematologic disease to be included. 
7.2
Analysis Sets

Safety population will include patients who receive at least 1 dose of study drug. The 
safety population will be used for all safety analyses.

PK population will include patients who:
–
Complete the protocol-specified pevonedistat dosing and PK assessment in Part A 
and/or protocol-specified pevonedistat and/or azacitidine dosing and PK 
assessment in Cycle 1 of Part B.
–
Do not receive any excluded concomitant medications through the completion of 
Part A.
–
Have sufficient concentration-time data to permit reliable estimation of PK 
parameters.

Response-evaluable population will include patients who receive at least 1 dose of 
study drug, have a baseline disease assessment, and have at least 1 postbaseline disease 
assessment for analyses of response.
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7.3
Disposition of Patients
A table of patient disposition data will include the number of patients for the following 
categories: patients treated (safety population), patients in the PK population, patients in the 
response-evaluable population, and patients discontinued from the study. The primary reason for 
study discontinuation will also be summarized in this table as well. The percentages in this table
will be calculated based on the safety population.
Data concerning patient disposition will be presented in by-patient listings.
7.4
Demographic and Other Baseline Characteristics
Demographic and baseline characteristics will be summarized using safety population in a
descriptive fashion, including sex, age, race, ethnicity, weight, height, body surface area (BSA), 
baseline disease characteristics, and other parameters as appropriate.
All patient demographic and other baseline characteristics listings will include a flag indicating 
whether a patient continued to Part B of the study. For patients who continue to Part B a SOC 
agent will be presented as well.
7.4.1
Demographics
Demographic data will include age at date of informed consent (continuous and by the following 
categories: 18-64 years, 65-84 years, 85 years and over), sex, ethnicity, race, height, weight, and 
BSA. BSA is calculated using the following formula based on the patient’s height and weight 
collected at screening. If a weight at screening is not available, the Cycle 1 Day 1 predose weight 
can be used.
 = 	
ℎ() × 
ℎ()
3600
A separate table will summarize the number and percentage of the patients by region, country 
and site.
Demographic data will also be presented in a by-patient listing.
7.4.2
Baseline Characteristics
Baseline disease characteristics will be summarized using safety population for MDS/CMML,
and AML patients separately. Baseline disease characteristics for MDS/CMML patients will 
include disease type (de novo MDS/CMML, secondary MDS/CMML), with disease subtype to 
be summarized for secondary MDS/CMML, months from initial diagnosis, French-American-
British category, World Health Organization (WHO) classification and Revised International 
Prognostic Scoring System (IPSS-R) category. Baseline disease characteristic for AML patients 
will include disease type (de novo AML and secondary AML), with disease subtype to be 
summarized for secondary AML, months from initial diagnosis, revised WHO classification, and 
evidence of extramedullary disease.
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Separate by-patient listings will also be presented for baseline disease characteristics and ECOG 
performance status.
Separate by-patient listings will also be presented for prior therapies and prior transplants.
A separate table will summarize the results of the bone marrow aspirate samples taken at 
screening for MDS/CMML or AML patients. This will include myeloid to erythroid ratio, 
myeloblast percentage, cytogenetic abnormalities identified, cell maturing status, and presence of 
auer rods. Baseline bone marrow aspirate will also be presented in by-patient listings.
A separate table will summarize the results of the bone marrow biopsy samples taken at 
screening for MDS/CMML or AML patients. This will include myeloblast percentage. Bone 
marrow biopsy data and sample collection will also be presented in by-patient listings.
MDS/CMML patients will be classified and presented in a separate table by five cytogenetic risk 
groups (Very Good, Good, Intermediate, Poor, and Very Poor) using their cytogenetic results 
collected at screening based on IPSS-R criteria. The cytogenetic risk classification results will 
also be included in a by-patient listing.
A listing will be generated for patients who receive hydroxycarbamide (hydroxyurea) at 
enrollment, which includes screening white blood cells (WBC) and screening bone marrow 
aspirate myeloblasts.
7.5
Medical History 
Medical history will be presented in a by-patient listing, including the medical and surgical 
history, date of onset and the status (whether it is resolved or ongoing).
7.6
Concomitant Medications
All concomitant medications will be mapped to preferred terms according to the WHO drug 
dictionary. The number and percentage of patients in the safety population taking concomitant 
medications will be tabulated by ATC classification and WHO drug generic term and presented 
for Part A and Part B. Hydroxyurea and hydration usage will also be captured in this table. 
Concomitant procedures will not be coded.
Concomitant medications and procedures will be presented in separate by-patient listings. In 
addition, a listing will be generated for patients who require hydration as a concomitant 
medication during the study to display transfusion trend over time (Week 1-4, Week 5-8, Week 
9-12, and Week 13+) for all patients by study arm, disease type and SOC.
7.7
Study Drug Exposure and Compliance
Study drug exposure of pevonedistat in Part A, and pevonedistat as well as azacitidine in Part B 
will be presented for safety population by-patient listings separately. The extent of exposure to 
pevonedistat and compliance with pevonedistat and azacitidine dosing requirements will be 
presented for Part B of the study only by tables and by-patient listings respectively. The extent of 
exposure to pevonedistat will be based on the number of cycles. Patients will be considered to 
have been treated for a cycle if they received at least one dose of pevonedistat during that cycle.  
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Pevonedistat (TAK-924/MLN4924)
Study No. Pevonedistat-1016
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Statistical Analysis Plan 
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CONFIDENTIAL
For pevonedistat, Percent Dosing Intensity will be calculated using the following equations for 
Daily Expected Dose (mg), Daily Prepared Dose (mg), and Daily Dose Received (mg):  
)
Volume
Prepared
(mL)
infused
actually 
bag
IV
of
Volume
(
*
Dose
Prepared
Daily 
Received
Dose
Daily 
)
(m
Area
Surface
Body 
*
)
(mg/m
Level
Dose
Scheduled
Dose
Prepared
Daily 
)
(m
Area
Surface
Body 
*
)
(mg/m
Entry 
Study 
at 
Assigned
Level
Dose
=
Dose
Expected
Daily 
2
2
2
2


Daily Expected Dose and Daily Prepared Dose may differ if there are dose decreases. The 
scheduled dose level will be collected on the electronic case report form (eCRF) for each dosing 
day. Body surface area (BSA) will be calculated at baseline, and at subsequent visits if the 
patient experiences a >5% change in body weight from the weight used for the most recent BSA 
calculation.  
Total Dose Received, Total Dose Expected, and Dosing Intensity for pevonedistat will be based 
on the following formulas:
100
*
Expected
Dose
Total
Received
Dose
Total
Intensity 
Dosing
Percent 
cycles
 treated
of
number 
*
cycle
per 
doses
  
3
*
Dose
Expected
Daily 
Expected
Dose
Total
ed
administer
at  was
pevonedist
 that 
days
all
across
Received
Dose
Daily 
of
Sum
Received
Dose
Total



If there are dose increases the Dosing Intensity may exceed 100%. 
The number of patients with ≥100% intensity, 80% - <100%, 50% - <80%, and <50% intensity 
will be summarized for pevonedistat and each SOC separately. The formulas for dosing intensity 
for SOC agents appear below.
For each SOC agent, the extent of exposure will be presented in a similar manner as
pevonedistat. A separate column will be generated for each dose level of pevonedistat, and the 
number of cycles of SOC agent administered will be summarized.
Daily Expected Dose, Total Dose Received, Total Dose Expected, and Dosing Intensity for 
azacitidine will be based on the following formulas:  
100
*
Expected
Dose
Total
Received
Dose
Total
Intensity 
Dosing
Percent 
cycles
 treated
all
across
cycle"
per 
doses
7
*
Dose
Expected
Daily 
"
of
Sum
  
Expected
Dose
Total
dosing
of
days
all
across
Dose
Actual
of
Sum
Received
Dose
Total
BSA
*
mg/m
75
Dose
Expected
Daily 
2




The actions on study drugs (Dose Held, Dose Missed, Dose Reduced, Dose Interrupted, Dose 
Delayed, Dose Incomplete, or Discontinued) will be summarized for Part B by dose level for 
pevonedistat and azacitidine separately. Data will be summarized for Cycle 1 only as well as all 
cycles combined. A patient will be counted only once for each type of action.  
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Statistical Analysis Plan 
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7.8
Efficacy Analysis
Efficacy measures will include disease response and duration of disease response. Efficacy 
analysis will be based on response-evaluable population and will be descriptive. 
Disease response in AML will be based on the overall response rate (ORR) (CR + CRi + PR) 
using the Revised Recommendations of the International Working Group (IWG) for Diagnosis, 
Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for 
Therapeutic Trials in AML [5].
Disease response in MDS/CMML patients will be based on the best overall response (CR + PR + 
HI) as determined by the investigator using the revised IWG response criteria for MDS (detailed 
in Appendix J of the protocol) [6].
The duration of response will be defined in all patients with disease response as the time between 
the first documentation of response and the first documentation of progressive disease (PD) or 
death if no prior PD is documented. Responders without disease progression will be censored at 
the last clinical assessment of response.
For the disease response (CR + CRi + PR + HI), AML patients and MDS/CMML patients will be 
combined and the number of patients and percentage will be presented by study arm, and total. 
The duration of response (in months) and time to first response (in months) will also be 
presented. In addition, the date of first response, the date of progressive disease, and the number 
of cycles of response will be shown in the by-patient listing.  
Pre-treatment disease status assessment and disease response category will be presented in by-
patient listings.
7.8.1
Primary Efficacy Endpoint(s)
Not applicable for this study.
7.8.2
Secondary Efficacy Endpoint(s)

CR, CRi, or PR for AML.

CR, PR, or HI for MDS and CMML.
7.8.3
Additional Efficacy Endpoint(s)
Not applicable for this study.
7.9
Pharmacokinetic/Pharmacodynamic Analysis
7.9.1
Pharmacokinetic Analysis
Individual and mean pevonedistat plasma concentration-time data following a single dose of 
pevonedistat during the PK assessment in Part A will be plotted and listed by study arm. 
Individual and mean pevonedistat and/or azacitidine plasma concentration-time data following 
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Statistical Analysis Plan 
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multiple-dose administration during Cycle 1 of Part B will be plotted and listed by study arm and 
by dose levels. Plasma pevonedistat and/or azacitidine PK parameters for each patient will be 
calculated using noncompartmental analysis methods. Unbound values of pevonedistat Cmax, 
AUClast, AUC∞and AUCin individual patients will be calculated as the product of the patient’s 
pevonedistat fu and the total values of Cmax, AUClast, AUC∞and AUC, respectively. Descriptive 
statistics will be presented for pevonedistat PK parameters (Cmax, AUClast, AUC∞, AUC, CL, 
t1/2z, CLR, fu, Vss, and unbound values of Cmax, AUClast, AUC∞and AUC) by study arm and dose 
levels. Descriptive statistics will be presented for azacitidine PK parameters (Cmax, Tmax, AUC, 
CL/F, t1/2z, CLR, Vss by study arm and dose levels.
The analysis for the effects of organ impairment on pevonedistat PK will be based on unbound 
pevonedistat plasma exposure (AUCs) following a single dose of pevonedistat in Part A. To 
assess the effects of severe renal impairment or mild hepatic impairment on pevonedistat PK 
(unbound AUClast and AUC∞), an analysis of variance (ANOVA) on the natural log-transformed 
PK parameters will be performed for severe renal impairment (Renal Arm) versus the normal 
group (Control Arm), and mild hepatic impairment (Mild Hepatic Arm) versus the normal group 
(Control Arm). The ANOVA results will be used to estimate the ratios of least squares geometric 
means (severe renal impairment vs normal, and mild hepatic impairment vs normal) and 
corresponding 90% CIs for pevonedistat unbound AUC. The PK population will be used for 
these analyses.
Individual concentration-time data of pevonedistat administered alone or in combination with 
azacitidine will be analyzed by noncompartmental methods using a validated version of 
Phoenix® WinNonlin® (version 6.3 or higher, Pharsight Corporation, Cary, NC). 
Plasma concentration values below the lower limit of quantification (<LLQ) of the bioanalytical 
assay will be set to zero for analysis. Actual PK sampling times will be used in the derivation of 
PK parameters. The exact date and time of each sample collection, as well as 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. Actual time after dosing 
(TAD) will be set to zero for pre-infusion samples and calculated as the difference between the 
sample collection date/time and the start date/time of the IV infusion.
The following plasma PK parameters will be estimated, as permitted by the data:
Parameters
Definition
Method of Determination
Cmax
Maximum observed concentration 
(theoretically end-of-infusion concentration)
Observed directly from data 
Tmax
Time at which Cmax occurs (theoretically 
infusion time)
Derived from the stop time of the IV infusion
AUClast
Area under the plasma concentration-time 
curve from time zero to the last measurable 
concentration
Linear-log trapezoidal method
AUC
Area under the plasma concentration-time 
curve from time zero to the end of the dosing 
interval (), where is equal to 48 hours
Linear-log trapezoidal method
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Statistical Analysis Plan 
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AUC48
Area under the plasma concentration-time 
curve from time zero to 48 hours post-dose
Linear-log trapezoidal method
AUC∞
Area under the plasma concentration-time 
curve extrapolated to infinity
AUClast + Clast/lambdaz, where AUClast is the 
AUC from time zero the last measurable 
concentration (Clast)  
Lambdaz
Terminal disposition phase rate constant
Estimated as the slope of a linear regression of 
the log-linear concentration-time profile
t1/2z
Terminal disposition phase half-life
ln(2) / lambdaz 
CL or CL/F
Total clearance
Dose / AUC∞after single dosing or dose / 
AUClast after multiple dosing
Vss or Vss/F
Volume of distribution at steady-state (after 
IV administration)
CL*MRT where the mean residence time 
(MRT) is derived as AUMC∞/ AUC∞- TI/2
with TI the infusion duration and AUMC∞ the 
area under the first moment curve from time 
zero to infinity calculated by trapezoidal 
method.
To report lambdaz, t1/2z, AUC∞, CL, and Vss, the terminal disposition phase data time span must 
be greater than or equal to 2, the number of data points included in the calculation must be at 
least 3, and R2 must be greater than or equal to 0.8.
Individual pevonedistat plasma concentration-time data (including nominal and actual times) and 
individual plasma PK parameters will be listed by patient ID and summarized descriptively by
study arm, dose levels and study day (Day 1 or Day 5 up to 48 hours, Cycle 1).
Summary statistics (N, arithmetic mean, standard deviation, geometric mean [where 
appropriate], coefficient of variation [CV], median, minimum, and maximum) will be calculated
as deemed appropriate.
For each study arm, individual and mean pevonedistat plasma concentration-time data will be 
plotted over time (using nominal time for mean and actual TAD for individual data) by study
arm, dose level and study day using linear and semi-logarithmic scales for overall population 
respectively as deemed appropriate (or as data permit). Box plots of pevonedistat dose-
normalized AUCs and Cmax on Day 1 and Day 5, Cycle 1 will be provided by study arm and total
as permitted by data.
7.9.2
Pharmacodynamic Analysis
Not applicable.
7.10
Other Outcomes
Not applicable.
7.11
Safety Analysis
A safety analysis will be conducted separately for Part A and Part B. The safety population will 
be used for the safety analysis. Safety will be evaluated based on the incidence of AEs, severity
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Statistical Analysis Plan 
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CONFIDENTIAL
and type of AEs, incidence of DLTs, and by changes from baseline in the patient’s vital signs, 
weight, clinical laboratory values, and ECGs.
7.11.1
Adverse Events
7.11.1.1
Adverse Events
AEs will be tabulated according to the Medical Dictionary for Regulatory Activities (MedDRA) 
coding dictionary for the purpose of summarization. TEAE that occur after administration of the 
first dose of study drug and through 30 days after the last dose of study drug, will be tabulated 
according to the MedDRA by system organ class, high level terms (HLT) and preferred terms
(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)

Treatment-emergent serious AEs (SAEs)

Treatment-emergent drug-related SAEs

Treatment-emergent AEs that require dose modification

Non-serious TEAEs (>5% in any arm)
Patients with the same AE more than once will have that event counted only once within each 
body system, once within each HLT, and once within each PT.
Treatment-emergent AEs (TEAE) will be tabulated by system organ class, HLT, PT, and highest 
intensity. 
A separate table for non-serious TEAEs which occur in >5% of the patients in one study arm will 
be tabulated by system organ class, PT, study arm and total. In addition to the number and 
percentage of the patients, the number of events will be presented in this table.
All TEAEs categories will be analyzed by study arm and total. All AEs will also be reported in 
by-patient listings by study arm, disease type and SOC.
A TEAE in Part A is defined as any AE that occurs after administration of the single dose of 
study drug in Part A and up through 30 days after the single dose of study drug in Part A for 
patients who do not continue into Part B; or up through Part B Cycle 1 Day 1 (predose) for 
patients who continue into Part B.
A TEAE in Part B is defined as any AE that occurs after administration of the first dose of study 
drug in Part B and up through 30 days after the last dose of study drug in Part B.
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Statistical Analysis Plan 
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7.11.1.2
Serious Adverse Events
The number and percentage of patients experiencing at least one treatment-emergent SAE will be 
summarized by system organ class, HLT, PT, study arm, and total. A similar table will be 
presented for treatment-emergent drug-related SAEs.
A separate table with the number of SAEs in addition to the number and percentage of patients 
experiencing SAEs will be summarized by system organ class, PT, study arm, and total.
A by-patient listing of the SAEs will be presented (the patient listing will contain all SAEs 
regardless of treatment emergent AE status).
An additional listing of treatment emergent events occurring within a day of first dosing (C1D1)
with grade 2 or higher SAEs will also be generated.
7.11.1.3
Deaths
A by-patient listing of the deaths will be presented for all patients by study arm, disease type and 
SOC. All deaths occurring on-study and during follow-up will be displayed (regardless of 
treatment emergent AE status). On-study death is defined as the death that occurs between the 
first dose of study drug and 30 days after the last dose of study drug.
7.11.1.4
Treatment-Emergent Adverse Events Resulting in Discontinuation of Study Drug
A by-patient listing of TEAEs resulting in discontinuation of study drug will be presented for all 
patients by study arm, disease type and SOC. All TEAEs resulting in discontinuation of study 
drug occurring on-study and during follow-up will be displayed.
7.11.1.5
Hemorrhages
By-patient line listing for patients who experienced ANY GRADE TEAE of Hemorrhages 
(defined by SMQ Hemorrhages, broad and narrow terms) and Thrombocytopenia/Platelet Count 
Decreased will be provided by study arm, disease type and SOC.
7.11.1.6
Acute Renal Failure Events
A listing of treatment-emergent acute renal failure events will be generated for all patients by 
study arm, disease type and SOC. The corresponding PTs are within the Acute renal failure 
SMQ, broad and narrow terms. 
7.11.1.7
Liver Function Test (LFT) Elevations
A listing of treatment-emergent LFT elevation events will be generated for all patients by study 
arm, disease type and SOC. The corresponding PTs, HLT and SMQ are listed as below:

Acute hepatic failure (PT)

Drug-induced liver injury (SMQ)

Hepatic encephalopathy (PT)

Liver function analyses (HLT)

Liver injury (PT)

Blood alkaline phosphatase abnormal 
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Statistical Analysis Plan 
31 January 2022
CONFIDENTIAL

Hepatocellular injury (PT)

Hepatotoxicity (PT)

Hyperbilirubinaemia (PT)

Hypertransaminasaemia (PT)
(PT)

Blood alkaline phosphatase increased 
(PT)

Hepatic function abnormal (PT)
7.11.1.8
Tachycardia Events
A listing of treatment-emergent tachycardia events will be generated for all patients by study 
arm, disease type and SOC. The corresponding PTs are listed as below:

Heart rate increased

Sinus tachycardia

Supraventricular tachycardia

Supraventricular tachyarrhythmia

Tachyarrhythmia

Tachycardia

Tachycardia paroxysmal

Palpitations
7.11.1.9
Hypotension
A listing of treatment-emergent hypotension events will be generated for all patients. Severity
and causality will be indicated for all patients by study arm, disease type and SOC. The 
corresponding PTs are listed as below:

Blood pressure ambulatory decreased

Blood pressure decreased

Blood pressure diastolic decreased

Blood pressure orthostatic abnormal

Blood pressure orthostatic decreased

Blood pressure systolic decreased

Diastolic hypotension

Hypotension

Orthostatic hypotension
7.11.1.10
Anemia
A listing of treatment-emergent anemia events will also be generated for all patients. Severity 
and causality will be indicated for all patients by study arm, disease type and SOC. The 
corresponding PTs are listed as below:

Anaemia of chronic disease

Anaemia of malignant disease

Anaemia

Red blood cell count abnormal

Haematocrit abnormal

Haematocrit decreased

Hemoglobin abnormal

Hemoglobin decreased
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Statistical Analysis Plan 
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CONFIDENTIAL

Red blood cell count decreased

Mean cell hemoglobin decreased
7.11.1.11
Neutropenia
A listing of treatment-emergent neutropenia will also be generated for all patients. Severity and 
causality will be indicated for all patients by study arm, disease type and SOC. The 
corresponding PTs are listed as below:

Agranulocytosis

Granulocyte count decreased

Band neutrophil count decreased

Band neutrophil percentage decreased

Leukopenia

Febrile neutropenia

Neutropenia

Neutropenic infection

Neutropenic sepsis

Neutrophil count abnormal

Neutrophil count decreased

White blood cell count abnormal

White blood cell count decreased

Neutrophil percentage abnormal

Neutrophil percentage decreased
By-patient line listing for patients who experienced ANY GRADE TEAE of Infections (defined 
by system organ class Infections and infestations, or High Level Group Term [HLGT]
Respiratory Tract Infections, or HLT Lower Respiratory Tract Inflammatory and Immunologic 
Conditions) and Febrile neutropenia (defined by PT Febrile neutropenia) will be generated. The 
listing will include: patient ID, study arm, Febrile neutropenia (reported term and PT, Start 
date/End date, Days from first dose/Days from last dose, Seriousness), Infections (reported term 
and PT, Start date/End date; Days from first dose/Days from last dose; Seriousness).
By-patient line listing for patients who experienced ANY GRADE TEAEs of Infections (defined 
by system organ class Infections and infestations, or HLGT Respiratory Tract Infections, or HLT 
Lower Respiratory Tract Inflammatory and Immunologic Conditions) and Neutropenia (defined 
by PT Neutropenia, PT Neutrophil Count Decreased, PT White Cell Count Decreased) will be 
generated. The listing will include: patient ID, study arm, Neutropenia (reported term and PT, 
Start date/End date, Days from first dose/Days from last dose, Seriousness), Infections (reported 
term and PT, Start date/End date; Days from first dose/Days from last dose; Seriousness).
7.11.1.12
Transfusion
A listing will be generated for patients who take platelets and/or red blood cells as concomitant 
medications during the study to display transfusion trend over time (Week 1-4, Week 5-8, Week 
9-12, and Week 13+) for all patients by study arm, disease type and SOC.
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Statistical Analysis Plan 
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7.11.1.13
Dose Modifications due to LFT Abnormalities
A listing will be generated for patients who require dose modification due to LFT abnormalities 
[defined by TEAEs included in section 7.11.1.7 (LFT elevations)] during the study to display 
trend over time (Week 1-4, Week 5-8, Week 9-12, and Week 13+) for all patients by study arm, 
disease type and SOC.
7.11.1.14
Dose Modifications due to Renal Abnormalities
A listing will be generated for patients who require dose modification due to renal abnormalities 
[as defined by the TEAEs listed in section 7.11.1.6 (Acute renal failure SMQ)] during the study 
to display trend over time (Week 1-4, Week 5-8, Week 9-12, and Week 13+) for all patients by 
study arm, disease type and SOC.
7.11.1.15
Dose Modifications due to Myelosuppression
A listing will be generated for patients who require dose modification due to myelosuppression 
[defined by the TEAEs listed in sections 7.11.1.10 (Anemia), 7.11.1.11 (Neutropenia), plus 2 
additional PTs of Thrombocytopenia and Platelet count decreased)] during the study to display 
trend over time (Week 1-4, Week 5-8, Week 9-12, and Week 13+) for all patients by study arm, 
disease type and SOC.
7.11.1.16
Overall Summary
The number and percentage of patients who experience any of the following will be summarized 
by study arm, and total.

Any TEAE (including separate summaries of maximum toxicity grade experienced 
(Grade 1 to Grade 5)

Drug-related TEAE (including separate summaries of maximum toxicity grade 
experienced (Grade 1 to Grade 5)

Serious TEAE

Drug related serious TEAE

TEAE that required dose modification
7.11.2
Dose Limiting Toxicities (DLTs)
A by-patient listing of DLTs will be presented for all patients by study arm, disease type and 
SOC.
7.11.3
Clinical Laboratory Evaluations
For the purposes of summarization, all laboratory values will be converted to standardized units. 
If a lab value is reported using a non-numeric qualifier (e.g., less than (<) a certain value, or 
greater than (>) a certain value), the given numeric value will be used in the summarization, 
ignoring the non-numeric qualifier.
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Statistical Analysis Plan 
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Laboratory test results from the central laboratory will be used when they are available.  
Laboratory test results from local laboratory will be used only when no central laboratory test 
result exists at the same scheduled sample collection time point. Clinical laboratory evaluations 
all have been done in local laboratories for P1016 study.
If a patient has repeated laboratory values for a given time point, the value from the last 
evaluation will be used.
Laboratory test results will be presented for Part A and Part B separately, summarized according 
to the scheduled sample collection time point. Given that lab tests are done for pre-dose and 4-
hour post-dose for Part A, the shift from baseline to worst post-baseline be presented for the 
whole period of the study. Unscheduled laboratory test results will be listed and included in 
laboratory shift tables.  
All the tables and graphs will be displayed for safety population and will be presented by study 
arm and total. Shift tables for laboratory parameters will be generated based on changes in NCI 
CTCAE grade from baseline to the worst post-baseline value. Summary tables will be generated 
to display the actual values and percent changes from baselines for selected labs. The following 
graphical displays will be used to show changes in laboratory measures over time:
1. Box graphs of mean laboratory values over time for key laboratory parameters (see table 
below). 
Panel
Test
CTCAE Shift 
Table
Box Graphs
Summary 
Tables
Chemistry
Albumin
X
X
ALT
X
X
X
AST
X
X
X
Alkaline Phosphatase
X
X
Carbon Dioxide
X
Direct Bilirubin
X
X
Total Bilirubin
X
X
X
Blood urea nitrogen
X
Calcium
X
X
Chloride
X
Creatinine
X
X
Creatinine Clearance
X
X
Glucose
X
X
Lactate dehydrogenase 
(LDH)
X
Magnesium
X
X
Phosphate
X
X
X
Potassium
X
X
X
Sodium
X
X
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Statistical Analysis Plan 
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Panel
Test
CTCAE Shift 
Table
Box Graphs
Summary 
Tables
Urate
X
X
Hematology
Platelets
X
X
X
Hemoglobin
X
X
Hematocrit
X
Leukocytes
X
X
Lymphocyte Count
X
X
Neutrophils (ANC)
X
X
X
Monocytes
X
Eosinophils
X
Basophils
X
For patients with neutrophil lab results reported as segmented neutrophils and neutrophil bands, 
ANC will be calculated as:
ANC=total leukocyte count × total percentage of neutrophils (segmented neutrophils + band 
neutrophils)
The following Modification in Renal Disease Study (MDRD) equation will be used to calculate 
eGFR (mdrd.com): 
eGFR (mL/min/1.73 m2) = 175 × (Scr, std)-1.154 × (Age)-0.203 × (0.742 if female) × (1.212 if African
American).
All chemistry and hematology lab data will also be presented in by-patient listings for all patients 
by study arm, disease type and SOC.
In addition, the urinalysis parameters will be presented in by-patient listings for all patients by 
study arm, disease type and SOC. These include turbidity and color, pH, specific gravity, protein, 
ketones, bilirubin, occult blood, nitrite, urobilinogen, glucose, erythrocytes, leukocyte esterase, 
and leukocytes.
Events that potentially meet the biochemical criteria for Hy’s law (eg, patients with any elevated
aminotransferase of >3x ULN and alkaline phosphatase <2x ULN, in association with an
increase in bilirubin >2x ULN) will also be provided for overall and by treatment cycles for all 
patients by study arm, disease type and SOC. Incidences of the following will be provided:

>3x-, >5x-, >10x-, and >20x ULN elevations of AST and/or ALT;

Any elevations of bilirubin: elevated total bilirubin to ≥2x ULN;

Any elevations of alkaline phosphatase >1.5x ULN;

Elevation of aminotransferase (>3x ULN) accompanied by elevated bilirubin (>1.5x
ULN, >2x ULN); and
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Statistical Analysis Plan 
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
Potential Hy’s law cases. The Sponsor qualifies these as "potential" cases, since a bona 
fide case definition requires that no other cause nor other drug has been shown to be 
causative than the test article. In some advanced cases with more cholestasis, the alkaline 
phosphatase may be >2x ULN.
7.11.4
Vital Signs
Tables for vital signs data will be displayed for safety population and will be presented for Part 
A and Part B separately by study arm and total.
Summary table of weight and percent change from baseline in weight over time will be provided.
Tables will be used to show changes in vital sign parameters, including oral temperature, heart 
rate, and systolic and diastolic blood pressure, over time.
Vital sign data will also be presented in a by-patient listing for all patients, by study arm, disease 
type, and SOC.
7.11.5
12-Lead ECGs
A 12-lead electrocardiogram (ECG) will be summarized over each time point, i.e., screening, 
pre-treatment Day 1 part B, end of the study. QTc intervals (QTcF and QTcB) will be derived by 
the Sponsor using the following formulas.
3
/
1
d
uncorrecte
Rate
r 
Ventricula
60
QT
QTcF







                
Rate
r 
Ventricula
60
QT
QTcB
d
uncorrecte

ECG findings will also be presented in by-patient listings separately for screening, pre-treatment 
Day 1 part B, end of the study. Shift tables of the change from baseline to the post baseline worst 
will be generated for the safety population and will be presented by study arm and total. 
ECG Parameter
Abnormal values
QTcF and QTcB
New absolute values >450, >480 and >500
Changes from baseline >30 and >60
HR
Decrease from baseline >25% and to a HR < 50
Increase from baseline >25% and to a HR > 100
PR
ECG Parameter
Increase from baseline >25% and to a value >200
Abnormal values 
QRS
Increase from baseline >25% and to a value >110
7.11.6
Safety Eastern Cooperative Oncology Group (ECOG) Performance Status
ECOG shifts from baseline to post-baseline assessment over time will be tabulated for the whole 
study period for the safety population and will be presented by study arm and total. 
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Statistical Analysis Plan 
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A listing will be presented for ECOG performance status for safety population, ordered by study 
arm, disease type, and SOC.
7.11.7
Protocol Deviations
A listing will be presented for significant protocol deviation for safety population, ordered by 
study arm, disease type, and SOC.
7.12
Interim Analysis
No interim analysis is planned.
7.13
Changes in the Statistical Analysis Plan 
The rationale of the SAP amendment is to decrease the scope of analysis due to the small number 
of enrolled subjects. The enrollment was discontinued after the pivotal Pevonedistat phase 3 
study (P3001) did not meet the primary efficacy endpoint, resulting in discontinuation of clinical 
development of Pevonedistat. As a consequence, further enrollment into P1016 was 
discontinued, leaving 17 subjected enrolled in total in this study. The main changes include:

Removal of all analyses of patients with moderate hepatic impairment because these is no 
patient enrolled in the moderate hepatic arm.

Removal of all analyses of patients with solid tumors because these is no patient with 
solid tumors enrolled in the study.

Some planned tabulations were removed. The events of interest will be captured in 
listings.
For further details, please refer to Clinical Study Protocol P1016 Amendment 04 (27 May 2021).
8.0
REFERENCES
1. Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. U.S. Department 
of Health and Human Services, National Institutes of Health, National Cancer Institute. 
November 2017.
2. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, et al. Proposals 
for the classification of the myelodysplastic syndromes. British Journal of Haematology 
1982;51(2):189-99.
3. Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A, et al. The 2008 
revision of the World Health Organization (WHO) classification of myeloid neoplasms and 
acute leukemia: rationale and important changes. Blood 2009;114(5):937-51.
4. Greenberg PL, Tuechler H, Schanz J, Sanz G, Garcia-Manero G, Sole F, et al. Revised 
international prognostic scoring system for myelodysplastic syndromes. Blood 
2012;120(12):2454-65.
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Study No. Pevonedistat-1016
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Statistical Analysis Plan 
31 January 2022
CONFIDENTIAL
5. Cheson BD, Bennett JM, Kopecky KJ, Buchner T, Willman CL, Estey EH. 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. Journal of Clinical Oncology 2003;21(24):4642-9.
6. Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD, et al. 
Clinical application and proposal for modification of the International Working Group (IWG) 
response criteria in myelodysplasia. Blood 2006;108(2):419-25.
7. Döhner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Büchner T et al. Diagnosis 
and management of AML in adults: 2017 ELN recommendations from an international 
expert panel. Blood. 2017;129(4):424-47.
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Statistical Analysis Plan 
31 January 2022
CONFIDENTIAL
9.0
APPENDICES
Appendix A
Schedule of Events (SOE)
SOE for Part A: Single-Agent Pevonedistat and PK (All Patients)
Procedure
Screening a
PK Period
EOS/
ET
Days
Day 1
Day 2
Day 3
Day 4 b
Window
(+10 days)
Informed consent
x
Inclusion/exclusion criteria c
x
Demographics
x
Medical history
x
Complete physical examination
x
x
Symptom-directed physical examination d
x e
Height
x
Weight f
x
x e
x
Vital signs g
x
x
x
ECOG PS
x
x e
x
12-lead ECG
x
x
Pregnancy test h
x
x e
x
Hematology i
x
x e
x
Coagulation
x
Complete chemistry panel j
x
x e
x
Urinalysis k
x
x
Pevonedistat IV infusion
x l
Plasma sample for pevonedistat PK (see Table A)
x
x
x
x
Plasma sample for pevonedistat protein binding (see 
Table A)
x
Bone marrow aspiration/biopsy and investigator disease 
assessment for patients with hematologic malignancies 
only m
x
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Statistical Analysis Plan 
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CONFIDENTIAL
Procedure
Screening a
PK Period
EOS/
ET
Days
Day 1
Day 2
Day 3
Day 4 b
Window
(+10 days)
Tumor assessment for solid tumors by RECIST, version 1.1 n
x
x o
Monitoring of concomitant medications and procedures
Recorded from the first dose of any study drug through 30 days (+10) days after the last dose of any study drug.
RBC and platelet transfusion documentation
Recorded from 8 weeks before enrollment through 30 days after the last dose of any study drug.
AE/SAE reporting
Recorded from the first dose of any study drug through 30 days (+10) days after the last dose of any study drug.
AEs 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 will be reported from signing of the ICF through 30 days after the last dose of any study drug.
AE: adverse event; ALP: alkaline phosphatase; ALT: alanine aminotransferase; AML: acute myelogenous leukemia; AST: aspartate aminotransferase; BSA: body surface area; 
BUN: blood urea nitrogen; CT: computerized tomography; ECG: electrocardiogram; ECOG PS: Eastern Cooperative Oncology Group performance status; eGFR: estimated 
glomerular filtration rate; EOS: end of study; ET: early termination; ICF: informed consent form; IV: intravenous(ly); MDRD: Modification of Diet in Renal Disease; PK: 
pharmacokinetic(s); RBC: red blood cells; RECIST: Response Evaluation Criteria in Solid Tumors; SAE: serious adverse event; SC: subcutaneous(ly); SOE: schedule of events; 
WBC: white blood cell.
An EOS visit is needed in Part A only if for any reason the patient does not continue into Part B.
a Unless otherwise noted, the screening visit must occur within 28 days before the day of the first dose of study drug on Day 1.
b Patients may start Part B 4 to 7 days after the pevonedistat dose in Part A.
c Confirmation of patient eligibility by the sponsor’s project clinician (or designee) is required prior to enrollment. A patient eligibility checklist must be completed and submitted
by the investigator for review and approval by the sponsor or designee prior to patient enrollment. For assessment of hepatic function, 2 blood samples (total bilirubin and ALT), 
will be required before the start of pevonedistat dosing on Day 1. These 2 samples should be obtained at least 48 hours apart, with the latest sample obtained no more than 48 hours 
before Day 1 and may be taken predose on Day 1. If the total bilirubin and ALT measurements from the 2 samples indicate the same liver function category for the patient (ie, 
normal, mild, or moderate hepatic impairment), pevonedistat can be administered as scheduled. If the results of the 2 samples indicate different liver function categories, a third 
sample must be obtained at least 48 hours after the second sample. If the results of the 2 most recent measurements (the second and third) denote the same liver function category, 
the patient may be enrolled and should receive a single dose of pevonedistat on Day 1 within 48 hours of the third sample. If the second and third measurements indicate different 
liver function categories, the patient will not be eligible for inclusion in the study. For assessment of renal function, at least 2 blood samples will be collected to determine spot 
serum creatinine for calculation of the eGFR according to the MDRD equation (see Section 9.4.15.1 of the Protocol). The sampling for spot serum creatinine should be done within 
14 days of starting treatment, with the most recent measurement performed within 7 days of starting treatment. The 2 measurements should both meet eligibility requirements 
based on the MDRD formula. If the 2 eGFR values do not both meet eligibility requirements, a third measurement will be taken and the 2 most recent measurements (the second 
and third) will be averaged to assess renal function status.
d The symptom-directed physical examination will be conducted within 3 days before dosing on Day 1. The symptom-directed physical examination may be performed at other 
visits during Part A of the study at the discretion of the investigator.
e Except for measurement of WBC count, procedures conducted during the screening period that are performed within 24 hours of Day 1 can also be used as the predose Day 1 
evaluation and do not need to be repeated. If dosing falls on a Monday, the collection window may be extended to collect samples on a previous Friday, with the exception of the 
hepatic and renal function assessments.
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Statistical Analysis Plan 
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f Weight will be measured during screening and within 3 days before Day 1 dosing for calculating BSA. BSA will be calculated using a standard formula (see example in
Appendix H of the Protocol) on Day 1.
g Vital signs, including diastolic and systolic blood pressure, heart rate, and body temperature will be obtained at screening. On Day 1, vital signs are to be measured predose 
(20 minutes [±10 minutes]) before the infusion of pevonedistat, 30 minutes (±10 minutes) after the start of the pevonedistat infusion, and 30 min (±10 minutes) after the 
completion of the pevonedistat infusion. When the timing of vital signs assessment coincides with the timing of a blood draw, vital signs will be measured before blood sample 
collection. Vital sign measurements will be taken with the patient in the supine (after 3-5 minutes in this position) or sitting position (after 3-5 minutes in this position). Either oral 
or axial body temperature may be used, but the same method for measuring body temperature (oral or axial) should be used consistently for the same patient throughout the study.
h A serum pregnancy test will be performed for women of childbearing potential at screening and within 3 days before study drug dosing on Day 1. The results from these tests 
must be available and negative before the first dose of study drug is administered.
i Hematology samples will be collected during screening and within 3 days before infusion/administration with study drug on Day 1. Please note: The sample for WBC count must 
be drawn before dosing on Day 1. For patients with hematologic disease, WBC count must be <50,000/μL before administration of pevonedistat; hydroxyurea may be used to 
control the level of WBCs to no lower than 10,000/μL while on pevonedistat. An additional sample will be taken on Day 1 at 4 hours after the completion of pevonedistat infusion.
j Samples for the full clinical chemistry panel will be collected predose on Day 1. In addition, samples will be taken on Day 1 at 4 hours after the completion of pevonedistat 
infusion (see Table 9.d in the Protocol).
k Urinalysis will be analyzed locally. See Section 9.4.15.1 of the Protocol. for additional details.
l All eligible patients will receive a single dose of 20 mg/m2 pevonedistat via a 1-hour IV infusion on Day 1. Plasma PK samples will be collected at a series of predetermined time 
points up to 72 hours (Day 4) following the single dose of pevonedistat. There will be no SOC agents or additional pevonedistat dosing in Part A.
m At screening and for study eligibility, a bone marrow aspiration and biopsy (performed locally) will be required to assess disease burden, cytogenetics, molecular 
characterizations, and cellular composition by flow cytometry. A bone marrow biopsy (in addition to bone marrow aspirate) is required only at screening to confirm the diagnosis. 
However, a bone marrow biopsy may be collected with bone marrow aspirate in accordance with institutional guidelines. If a biopsy was done within 28 days before enrollment, 
this archival biopsy may be used and does not need to be repeated. If a bone marrow biopsy is not collected routinely per country/institutional guidelines, it is not required.
n Radiological imaging (CT scan or magnetic resonance imaging) of chest, abdomen, and pelvis are required as entry criteria for this study to assess the status of the patient’s 
underlying disease. If the patient has had appropriate imaging scans performed within 28 days before the first dose of study drug in Part A, the results of those scans may be used.
o An EOS/ET CT scan does not need to be completed/repeated if a scan was performed within the previous 28 days.
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Statistical Analysis Plan 
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Table A
Part A: Pevonedistat Plasma PK Sampling Schedule – Pevonedistat Single-Dose PK (All Patients)
Pevonedistat Plasma PK Sample
Day 1
Day 2
Day 3
Day 4
Predose
x a,c
End of pevonedistat infusion
x b,c
30 minutes (± 5 minutes) post infusion of pevonedistat
x d
1 hour (± 15 minutes) post infusion of pevonedistat
x d
2 hours (±20 minutes) post infusion of pevonedistat
x d
3 hours (±20 minutes) post infusion of pevonedistat
x d
4 hours (±30 minutes) post infusion of pevonedistat
x d
6 hours (±30 minutes) post infusion of pevonedistat
x d
8 hours (±30 minutes) post infusion of pevonedistat
x d
24 hours (±1 hour) postdose of pevonedistat
x e
48 hours (±1 hour) postdose of pevonedistat
x e
72 hours (±1 hour) postdose of pevonedistat
x e
IV: intravenous(ly); PK: pharmacokinetics.
a The predose sample is to be collected within 1 hour before pevonedistat infusion.
b The sample is to be collected at the end of pevonedistat infusion (immediately before stopping the IV infusion). The infusion takes approximately 1 hour.
c Samples for pevonedistat plasma protein binding measurement should be collected predose and at the end of infusion. The end of infusion sample will be used if bioanalytically 
feasible. If not feasible, the predose sample will also be used for pevonedistat plasma protein binding measurement.
d The time of sample collection is to be based on the time of completion of pevonedistat infusion.
e The time of sample collection is to be based on the time of initiation of pevonedistat infusion.
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Statistical Analysis Plan 
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CONFIDENTIAL
SOE for Part B: Treatment Cycle 1 (28-Day Cycle) Through EOS (Patients with Hematologic Malignancies Only)
Day
Cycle 1 and Subsequent Cycles (28 days)
EOS/ET
Day 1
Day 3
Day 4
Day 5
Day 8 a
Day 15 a
Day 22
Procedure
Window
(±1 day)
(±3 day)
(±3 days)
(+10 days) b
Symptom-directed physical 
examination c
x
Complete physical examination
x
Weight
x d
x
Vital signs e
x
x
x
x
ECOG PS f
x
x
12-lead ECG g
x
x
Pregnancy test h
x
x
Hematology i
x
x
x
x
x
x
x
Complete chemistry panel
x
x
Select chemistry panel j
x
x
x
x
x
Urinalysis k
x
x
Plasma sample for pevonedistat PK 
(Cycle 1 only, see Table B)
x
x
x
Plasma sample for azacitidine PK 
(Cycle 1 only, see Table B)
x
Urine sample for pevonedistat PK 
(Cycle 1 only, see Table B)
x
Urine sample for azacitidine PK 
(Cycle 1 only, see Table B)
x
Bone marrow aspiration/biopsy and 
investigator disease assessment
See the Bone Marrow Collection and Assessment Schedule (Table C).
Pevonedistat IV infusion l
Days 1, 3, and 5 of each cycle.
Azacitidine SC administration l
Days 1-5, 8, and 9 of each cycle.
Monitoring of concomitant 
medications and procedures
Recorded from the first dose of any study drug through 30 days (+10) days after the last dose of any study drug.
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Statistical Analysis Plan 
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CONFIDENTIAL
Day
Cycle 1 and Subsequent Cycles (28 days)
EOS/ET
Day 1
Day 3
Day 4
Day 5
Day 8 a
Day 15 a
Day 22
Procedure
Window
(±1 day)
(±3 day)
(±3 days)
(+10 days) b
RBC and platelet transfusion 
documentation
Recorded from 8 weeks before enrollment through 30 days after the last dose of any study drug.
AE/SAE reporting
Recorded from the first dose of any study drug through 30 days (+10) days after the last dose of any study drug.
AEs 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 will be reported from signing of the ICF through 30 days after the last dose of any study drug.
AE: adverse event; ALP: alkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase; BSA: body surface area; BUN: blood urea nitrogen; 
ECG: electrocardiogram; ECOG PS: Eastern Cooperative Oncology Group performance status; EOS: end of study; ET: early termination; IV: intravenous(ly); 
PK: pharmacokinetic(s); RBC: red blood cells; SAE: serious adverse event; SC: subcutaneous(ly); SOE: schedule of events; WBC: white blood cell.
Study completion is defined as completion of study treatment and the EOS visit.
Nonessential protocol visits in Part B 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 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 for the assessments performed are to be captured in the electronic data capture (EDC).
a Hematology samples and select chemistry panels will be collected on Days 8 (±1 day) and 15 (±1 day) in Cycle 1 and in any cycle in which intrapatient dose escalation of any 
study drug occurs.
b The EOS/ET visit will occur 30 days (+10 days) after the last dose of study drugs or before the start of subsequent antineoplastic therapy, if that occurs sooner.
c The symptom-directed physical examination will be conducted within 3 days before dosing on Day 1 of each treatment cycle. The symptom-directed physical examination may 
be performed at other visits during the treatment cycle at the discretion of the investigator.
d 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 H of
the Protocol) 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.
e Vital signs, including diastolic and systolic blood pressure, heart rate, and body temperature will be collected predose (30 minutes [±10 minutes]) before the infusion of 
pevonedistat and 30 minutes (±10 minutes) after the start of the pevonedistat infusion on Days 1, 3, and 5 of each cycle, at EOS/ET, and as clinically indicated at the discretion of 
the investigator. On Cycle 1 Day 1, vital signs are to be measured predose (20 minutes [±10 minutes]) before the infusion of pevonedistat, 30 minutes (±10 minutes) after the start 
of the pevonedistat infusion, and 30 min (±10 minutes) after the completion of the pevonedistat infusion. Vital sign measurements will be taken with the patient in the supine (after 
3-5 minutes in this position) or sitting position (after 3-5 minutes in this position). Either oral or axial body temperature may be used, but the same method for measuring body 
temperature (oral or axial) should be used consistently for the same patient throughout the study.
f ECOG PS will be performed within 3 days before the beginning (Day 1) of each treatment cycle and at the EOS/ET visit.
g A 12-lead ECG will be performed Day 1 predose of every cycle and at EOS/ET. Predose assessment may be performed up to 3 days in advance if necessary. ECGs may be 
obtained as clinically indicated at the discretion of the investigator. ECG assessments are to be performed with the patient supine and rested for 5 minutes.
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Statistical Analysis Plan 
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h A serum pregnancy test will be performed for women of childbearing potential within 3 days before Day 1 of each cycle and at EOS/ET. The results from these tests must be 
available and negative before the study drug is administered on Day 1. If the Day 1 serum pregnancy results will not be available before dosing, a urine pregnancy test may be 
performed.
i Hematology samples will be collected before infusion with study drug(s) on Days 1, 3, and 5, and on Day 22 of each cycle, and at EOS/ET. Samples may be drawn up to 1 day 
before dosing. If dosing falls on a Monday, the collection window may be extended to collect samples on the previous Friday. Additional collections on Days 8 (±1 day) and 
15 (±1 day) will be performed in Cycle 1 or in any cycle in which study drug dose is escalated. Please note: The sample for WBC count must be drawn before each dose on 
Days 1, 3, and 5. WBC count must be <50,000/μL before administration of pevonedistat; hydroxyurea may be used to control the level of WBCs to no lower than 10,000/μL while 
on pevonedistat.
j The select chemistry panel will be collected predose on Days 3 and 5 and on Day 22 of each cycle. For Days 3 and 5, samples may be drawn up to 1 day before dosing. If dosing 
falls on a Monday, the collection window may be extended to collect samples on the previous Friday. Additional collections on Days 8 (±1 day) and 15 (±1 day) will be performed 
in Cycle 1 or in any cycle in which study drug dose is escalated. The select chemistry panel will include the following: BUN, creatinine, total bilirubin, ALP, AST, and ALT.
k Urinalysis will be analyzed locally. See Section 9.4.15.1 of the Protocol for additional details.
l Following a 4- to 7-day washout period after single-dose pevonedistat administration in Part A, starting on Day 1 patients will receive pevonedistat on Days 1, 3, and 5 in 
combination with azacitidine on Days 1 through 5, 8, and 9 in 28-day cycles. On Days 1, 3, and 5, when both study drugs are administered, azacitidine will be administered first, 
followed by pevonedistat. The pevonedistat infusion may be slowed or stopped and restarted for any associated infusion-related reactions. Following sponsor and investigator 
discussion of the available safety data, patients who tolerate treatment well at the initially assigned dose of pevonedistat may be allowed to increase their dose during Cycle 2 or in 
subsequent cycles of treatment. Eligible patients may continue to receive treatment in Part B until they experience symptomatic deterioration or disease progression, treatment is 
discontinued for another reason, or until the study is stopped by the sponsor. See Section 8.0 of the Protocol for details of study drug administration.
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Statistical Analysis Plan 
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Table B
Part B: Azacitidine and Pevonedistat Plasma and Urine PK Sampling Schedule in Cycle 1 (Patients with 
Hematologic Malignancies Only)
Day
Dosing a
Azacitidine Plasma PK
Pevonedistat Plasma PK
Urine PK for Azacitidine and 
Pevonedistat
Azacitidine
Pevonedistat
Timepoint
Sample
Timepoint
Sample
Timepoint
3
x
Predose
x b
Predose b
x b
Predose c
x (start infusion)
5 minutes (±5 minutes)
x d
0–2 hours postdose interval g
15 minutes (±5 minutes)
x d
30 minutes (±10 minutes)
x d
45 minutes (±10 minutes)
x d
x (end infusion)
1 hour (±10 minutes)
x d,e
End of pevonedistat infusion
x e,f
1.5 hours (±10 minutes)
x d,e
30 minutes (±5 minutes)
x e,h
2 hours (±20 minutes)
x d,e
1 hour (±15 minutes)
x e,h
3 hours (±20 minutes)
x d,e
2 hours (±20 minutes)
x e,h
4 hours (±30 minutes)
x d,e
3 hours (±30 minutes)
x e,h
2-4 hours postdose interval g
5 hours (±30 minutes)
x d,e
4 hours (±30 minutes)
x e,h
7 hours (±30 minutes)
x d,e
6 hours (±30 minutes)
x e,h
4-6 hours postdose interval g
8 hours (±30 minutes)
x h
6–8 hours postdose interval g
4
24 hours (±1 hour)
x i
5
48 hours (±1 hour)
x i, j
IV: intravenous; PK: pharmacokinetic(s); SC: subcutaneous(ly).
a For days when azacitidine is coadministered with pevonedistat, azacitidine SC will be given first, followed by pevonedistat infusion.
b The predose plasma sample is to be collected within 10 minutes before the start of azacitidine administration.
c Patients should be asked to void completely in a container approximately 30 minutes before administration of the first dose of study drug. An aliquot of this spot urine specimen 
will be a predose urine sample. Detailed instructions on the procedure for collection, processing, storage, and shipment of the urine samples will be provided in the Study Manual.
d Samples should be collected after azacitidine SC administration.
e These samples are collected to measure both azacitidine and pevonedistat plasma concentrations.
f The sample is to be collected at the end of pevonedistat infusion (immediately before stopping the IV infusion). The pevonedistat infusion takes approximately 1 hour.
g Postdose intervals are based on completion of azacitidine SC administration.
h The time of sample collection is to be based on the time of completion of pevonedistat IV infusion on Day 3.
i The time of sample collection is to be based on the time of initiation of pevonedistat IV infusion on Day 3.
j The sample is to be collected before the combination dose administration on Day 5.
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Pevonedistat (TAK-924/MLN4924)
Study No. Pevonedistat-1016
Page 40 of 45
Statistical Analysis Plan 
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Table C
Bone Marrow Collection and Assessment Schedule (Patients with Hematologic Malignancies Only)
Assessment
Screening
Cycle 2
Day 22
(+6 Days)
Cycle 5
(Between
Days 15-28)
Cycle 8
(Between
Days 15-28)
Cycle 11
(Between
Days 15-28)
Subsequent Cycles
(Between Days 15-28);
Every 6 Cycles Thereafter
Relapse
Bone marrow blast count
x a
x b
x b
x b
x b
x b
x
Cytogenetics c
x
x
x 
x 
x 
x 
x
eCRF: electronic case report form; FISH: fluorescence in situ hybridization.
All samples will be collected and analyzed locally.
a At screening and for study eligibility, a bone marrow aspiration and biopsy (performed locally) will be required to assess disease burden, cytogenetics, molecular 
characterizations, and cellular composition by flow cytometry. A bone marrow biopsy (in addition to bone marrow aspirate) is required only at screening to confirm the diagnosis. 
However, a bone marrow biopsy may be collected with bone marrow aspirate in accordance with institutional guidelines. If a biopsy was done within 28 days before enrollment, 
this archival biopsy may be used and does not need to be repeated. If bone marrow biopsy is not collected routinely per country/institutional guidelines, it is not required.
b A bone marrow aspirate for blast count (to determine disease response) will be performed on Day 22 (+6 days) of Cycle 2, and between Days 15 and 28 of Cycle 5, Cycle 8, 
Cycle 11, and then every 6 cycles afterward or otherwise as clinically indicated at the discretion of the investigator. Results must be available before dosing starts in the next cycle.
c Cytogenetics analysis will be done at the clinical site: a bone marrow aspirate sample will be tested according to institutional guidelines in a cytogenetics laboratory routinely 
used by the site. Analyses should be done by karyotype, and by FISH if possible. Results will be collected in the eCRF.
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Pevonedistat (TAK-924/MLN4924)
Study No. Pevonedistat-1016
Page 41 of 45
Statistical Analysis Plan 
31 January 2022
CONFIDENTIAL
SOE for Part B: Treatment Cycle 1 (21-Day Cycle) Through EOS (Patients with Advanced Solid Tumors Only)
Day
Cycle 1 and Subsequent Cycles (21 days)
EOS/ET
Day 1
Day 3
Day 4
Day 5
Day 8 a
Day 15 a
Procedure
Window
(±3 day)
(±3 day)
(+10 days) b
Symptom-directed physical 
examination c
x
Complete physical examination
x
Weight
x d
x
Vital signs e
x
x
x
x
ECOG PS f
x
x
12-lead ECG g
x
x
Pregnancy test h
x
x
Hematology i
x
x
x
x
x
x
Complete chemistry panel
x
x
Select chemistry panel j
x
x
x
x
Urinalysis k
x
x
Plasma sample for pevonedistat 
PK (Cycle 1 only, see Table D)
x
x
x
Tumor assessment for solid 
tumors by RECIST, version 1.1 l
To be completed within 28 days before dosing in Part B, end of Cycle 2, Cycle 5, and every 6 cycles thereafter.
x
Pevonedistat IV infusion m
Days 1, 3, and 5 of each cycle.
Chemotherapy IV infusion m
Day 1 of each cycle.
Monitoring of concomitant 
medications and procedures
Recorded from the first dose of any study drug through 30 days (+10) days after the last dose of any study drug.
RBC and platelet transfusion 
documentation
Recorded from 8 weeks before enrollment through 30 days after the last dose of any study drug.
AE/SAE reporting
Recorded from the first dose of any study drug through 30 days (+10) days after the last dose of any study drug.
AEs 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 will be reported from signing of the ICF through 30 days after the last dose of any study drug.
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Pevonedistat (TAK-924/MLN4924)
Study No. Pevonedistat-1016
Page 42 of 45
Statistical Analysis Plan 
31 January 2022
CONFIDENTIAL
AE: adverse event; ALP: alkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase; BSA: body surface area; BUN: blood urea nitrogen; 
CT: computerized tomography; ECG: electrocardiogram; ECOG PS: Eastern Cooperative Oncology Group performance status; EOS: end of study; ET: early termination; 
ICF: informed consent form; IV: intravenous(ly); MRI: magnetic resonance imaging; PK: pharmacokinetic(s); RBC: red blood cells; RECIST: Response Evaluation Criteria in 
Solid Tumors; SAE: serious adverse event; SOE: schedule of events
Study completion is defined as completion of study treatment and the EOS visit.
Nonessential protocol visits in Part B 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 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 for the assessments performed are to be captured in the electronic data capture (EDC).
a Hematology samples and select chemistry panels will be collected on Days 8 (±1 day) and 15 (±1 day) in Cycle 1 and in any cycle in which intrapatient dose escalation of any 
study drug occurs.
b The EOS/ET visit will occur 30 days (+10 days) after the last dose of study drugs or before the start of subsequent antineoplastic therapy, if that occurs sooner.
c The symptom-directed physical examination will be conducted within 3 days before dosing on Day 1 of each treatment cycle. The symptom-directed physical examination may 
be performed at other visits during the treatment cycle at the discretion of the investigator.
d 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 H of 
the Protocol) 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.
e Vital signs, including diastolic and systolic blood pressure, heart rate, and body temperature will be collected predose (30 minutes [±10 minutes]) before the infusion of 
pevonedistat and 30 minutes (±10 minutes) after the start of the pevonedistat infusion on Days 1, 3, and 5 of each cycle, at EOS/ET, and as clinically indicated at the discretion of 
the investigator. On Cycle 1 Day 1, vital signs are to be measured predose (20 minutes [±10 minutes]) before the infusion of pevonedistat, 30 minutes (±10 minutes) after the start 
of the pevonedistat infusion, and 30 min (±10 minutes) after the completion of the pevonedistat infusion. Vital sign measurements will be taken with the patient in the supine (after 
3-5 minutes in this position) or sitting position (after 3-5 minutes in this position). Either oral or axial body temperature may be used, but the same method for measuring body 
temperature (oral or axial) should be used consistently for the same patient throughout the study.
f ECOG PS will be performed within 3 days before the beginning (Day 1) of each treatment cycle and at the EOS/ET visit.
g A 12-lead ECG will be performed Day 1 predose of every cycle and at EOS/ET. Predose assessment may be performed up to 3 days in advance if necessary. Additional ECGs 
may be obtained as clinically indicated at the discretion of the investigator. ECG assessments are to be performed with the patient supine and rested for 5 minutes.
h A serum pregnancy test will be performed for women of childbearing potential within 3 days before Day 1 of each cycle and at EOS/ET. The results from these tests must be 
available and negative before the study drug is administered on Day 1. If the Day 1 serum pregnancy results will not be available before dosing, a urine pregnancy test may be 
performed.
i Hematology samples will be collected before infusion with study drug(s) on Days 1, 3, and 5, and EOS/ET. Samples may be drawn up to 1 day before dosing. If dosing falls on a 
Monday, the collection window may be extended to collect samples on the previous Friday. Additional collections on Days 8 (±1 day) and 15 (±1 day) will be performed in 
Cycle 1 or in any cycle in which study drug dose is escalated.
j The select chemistry panel will be collected predose on Days 3 and 5 and will include the following: BUN, creatinine, total bilirubin, ALP, AST, and ALT. On Days 3 and 5 
samples may be drawn up to 1 day before dosing. If dosing falls on a Monday, the collection window may be extended to collect samples on the previous Friday. Additional 
collections on Days 8 (±1 day) and 15 (±1 day) will be performed in Cycle 1 or in any cycle in which study drug dose is escalated.
k Urinalysis will be analyzed locally. See Section 9.4.15.1 of the Protocol for additional details.
l Tumor assessment will be performed before the start of the study and at the completion of Cycle 2, Cycle 5, and every 6 cycles thereafter in Part B. Patients will undergo CT 
(with IV contrast, except for patients with an allergy to contrast agents), MRI, x-ray, and/or bone scanning to monitor and assess disease progression. If the anatomic region cannot 
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Pevonedistat (TAK-924/MLN4924)
Study No. Pevonedistat-1016
Page 43 of 45
Statistical Analysis Plan 
31 January 2022
CONFIDENTIAL
be adequately imaged by CT, MRI may be used instead; see Section 9.4.17.2 of the Protocol. An EOS/ET CT scan does not need to be completed/repeated if a scan was performed 
within the previous 28 days. Response will be determined according to RECIST version 1.1.
m The investigator will select which chemotherapy (docetaxel or carboplatin plus paclitaxel) that each patient will receive in combination with pevonedistat. Following a 4- to 7-
day washout period after single-dose pevonedistat administration in Part A, starting on Cycle 1 Day 1, patients will receive pevonedistat and chemotherapy agents on Day 1 and 
pevonedistat alone on Days 3 and 5 in 21-day cycles. The infusion of pevonedistat may be slowed or stopped and restarted for any associated infusion-related reactions. Following 
sponsor and investigator discussion of the available safety data, patients who tolerate treatment well at the initially assigned dose of pevonedistat may be allowed to increase their 
dose during Cycle 2 or in subsequent cycles of treatment. The chemotherapeutic agent may be dose reduced because of toxicities in accordance with Section 8.3.2.3 of the 
Protocol. See Section 8.0 of the Protocol for the details of study drug administration.
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Pevonedistat (TAK-924/MLN4924)
Study No. Pevonedistat-1016
Page 44 of 45
Statistical Analysis Plan 
31 January 2022
CONFIDENTIAL
Table D
Part B: Pevonedistat Plasma PK Sampling Schedule in Cycle 1 (Patients with Advanced Solid Tumors)
Day
Dosing
Pevonedistat Plasma PK
Pevonedistat
Timepoint
Sample
3
Predose a
x a
x (start infusion)
x (end infusion)
End of pevonedistat infusion
x b
30 minutes (±5 minutes)
x c
1 hour (±15 minutes)
x c
2 hours (±20 minutes)
x c
3 hours (±30 minutes)
x c
4 hours (±30 minutes)
x c
6 hours (±30 minutes)
x c
8 hours (±30 minutes)
x c
4
24 hours (±1 hour)
x d
5
48 hours (±1 hour)
x d
IV: intravenous; PK: pharmacokinetic(s).
a The predose plasma sample is to be collected within 10 minutes before the start of pevonedistat infusion.
b The sample is to be collected at the end of pevonedistat infusion (immediately before stopping the IV infusion). The pevonedistat infusion takes approximately 1 hour.
c The time of sample collection is to be based on the time of completion of pevonedistat IV infusion on Day 3.
d The time of sample collection is to be based on the time of initiation of pevonedistat IV infusion on Day 3.
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Pevonedistat (TAK-924/MLN4924)
Study No. Pevonedistat-1016
Page 45 of 45
Statistical Analysis Plan 
31 January 2022
CONFIDENTIAL
Appendix B
Study Diagrams
0- 8hr 24hr
48hr
72hr
0- 8hr 24hr
48hr
D 1
D 2
D 3
D 4
D 5
D 6
D 7
D1
D2
D3
D4
D5
D6
D7
D8
D9
D10
D 28
urine*
sample collection for PK
Pevonedistat dose (IV)
Azacitidine dose (SC)
*
Urine collection for PK
Part A
Part B
PEVONEDISTAT-1016   PART A: SINGLE DOSE PEVONEDISTAT AND PART B: PEVONEDISTAT IN 
COMBINATION WITH AZACITIDINE (PATIENTS WITH HEMATOLOGIC MALIGNANCIES)
Pevonedistat 
Azacitidine 
Pevonedistat 
20 mg/m2
SCREENING 
(28 days)
D, Day; IV, intravenous; PK, pharmacokinetic; SC, subcutaneous
In Part A, patients will receive a single dose of pevonedistat forPK assessment.  In Part B, patients with hematologic 
malignancies will receive an IV infusion of pevonedistat on Days 1, 3, and 5 in combination with azacitidine SC on Days 1–5, 8, 
and 9 in a 28 -day treatment period. Part B may start 4-7 days after the dose of pevonedistat administered in Part A. 
Intrapatient dose escalation may start in Cycle 2 or in subsequent cycles. See Section 8.1 for details of study drug 
administration.
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ELECTRONIC SIGNATURES 
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm ‘UTC’) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
090101d6812b33cb
P1016_SAP_Amendment 4_Final
Biostatistics Approval
23-Feb-2022 13:48 UTC
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