Clinical trial NCT03486314
Conditions: Advanced Solid Neoplasm
Keywords: Drug therapy
Sponsor: Millennium Pharmaceuticals, Inc.
Start date: 2018-08-13; Completion date: 2021-02-28
Enrollment: 20 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The purpose of this study is to assess the effect of multiple-dose administration of rifampin on the single dose PK of pevonedistat in adult participants with advanced solid tumors.

Detailed description:
The study will enroll approximately 20 participants. The study will be conducted in two Parts: Part A and optional Part B. Part A will have a drug-drug interaction (DDI) assessment. In Part A, participants will be assigned to:

• Pevonedistat 50 mg/m\^2 + Rifampin

Eligible participants from Part A will continue treatment in optional Part B with pevonedistat in combination with SoC chemotherapy, docetaxel or carboplatin plus paclitaxel. The investigator will decide which SoC combination partner a participant will receive.

* Pevonedistat 25 mg/m\^2 + Docetaxel
* Pevonedistat 20 mg/m\^2 + Carboplatin + Paclitaxel

This multi-center trial will be conducted in the United States. The overall time to participate in this study is 18 months. Participants will make a final visit to the clinic 30 days after receiving their last dose of study drug or before the start of subsequent therapy.

Arms: arm 1: Pevonedistat 50 milligram per square meter (mg/m\^2), intravenous infusion, once on Day 1 and 10 along with rifampin 600 milligram (mg), capsule, orally, once daily from Day 3 up to Day 11 in Part A. After completion of Part A, participants had opportunity to continue into optional Part B. arm 2: Pevonedistat 25 mg/m\^2 intravenously in combination with docetaxel 75 mg/m\^2 or at 20 mg/m\^2 in combination with carboplatin +paclitaxel 175 mg/m\^2; pevonedistat was given in combination on Day 1 and as a single agent on Days 3 and 5 of each 21-day cycle. Participants were treated for up to 12 cycles or symptomatic deterioration or PD, treatment was discontinued for another reason, or until the study is stopped in Part B. The choice of combination partner (docetaxel or carboplatin + paclitaxel) was based on investigator discretion. If the sponsor and investigator determine that a participant would derive clinical benefit from continued treatment, the participant may remain on the current combination therapy or receive pevonedistat as a single agent beyond 12 cycles.
Interventions: intervention 1: Pevonedistat intervention 2: Rifampin intervention 3: Docetaxel intervention 4: Carboplatin intervention 5: Paclitaxel
Intervention descriptions: intervention 1: Pevonedistat intravenous infusion. intervention 2: Rifampin capsules. intervention 3: Docetaxel intravenous infusion. intervention 4: Carboplatin intravenous infusion. intervention 5: Paclitaxel intravenous infusion.

Protocol documents:
Prot_000.pdf: 



Title: A Phase 1 Study to Evaluate the Effects of Rifampin on Pharmacokinetics of Pevonedistat in 
Patients with Advanced Solid Tumors
NCT Number: NCT03486314
Protocol Approve Date: 04 September 2018
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
view with a black/blue bar) to protect either personally identifiable information (PPD) or company 
confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal information, or 
to otherwise protect the integrity of the clinical study.


PRE-TEAM.0 TITLE PAGE
PROTOCOL
A Phase 1 Study to Evaluate the Effects of Rifampin on Pharmacokinetics of Pevonedistat in 
Patients With Advanced Solid Tumors
TAK-924/MLN4924: Effect of Rifampin (Strong Metabolic Enzyme Inducer)
on 50 mg/m2 Dosing of Pevonedistat
Sponsor:
Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda 
Pharmaceutical Company Limited
40 Lansdowne Street
Cambridge, MA 02139
USA
Telephone: +1 (617) 679-7000
Please note: Millennium Pharmaceuticals, Inc, a wholly owned 
subsidiary of Takeda Pharmaceutical Company Limited, may be 
referred to in this protocol as “Millennium,” “Sponsor,” or “Takeda”.
Study Number:
Pevonedistat-1015
IND Number:
78,427
EudraCT Number: Not Applicable
Compound:
Pevonedistat (TAK-924/MLN4924)
Date:
04 September 2018
Version/Amendment 
Number: 
02
Date
Amendment No.
Amendment Type
Region
29 November 2017
Initial Protocol
Not applicable
United States
28 February 2018
01
Substantial
United States
04 September 2018
02
Nonsubstantial
United States
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1.0
ADMINISTRATIVE 
1.1
Contacts 
A separate contact information list will be provided to each site.
Serious adverse event and pregnancy reporting information is presented in Section 10.0, as is 
information on reporting product complaints.
Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical 
Company Limited-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
United States of America (USA)
Contact
Serious adverse event and pregnancy reporting
See Section 10.0
Medical Monitor
(medical advice on protocol and compound)
Refer to Study Manual
Responsible Medical Officer 
(carries overall responsibility for the conduct of the study)
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.
PPD
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wing:
GCP):
GCP):
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INVESTIGATOR AGREEMENT 
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, and any 
other product information provided by the sponsor. I agree to conduct this study in accordance 
with the requirements of this protocol and also to protect the rights, safety, privacy, and well-being 
of study subjects in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

ICH, E6 GCP: Consolidated Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting serious adverse events defined in Section 10.2 of this 
protocol.

Terms outlined in the Clinical Study Site Agreement.

Responsibilities of the Investigator (Appendix B).
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 02 Summary of Changes
Rationale for Amendment 02
This document describes the changes in reference to the protocol incorporating Amendment 02. 
The primary reason for this amendment is to clarify the timing of the assessment of left ventricular 
ejection fraction (LVEF) as it relates to study eligibility.
Minor grammatical, editorial, formatting, and administrative changes not affecting the conduct of 
the study are included for clarification and administrative purposes only.
For specific descriptions of text changes, the rationale for each change, and where the changes are 
located, see Appendix L.
Changes in Amendment 02
1.
Clarify the exclusion criterion regarding the assessment of LVEF.
2. Delete the requirement that, for inclusion in the study, patients must have a tumor that is 
radiographically or clinically evaluable and/or measurable.
3. Change serious adverse event reporting from a paper-based system to electronic data capture.
4. Clarify the timing of chemistry and hematology laboratory assessments before administration 
of the Day 1 dose of pevonedistat in Part A (drug-drug interaction) of the study.
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TABLE OF CONTENTS
1.0
ADMINISTRATIVE.......................................................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
1.3
Protocol Amendment 02 Summary of Changes ..........................................................5
2.0
STUDY SUMMARY ....................................................................................................12
3.0
STUDY REFERENCE INFORMATION ......................................................................17
3.1
Study-Related Responsibilities.................................................................................17
3.2
Principal Investigator...............................................................................................17
3.3
List of Abbreviations ...............................................................................................18
3.4
Corporate Identification...........................................................................................19
4.0
INTRODUCTION.........................................................................................................20
4.1
Background .............................................................................................................20
4.1.1
Study Drug.........................................................................................................20
4.1.2
Nonclinical Background Information .................................................................20
4.1.3
Clinical Background Information .......................................................................21
4.1.4
Potential Risks and Benefits...............................................................................22
4.2
Rationale for the Proposed Study.............................................................................27
4.2.1
Rationale for Dose and Duration of PK Assessments in Part A...........................27
4.2.2
Rationale for Continued Treatment With Pevonedistat in Combination With 
Chemotherapy in Optional Part B.......................................................................28
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................30
5.1
Objectives................................................................................................................30
5.1.1
Primary Objectives.............................................................................................30
5.1.2
Secondary Objectives.........................................................................................30
5.1.3
Safety Objectives ...............................................................................................30
5.1.4
Exploratory/Additional Objectives .....................................................................30
5.2
Endpoints.................................................................................................................30
5.2.1
Primary Endpoint...............................................................................................30
5.2.2
Secondary Endpoints..........................................................................................31
5.2.3
Safety Endpoints................................................................................................31
5.2.4
Exploratory/Additional Endpoints......................................................................31
6.0
STUDY DESIGN..........................................................................................................32
6.1
Overview of Study Design.......................................................................................32
6.2
Number of Patients ..................................................................................................34
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6.3
Duration of Study ....................................................................................................34
6.3.1
Duration of an Individual Patient’s Study Participation ......................................34
6.3.2
EOS/Study Completion Definition and Planned Reporting.................................35
6.3.3
Timeframes for Primary and Secondary Endpoints to Support Disclosures.........35
6.3.4
Total Study Duration..........................................................................................35
6.3.5
Post Trial Access ...............................................................................................36
6.3.6
Duration of PTA ................................................................................................36
7.0
STUDY POPULATION................................................................................................37
7.1
Inclusion Criteria .....................................................................................................37
7.2
Exclusion Criteria ....................................................................................................38
7.3
Criteria for Continuation into Optional Part B..........................................................40
8.0
STUDY DRUG .............................................................................................................42
8.1
Study Drug Administration......................................................................................42
8.1.1
Part A: Pevonedistat and Rifampin Administration.............................................42
8.1.2
Part B (Optional): Pevonedistat in Combination With SOC Chemotherapy 
Agents ...............................................................................................................43
8.2
Reference/Control Therapy......................................................................................44
8.3
Dose Modification Guidelines (Part B) ....................................................................45
8.3.1
Criteria for Beginning or Delaying a Subsequent Treatment Cycle.....................45
8.3.2
Criteria for Dose Interruption During a Cycle.....................................................45
8.3.3
Criteria for Dose Reduction................................................................................45
8.3.4
Criteria for Discontinuation of Study Drug.........................................................46
8.4
Excluded Concomitant Medications and Procedures ................................................47
8.4.1
Part A ................................................................................................................47
8.4.2
Part B.................................................................................................................47
8.5
Permitted Concomitant Medications and Procedures................................................48
8.5.1
Part A ................................................................................................................48
8.5.2
Part B.................................................................................................................48
8.6
Precautions and Restrictions ....................................................................................49
8.6.1
Pevonedistat.......................................................................................................49
8.6.2
Rifampin............................................................................................................50
8.6.3
Docetaxel...........................................................................................................50
8.6.4
Carboplatin ........................................................................................................51
8.6.5
Paclitaxel ...........................................................................................................51
8.7
Management of Clinical Events ...............................................................................51
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8.7.1
Guidance for Clinical Assessment and Management of Hemodynamic 
Compromise (Part A and Part B)........................................................................52
8.7.2
Guidance for Use of Granulocyte-Colony Stimulating Factor.............................52
8.7.3
Guidance for Clinical Assessment and Management of Anemia .........................52
8.7.4
Guidance for Management of Extravasation.......................................................53
8.8
Blinding and Unblinding..........................................................................................53
8.9
Description of Investigational Agents ......................................................................53
8.9.1
Pevonedistat.......................................................................................................53
8.9.2
Rifampin............................................................................................................53
8.9.3
Docetaxel...........................................................................................................53
8.9.4
Carboplatin ........................................................................................................53
8.9.5
Paclitaxel ...........................................................................................................54
8.10
Preparation, Reconstitution, and Dispensation..........................................................54
8.10.1 Pevonedistat.......................................................................................................54
8.10.2 Docetaxel, Carboplatin, Paclitaxel and Rifampin................................................54
8.11
Packaging and Labeling...........................................................................................54
8.11.1 Pevonedistat.......................................................................................................54
8.11.2 Docetaxel, Carboplatin, and Paclitaxel...............................................................54
8.11.3 Rifampin............................................................................................................55
8.12
Storage, Handling, and Accountability.....................................................................55
8.12.1 Pevonedistat.......................................................................................................55
8.12.2 Docetaxel, Carboplatin, Paclitaxel and Rifampin................................................55
8.13
Other Protocol-Specified Materials ..........................................................................55
9.0
STUDY CONDUCT......................................................................................................56
9.1
Study Personnel and Organizations..........................................................................56
9.2
Arrangements for Recruitment of Patients................................................................56
9.3
Treatment Group Assignments.................................................................................56
9.4
Study Procedures.....................................................................................................56
9.4.1
Informed Consent...............................................................................................56
9.4.2
Patient Demographics ........................................................................................56
9.4.3
Medical History .................................................................................................56
9.4.4
Physical Examination.........................................................................................57
9.4.5
Patient Height ....................................................................................................57
9.4.6
Vital Signs .........................................................................................................57
9.4.7
Pregnancy Test...................................................................................................57
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9.4.8
Concomitant Medications and Procedures..........................................................57
9.4.9
AEs....................................................................................................................58
9.4.10 Enrollment .........................................................................................................58
9.4.11 Electrocardiogram..............................................................................................58
9.4.12 Echocardiogram.................................................................................................58
9.4.13 Clinical Laboratory Evaluations .........................................................................58
9.4.14 Disease Assessment ...........................................................................................59
9.4.15 Biomarker, Pharmacodynamic, and PK Samples ................................................60
9.4.16 PK Measurements..............................................................................................60
9.4.17 Pharmacodynamic Measurements ......................................................................61
9.4.18 DNA Measurements...........................................................................................61
9.4.19 Banked Tumor Specimen Measurements............................................................61
9.4.20 Immunogenicity Sample Collection ...................................................................61
9.5
Completion of Study Treatment (for Individual Patients) .........................................61
9.5.1
Part A ................................................................................................................61
9.5.2
Part B.................................................................................................................61
9.6
Discontinuation of Treatment With Study Drug and Patient Replacement................62
9.7
Withdrawal of Patients From Study .........................................................................62
9.8
Study Compliance....................................................................................................63
10.0
ADVERSE EVENTS ....................................................................................................64
10.1
Definitions...............................................................................................................64
10.1.1 PTE Definition...................................................................................................64
10.1.2 AE Definition ....................................................................................................64
10.1.3 SAE Definition ..................................................................................................64
10.2
Procedures for Recording and Reporting AEs and SAEs..........................................65
10.3
Monitoring of AEs and Period of Observation .........................................................66
10.4
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events.........66
10.5
Procedures for Reporting Product Complaints or Medication Errors (Including 
Overdose) ................................................................................................................67
10.6
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities...........67
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................68
12.0
DATA HANDLING AND RECORDKEEPING............................................................69
12.1
eCRFs......................................................................................................................69
12.2
Record Retention .....................................................................................................69
13.0
STATISTICAL METHODS..........................................................................................71
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13.1
Statistical and Analytical Plans ................................................................................71
13.1.1 Analysis Sets......................................................................................................71
13.1.2 Analysis of Demographics and Other Baseline Characteristics ...........................71
13.1.3 Efficacy Analysis...............................................................................................71
13.1.4 PK Analysis .......................................................................................................71
13.1.5 Safety Analysis ..................................................................................................72
13.2
Interim Analysis and Criteria for Early Termination ................................................73
13.3
Determination of Sample Size..................................................................................73
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................74
14.1
Study-Site Monitoring Visits ...................................................................................74
14.2
Protocol Deviations..................................................................................................74
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................74
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................75
15.1
IRB and/or IEC Approval ........................................................................................75
15.2
Subject Information, Informed Consent, and Subject Authorization .........................76
15.3
Subject Confidentiality ............................................................................................77
15.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................77
15.4.1 Publication.........................................................................................................77
15.4.2 Clinical Trial Registration..................................................................................78
15.4.3 Clinical Trial Results Disclosure ........................................................................78
15.5
Insurance and Compensation for Injury....................................................................78
16.0
REFERENCES..............................................................................................................79
LIST OF IN-TEXT TABLES
Table 6.a
Primary and Secondary Endpoints for Disclosures: Part A .................................35
Table 6.b
Primary and Secondary Endpoints for Disclosures: Part B..................................35
Table 8.a
Dose Modification Guidelines for Specific Toxicities ........................................46
Table 8.b
Excluded Concomitant Medications and Procedures During Part A....................47
Table 8.c
Excluded Concomitant Medications and Procedures During Part B....................47
Table 8.d
Permitted Concomitant Medications and Procedures During Part A ...................48
Table 8.e
Permitted Concomitant Medications and Procedures During Part B....................49
Table 9.a
Clinical Chemistry and Hematology Tests..........................................................59
Table 9.b
Clinical Urinalysis Tests ....................................................................................59
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LIST OF IN-TEXT FIGURES
Figure 6.a
Study Overview .................................................................................................33
LIST OF APPENDICES
Appendix A
Schedules of Events ...........................................................................................80
Appendix B
Responsibilities of the Investigator.....................................................................85
Appendix C
Investigator Consent to Use of Personal Information..........................................87
Appendix D
ECOG Scale for Performance Status ..................................................................88
Appendix E
Drugs Associated With Nephrotoxicity ..............................................................89
Appendix F
Definition of Postmenopausal ............................................................................90
Appendix G
Acceptable Methods of Contraception Considered Highly Effective...................91
Appendix H
Response Criteria...............................................................................................93
Appendix I
Hematologic Toxicity of Carboplatin Alone and in Combination With 
Paclitaxel ...........................................................................................................94
Appendix J
New York Heart Association Classification of Cardiac Disease..........................96
Appendix K
Excluded Strong CYP3A Inducers .....................................................................97
Appendix L
Detailed Description of Amendments to Text.....................................................98
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2.0
STUDY SUMMARY
Name of Sponsor(s):
Millennium Pharmaceuticals, Inc, a wholly owned 
subsidiary of Takeda Pharmaceutical Company Limited
Compound:
Pevonedistat (TAK-924; MLN4924)
Title of Protocol: A Phase 1 Study to Evaluate the Effects 
of Rifampin on Pharmacokinetics of Pevonedistat in 
Patients with Advanced Solid Tumors
IND No.: 78,427
EudraCT No.:
Not applicable
Study Number: Pevonedistat-1015
Phase: 1
Study Design:
Part A: Assessment of the effect of rifampin on pevonedistat pharmacokinetics (PK)
Eligible patients will receive a single dose of 50 mg/m2 pevonedistat via a 1-hour intravenous (IV) infusion on Day 1. 
Plasma PK samples will be collected at a series of predetermined time points up to 48 hours (Day 3) following the 
single dose of pevonedistat. Patients will then receive an oral dose of 600 mg rifampin once daily (QD) starting from 
Day 3 (after collecting the 48-hour PK sample) through Day 11. There will be no pevonedistat doses from Day 2 
through Day 9. On Day 10, a single dose of 50 mg/m2 pevonedistat will be administered, and plasma samples will be 
collected at predetermined time points up to 48 hours (Day 12) following the second single dose of pevonedistat. 
Study drug will be discontinued early if a patient experiences study drug‒related toxicities.
Both doses of pevonedistat (Days 1 and 10) will be administered in the clinic, followed by the required PK sampling. 
Serial blood plasma samples for determination of the plasma concentration of pevonedistat will be obtained during 
Part A at prespecified time points. The first dose of rifampin will be given orally in the clinic on the morning of Day 3 
after collection of the 48-hour PK sample. Patients will self-administer rifampin (oral capsules) QD on Days 4, 5, 6, 7, 
8, and 9 at home. Patients are encouraged to take rifampin at approximately the same time each day (±2 hours from the 
time of first rifampin dose). On Days 10 and 11, patients will report to the clinic to continue to receive oral 600 mg 
rifampin co-administered with pevonedistat on Day 10, and at the time of the 24-hour pevonedistat PK sampling on 
Day 11. The last PK sampling is on Day 12 (48-hour post pevonedistat infusion on Day 10). There will be no 
pevonedistat dosing on Days 11 and 12. There will be no rifampin dosing on Day 12.
All doses of rifampin will be administered on an empty stomach with patients taking nothing by mouth (NPO) except 
for water and prescribed medications for 2 hours before and at least 1 hour after each rifampin dose. Patients who miss 
any rifampin doses on Days 3 to 9 will not be considered evaluable and pevonedistat dosing and PK sampling on 
Day 10 will not be required for these patients. Patients will have a washout period from the last dose of rifampin for at 
least 1 week to allow reversal of metabolic enzyme induction before the start of Part B of the study.
Part B (OPTIONAL): Continued Treatment with Pevonedistat in Combination with Standard of Care (SOC)
After completion of Part A of this study, patients will have the option of participating in Part B. Any patient who 
decides to participate in Part B will need to meet the continuation criteria of the study before treatment in Part B can 
begin. Patients will receive pevonedistat in combination with either docetaxel or carboplatin+paclitaxel, as 
recommended by the investigator. As in Part A, safety assessments will also be conducted in Part B of the study. In 
addition, Part B will conduct disease assessments using radiological evaluations (computed tomography scan or 
magnetic resonance imaging).
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Primary Objective:
To assess the effect of multiple-dose administration of rifampin on the single-dose PK of pevonedistat in adult patients 
with advanced solid tumors (Part A).
Secondary Objectives:
Part A: The secondary objective of Part A is to further characterize pevonedistat PK following a single dose at 
50 mg/m2 in the absence or presence of rifampin.
Part B: The secondary objective of Part B is to evaluate disease response that may be observed following treatment 
with pevonedistat in combination with either docetaxel or carboplatin+paclitaxel in patients with advanced solid 
tumors.
Safety Objectives:
Part A: The safety objective for Part A is to evaluate the safety and tolerability of pevonedistat in patients with 
advanced solid tumors following a single IV dose at 50 mg/m2 in the absence or presence of rifampin.
Part B: The safety objective for Part B is to evaluate the safety and tolerability of pevonedistat in combination with 
either docetaxel or carboplatin+paclitaxel in patients with advanced solid tumors.
Subject Population: Adult patients, aged ≥18 years, 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+paclitaxel in Part B of this study, or have progressed, despite standard therapy, or for whom 
conventional therapy is not considered effective.
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Number of Subjects:
Approximately 20 patients (for approximately 
12 PK-evaluable patients).
Number of Sites:
Estimated total: approximately 4 to 6 sites in the 
United States of America (USA).
Dose Level(s):
Part A:
Pevonedistat is given IV at 50 mg/m2 on Day 1 and Day 10.
Rifampin is given orally at 600 mg on Days 3 through 11; it 
is co-administered with pevonedistat on Day 10.
Part B:
Pevonedistat is given IV at 25 mg/m2 in combination with 
docetaxel 75 mg/m2 or at 20 mg/m2 in combination with 
carboplatin AUC5+paclitaxel 175 mg/m2; pevonedistat is 
given in combination on Day 1 and as a single agent on 
Days 3 and 5 of each 21-day cycle.
Route of Administration:
Part A:
Pevonedistat: IV infusion
Rifampin: oral dose
Part B (Optional):
Pevonedistat: IV infusion
Docetaxel, carboplatin, and paclitaxel: IV infusion
Duration of Treatment:
Part A: Single IV dose of pevonedistat at 50 mg/m2 on 
Day 1 and Day 10, followed by a period of at least 1 week 
for washout and safety observation.
Part B (Optional): Eligible patients may continue to 
receive treatment in Part B of this study until they 
experience symptomatic deterioration or disease 
progression, treatment is discontinued for another reason, or 
until the study is stopped.
Follow-up: Patients will attend an End of Study (EOS) visit 
30 days (+10 days) after the last dose of study drug or 
before the start of subsequent therapy in Part B, if that 
occurs sooner.
Period of Evaluation:
Screening: Within 28 days before the first dose of 
study drug in Part A.
Part A: 12 days with an EOS visit at 30 (+10) days 
(safety follow-up) after the last dose of study drug for 
patients who do not continue on to optional Part B.
Part B (Optional): The duration of treatment for 
Part B is 12 cycles. If the sponsor and investigator 
determine that a patient would derive clinical benefit 
from continued treatment, the patient may remain on 
the current combination therapy or receive 
pevonedistat as a single agent beyond 12 cycles.
Patients who have achieved clinical benefit from 
combination therapy (chemotherapy+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 by the sponsor.
All patients in optional Part B will attend an EOS visit 
at 30 (+10) days (safety follow-up) after the last dose 
of study drug or before the start of subsequent therapy 
for their disease, if that occurs sooner.
Main Criteria for Inclusion:

Adult patients who have a histologically or cytologically confirmed metastatic or locally advanced solid tumor 
that is appropriate for treatment with 1 of the 2 combination therapies in Part B of this study, or have progressed 
despite standard therapy, or for whom conventional therapy is not considered effective.

Adequate renal, hepatic, and cardiac functions, and other safety parameters to reflect the risk mitigation strategy 
in place in all ongoing pevonedistat studies, and with special consideration to the safety profile of the SOC agents 
(Part B of the study).
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Main Criteria for Exclusion:

Systemic treatment with strong metabolic enzyme inducers must be discontinued at least 14 days before the first 
dose of pevonedistat.

Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of 
rifampin, including difficulty swallowing capsules.
Main Criteria for Evaluation and Analyses:

Primary

Ratios of geometric mean pevonedistat maximum observed plasma concentration (Cmax), area under the plasma 
concentration versus time curve from time 0 to the time of the last quantifiable concentration (AUClast), and area 
under the plasma concentration versus time curve from time 0 to infinity (AUC∞) in the presence of rifampin in 
reference to Cmax, AUClast, and AUC∞in the absence of rifampin and associated 90% CIs.

Secondary

Part A:

PK parameters: total clearance after intravenous administration (CL), volume of distribution at steady state 
after intravenous administration (Vss), and terminal disposition phase half-life (t1/2z) of pevonedistat 
following a single dose administration of 50 mg/m2 on Day 1 (in the absence of rifampin) and Day 10 (in the 
presence of rifampin).

Part B:

Measures of disease response based on the investigator’s assessment using the Response Evaluation Criteria in 
Solid Tumors (RECIST, Version 1.1) guideline.
Safety Endpoints:
Part A

Adverse events (AEs), serious adverse events (SAEs), assessments of clinical and laboratory values, and vital 
signs measurements following a single dose administration of pevonedistat at 50 mg/m2.
Part B

AEs, SAEs, assessments of clinical and laboratory values, and vital signs measurements following administration 
of pevonedistat in combination with either docetaxel or carboplatin+paclitaxel.
Statistical Considerations:
Statistical analyses will be primarily descriptive and will be listed and/or summarized in tabular and/or graphical form. 
No formal statistical hypothesis testing will be performed. A formal statistical analysis plan will be developed and 
finalized before database lock. 
Demographic and baseline characteristics will be summarized, including sex, age, race, ethnicity, weight, height, body 
surface area (BSA), baseline disease characteristics, and other parameters as appropriate.
All available efficacy and safety data will be included in data listings and/or tabulations and/or graphs.
Individual values and descriptive statistics of pevonedistat plasma concentration time data and PK parameters 
including but not limited to CL, Vss, and t1/2z will be listed and tabulated by Day 1 (pevonedistat in the absence of 
rifampin) and Day 10 (pevonedistat in the presence of rifampin).
For pevonedistat-rifampin drug-drug interaction assessment, the ratios of geometric mean Cmax, AUClast, and AUC∞of 
pevonedistat in the presence of rifampin versus Cmax, AUClast, and AUC∞in the absence of rifampin and associated 
90% CIs will be calculated.
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Sample Size Justification: The sample size calculation is based on the expected two-sided 90% CI for the difference 
in the paired, log-transformed area under the plasma concentration-time curve (AUC) (or Cmax) means of pevonedistat 
co-administered with rifampin and pevonedistat administered alone. Based on the preliminary data obtained from 
Study C15011, the within-subject coefficient of variation was estimated to be 13% for AUC and 58% for Cmax, 
respectively. Assuming the AUC (or Cmax) ratio is 1.0, with a sample size of 12 evaluable patients, the 90% CI of the 
ratio of geometric means is expected to be (0.907, 1.102) for AUC and (0.671, 1.49) for Cmax based on the previously 
discussed variance assumptions. If the ratio is X, the 90% CI of the ratio of geometric means is expected to be within 
(0.907X, 1.102X) and (0.671X, 1.49X), respectively. Patients who are not PK evaluable will be replaced to ensure 
availability of approximately 12 PK-evaluable patients for the final analysis.
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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 in the template for specific study-related 
activities will perform these activities in full or in partnership with the sponsor.
3.2
Principal Investigator
Takeda will select a Signatory Coordinating Investigator from the investigators who participate in 
the study. Selection criteria for this investigator will include significant knowledge of the study 
protocol, the study medication, their expertise in the therapeutic area and the conduct of clinical 
research as well as study participation. The Signatory Coordinating Investigator will be required to 
review and sign the clinical study report and by doing so agrees that it accurately describes the 
results of the study.
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3.3
List of Abbreviations
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AML
acute myeloid leukemia
ANC
absolute neutrophil count
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AUC
area under the plasma concentration-time curve
AUC∞
area under the plasma concentration versus time curve from time 0 to infinity
AUClast
area under the plasma concentration-time curve from time 0 to time of the last quantifiable 
concentration 
BCRP
breast cancer resistance protein
BP
blood pressure
BSA
body surface area
CDLs
cullin-dependent ubiquitin E3 ligases
CL
total clearance after intravenous administration
Cmax
maximum observed plasma concentration
CR
complete response
CrCl
creatinine clearance
CRO
contract research organization
CT
computed tomography
CYP
cytochrome P-450
DDI
drug-drug interaction
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EOS
end of study
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GFR
glomerular filtration rate
GI
gastrointestinal
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
IEC
independent ethics committee
IRB
institutional review board
IV
intravenous
LVEF
left ventricular ejection fraction
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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
NPO
nothing-by-mouth (nil per os)
NSCLC
non–small cell lung cancer
Pgp
P-glycoprotein
PD
progressive disease
PK
pharmacokinetic(s)
PR
partial response
PTA
post trial access
PTE
pretreatment event
QD
once daily
QTc
corrected QT interval
RECIST
Response Evaluation Criteria in Solid Tumors
RBC
red blood cell
RP2D
recommended phase 2 dose
SAE
serious adverse event
SC
subcutaneous
SD
stable disease
SOC
standard of care
SOE
Schedule of Events
SUSAR
suspected unexpected serious adverse reaction
t1/2z
terminal disposition phase half-life
TEAE
treatment-emergent adverse event
ULN
upper limit of normal
USP
United States Pharmacopeia
USPI
United States package insert
Vss
volume of distribution at steady state after intravenous administration
WBC
white blood cells
3.4
Corporate Identification 
Millennium
Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda 
Pharmaceutical Company Limited.
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4.0
INTRODUCTION
4.1
Background
Pevonedistat is a cytotoxic agent and cannot be administered to healthy subjects. Pevonedistat is 
currently in phase 2/3 of clinical development for higher-risk myelodysplastic syndromes, chronic 
myelomonocytic leukemia, and low-blast acute myeloid 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. In 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 docetaxel 75 mg/m2 on Day 1 in 21-day 
cycles. The MTD and RP2D of pevonedistat in combination with paclitaxel+carboplatin is 
20 mg/m2 pevonedistat dosed on Days 1, 3, and 5 and 175 mg/m2 paclitaxel+carboplatin (AUC5) 
on Day 1 in 21-day cycles.
4.1.1
Study Drug
Pevonedistat (TAK-924/MLN4924) 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 ligase, is an essential component of 
the NEDD8 conjugation pathway that controls the activity of a subset of ubiquitin E3 ligases, 
multiprotein complexes that transfer ubiquitin molecules to protein substrates that are then 
targeted to the proteasome for degradation. Cullin-dependent ubiquitin E3 ligases (CDLs) require 
conjugation to NEDD8 to be activated. CDLs control the timely ubiquitination and consequent 
proteasomal degradation of proteins with important roles in cell cycle progression and signal 
transduction, cellular processes that are integral to tumor cell growth, proliferation, and survival. 
Inhibitors of NAE activity may be of therapeutic value in the treatment of various cancers, such as 
solid tumors, by inhibiting the degradation of a subset of proteins that are regulated by the 
proteasome. Pevonedistat treatment results in tumor growth inhibition in mouse tumor xenografts 
models.
4.1.2
Nonclinical Background Information
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 (see the current Investigator’s 
Brochure [IB]).
Pevonedistat demonstrated antitumor activity in xenograft models when administered to 
immunocompromised mice by the subcutaneous (SC) route. The degree of the pharmacodynamic 
effect in HCT-116 xenograft tumors was dose dependent and correlated with dose-dependent 
antitumor activity after 21 consecutive days of twice-daily treatment. Pevonedistat also 
demonstrated a dose-dependent pharmacodynamic response in additional xenograft models (AML 
model HL-60, the Calu-6 lung tumor model, and 2 xenograft models of diffuse large B cell 
lymphoma: OCI-Ly10 and OCI-Ly19). Pevonedistat demonstrated antitumor activity in these 
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models with less frequent treatment, showing that continuous dosing is not necessary for antitumor 
activity.
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 the bile in bile duct cannulated rats; excretion was almost complete by 24 hours 
postdose. No plasma metabolite accounted for more than 10% of the total plasma radioactivity, 
suggesting potentially low systemic exposure to metabolites.
Detailed information regarding the nonclinical pharmacology and toxicology of pevonedistat may 
be found in the current 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 (C15001, C15002, C15003, and C15005) and pevonedistat in combination 
with standard-of-care chemotherapy (C15009 and C15010) in patients with solid tumor or 
hematological malignancies. The database contained 335 subjects contributing 3768 PK 
observations. Pevonedistat plasma concentration-time profiles were well described by a 
2-compartment model with linear elimination. Body surface area (BSA) was an important 
predictor of total clearance after intravenous administration (CL), distributional clearance, and 
both central and peripheral volumes. For a typical patient with a BSA of 1.73 m2, an alpha half-life 
of 1.27 hours and a beta (elimination) half-life of 7.85 hours are estimated. Concurrent 
administration of carboplatin and paclitaxel decreased the CL of pevonedistat by approximately 
44%, translating to an approximately 80% higher pevonedistat exposure (area under the plasma 
concentration-time curve [AUC]) during coadministration with carboplatin and paclitaxel, 
consistent with pevonedistat concentration data observed in C15010. Coadministration with 
azacitidine, gemcitabine, or docetaxel did not appear to affect the CL of pevonedistat. Race, sex, 
age, tumor type (hematologic vs solid), mild or moderate renal impairment (creatinine clearance 
[CrCl] ≥30 mL/minute), or mildly impaired liver function, to the extent represented in this dataset, 
had no impact on pevonedistat PK.
In a drug-drug interaction (DDI) study (C15011), preliminary data from 26 evaluable patients 
(13 from the itraconazole arm and 13 from the fluconazole arm) demonstrate that steady-state 
exposures to fluconazole had a minimal effect on the single-dose IV pevonedistat PK at 8 mg/m2, 
while mean systemic exposure to pevonedistat increased by approximately 23% in the presence of 
itraconazole.
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On the basis of these observations, additional patients were enrolled to evaluate the effects of 
itraconazole on pevonedistat PK at the clinical dose of 20 mg/m2. Preliminary data from 
11 patients who completed protocol-specified dosing and PK evaluations indicated that 
pevonedistat systemic exposures following IV administration at 20 mg/m2 in the presence of 
itraconazole were similar to those in the absence of itraconazole (geometric mean ratio of 0.996 
with an associated 90% CI of 0.913 and 1.09). These findings with established moderate and 
strong cytochrome P-450 (CYP)3A inhibitor probes indicate a minor contribution of CYP3A to 
pevonedistat metabolism in humans. On the basis of these results, moderate and strong CYP3A 
inhibitors and P-glycoprotein (Pgp) inhibitors can be used in patients receiving pevonedistat. For 
individual studies in the pevonedistat clinical program, reference should be made to the respective 
protocols for specific information relating to excluded and permitted medications.
4.1.3.2
Clinical Experience
As of 22 January 2017, the clinical development program includes 9 clinical studies in patients 
with advanced malignancies. Four of the 9 clinical studies are completed phase 1 monotherapy 
studies (C15001, C15002, C15003, and C15005) and 5 are ongoing phase 1/1b/2 studies (Studies 
C15009, C15010, C15011, Pevonedistat-1012, and Pevonedistat-2001). Pevonedistat is under 
development as a component of regimens with azacitidine (Study C15009, Pevonedistat-1012, and 
Pevonedistat-2001) and with docetaxel or in combination with carboplatin and paclitaxel 
(Study C15010), and DDIs of pevonedistat with fluconazole or itraconazole (Study C15011). Per 
the data available as of 22 January 2017, a total of approximately 451 patients received at least 
1 dose of pevonedistat in the overall clinical development program.
4.1.4
Potential Risks and Benefits
Pevonedistat will be administered in Part A of this study as a single 1-hour IV infusion at 50 mg/m2
on Days 1 and 10. Patients will also receive rifampin (Days 3 through 11), a strong CYP3A 
inducer. In vitro, pevonedistat is predominantly metabolized by the CYP isozyme 3A4; however, 
the in vivo contribution of CYP3A to overall clearance is inferred to be minimal, based on the lack 
of clinically meaningful effect of the strong CYP3A inhibitor itraconazole on pevonedistat PK. 
Because this is an induction DDI evaluation, it is hypothesized that the exposures of pevonedistat 
may be decreased upon co-administration with rifampin. The safety profile of this combination 
(pevonedistat+rifampin) is not known at this time.
It is anticipated that the chemotherapies used in Part B of this study may provide clinical benefit to 
patients. Study C15010 was an open-label, phase 1b study whose primary objective was to 
establish the MTD and assess the safety and tolerability of pevonedistat in combination with 
docetaxel, carboplatin, paclitaxel+carboplatin, or gemcitabine in patients with solid tumors. As of 
22 January 2017, enrollment was complete. As of October 2017, 2 patients in complete response 
(CR) (still active in cycles 43+) remain on the study.
Data are available for 64 patients who received at least 1 dose of pevonedistat in combination with 
standard of care (SOC) (data cutoff: 15 February 2016). The safety profile of pevonedistat in 
combination with docetaxel (75 mg/m2), in patients with solid tumors was favorable, and the study 
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objective to establish the MTD for pevonedistat (25 mg/m2 on Days 1, 3, and 5 of a 21-day 
treatment cycle) was achieved. The safety profile of pevonedistat in combination with paclitaxel 
(175 mg/m2) and carboplatin (AUC5) in patients with solid tumors was favorable. No new safety 
signals were observed for pevonedistat in this study compared to an earlier solid tumor study of 
pevonedistat as a single agent.
The most common (any grade) adverse event (AE) for patients in Arm 1 (pevonedistat+docetaxel) 
and Arm 2 (pevonedistat+carboplatin+paclitaxel) were fatigue (55%, 65%), nausea (36%, 54%), 
diarrhea (41%, 42%), anemia (32%, 46%), constipation (18%, 42%), increased aspartate 
aminotransferase (AST) (27%, 35%), vomiting (18%, 42%), and alopecia (23%, 38%), 
respectively. For patients who had an AE ≥Grade 3 in Arm 1 and Arm 2, the most common events 
were decreased neutrophil count (27% each arm) and increased AST (18% and 23%), respectively.
Of the 54 response-evaluable patients diagnosed with a solid tumor, responses of stable disease 
(SD) or better were observed in 41 patients. Twelve patients experienced a best response of CR or 
partial response (PR); 15.8% in response-evaluable patients in Arm 1 (pevonedistat+docetaxel) 
and 34.8% in Arm 2 (pevonedistat+paclitaxel+carboplatin). For patients treated in Arm 2 
(pevonedistat+paclitaxel+carboplatin), the median duration of response (CR and PR) was 
7.375 months or 10 cycles (8 patients); and for Arm 1 (pevonedistat+docetaxel), the median 
duration of response (PR) was 3.060 months or 5 cycles (3 patients). For the 12 patients with a 
response of CR or PR, the time to response was between 1 and 3 months in all treatment arms. 
Two patients achieved a best response of CR that, at the time of data cutoff (15 February 2016), 
had durations of 6.57 (9 cycles) and 8.48 months (11 cycles), respectively, indicating that with 
repeat cyclic dosing of pevonedistat in combination with paclitaxel+carboplatin a complete 
response was feasible for at least 11 cycles.
The additional benefit in response rate derived from the combination of pevonedistat and SOC 
compared to historical data from SOC did not appear to be associated with additional toxicity with 
the exception of increased liver function tests. Broad-based activity in the various tumor types 
offers clinical benefit in variety of patient populations, including patients with adenocarcinoma 
and squamous carcinoma.
4.1.4.1
Risks of Pevonedistat Therapy
Safety information gained from single-agent clinical studies of pevonedistat and from toxicology 
studies in rats and dogs has been used to guide the safety evaluation of pevonedistat. Additional 
information on risks is provided in the current IB, which includes the development core safety 
information.
The risks of pevonedistat treatment, based on preliminary findings from the single-agent clinical 
studies and the toxicities noted in the toxicology studies done in rats and dogs, are presented 
below. 
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Identified Risks

Increased heart rate.

Diarrhea.

Nausea.

Vomiting.

Pyrexia.

Liver function test abnormal.

Musculoskeletal pain.

Myalgia.
Potential Risks
There are potential risks in the pevonedistat program that require further monitoring. While the 
potential toxicities listed below may be severe or life-threatening, it is anticipated that they can be 
managed by clinical monitoring and intervention. Patients will be monitored for these potential 
toxicities and for unanticipated toxicities for at least 30 days after their last dose of pevonedistat.
Potential Risks From Phase 1 Studies (at High Doses)
There are events that have been reported in phase 1 studies at doses and schedules substantially 
higher (≥110 mg/m2) than those being used in current clinical studies of pevonedistat. These 
events are considered potential risks for the doses and schedules proposed in this study.

Multi-organ failure that could result in death.

Renal failure. 
–
The events of multi-organ failure (hepatic, renal, and cardiac) with a fatal outcome, and 
renal failure alone, have been reported at doses of pevonedistat ranging from 110 to 
278 mg/m2. Refer to the current IB for additional information about multi-organ failure 
and dosing.

Cardiac arrhythmias.
–
All events were supraventricular arrhythmias; all except 1 were unrelated. The case of 
atrial fibrillation, assessed by the investigator as related, occurred in a patient with a risk 
factor for cardiovascular disease (uncontrolled hypertension).

Myelosuppression with increased susceptibility to infection, bleeding, and anemia.

Acute phase response.

Gastrointestinal (GI) toxicity including or resulting in dehydration and electrolyte imbalance.
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
Hypophosphatemia.
Potential Risks Confounded by Underlying Disease or Malignancy
Events have been reported from clinical studies that are confounded by the patients’ underlying 
medical conditions, including malignancy. These events are noted in the absence of randomized, 
controlled data:

Fatigue.

Chills.

Decreased appetite.

Neutropenia.

Febrile neutropenia.

GI bleeding.
–
All events were assessed by the investigator as unrelated; most occurred in the setting of 
thrombocytopenia.

Multi-organ failure in the setting of infection.
Potential Risks Primarily Based on Findings From Animal Studies
Potential risks that are derived from findings in animal studies in rats and dogs include the 
following:

Myocardial degeneration and thrombosis.

Pulmonary hypertension.

Cardiovascular changes that could result in tachycardia, decreased or increased systolic blood 
pressure (BP), and increased diastolic BP.

Enteropathy (including dehydration and electrolyte loss) with secondary sepsis.

Effects on the testes and ovaries that represent a reproductive hazard, including sterility.

Increased developmental risk to the fetus or embryo.

Decreased trabecular bone (graded minimal to moderate) noted in the femur and in the sternum 
in rats at all dose groups (low, medium, and high) but not in dogs. This finding was considered 
adverse in the high-dose group; however, no bone fractures were noted at any of the doses.

Prolongation of the activated partial thromboplastin time (aPTT).

Local tissue injury when administered SC.
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It is possible that pevonedistat will have toxicities, which may be severe or fatal, that were not 
observed in or predicted from the studies completed in rats and dogs or have not yet been identified 
in patients.
Hepatotoxicity has been noted following administration of pevonedistat in patients with advanced 
malignancy, including elevations of liver transaminases, alkaline phosphatase (ALP), and 
bilirubin. Liver enzymes and liver function are frequently monitored during clinical studies of 
pevonedistat. 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 (see Sections 8.4 and 
8.5).
Patients must be carefully evaluated at screening and before each pevonedistat dose for early 
symptoms and signs of hemodynamic compromise or active infection. Particular attention should
be paid to unexplained fever, tachycardia, hypotension, orthostasis, tachypnea, recent nausea and 
vomiting, and clinical evidence of dehydration. Guidance on rehydration is provided in 
Section 8.7.1.
These potential toxicities will be managed by careful, frequent monitoring and intervention, as 
needed, with supportive care. It is possible that pevonedistat will have toxicities that were not 
observed in or predicted from the studies completed in rats and dogs or have not yet been identified 
in patients.
This study will be conducted in compliance with the protocol, Good Clinical Practice (GCP), and 
the applicable regulatory requirements (including International Council for Harmonisation [ICH] 
guidelines).
4.1.4.2
Risks of Docetaxel Treatment
Details of risks related to docetaxel treatment are provided in the applicable United States package 
insert (USPI).
4.1.4.3
Risks of Pevonedistat and Docetaxel as Combination Therapy
The following potential risks, based on the known individual safety profiles of pevonedistat and 
docetaxel, of combination therapy may apply: death, hypersensitivity, hepatotoxicity, neutropenia, 
and fluid retention (cardiac/pulmonary). With regard to docetaxel, treatment related mortality 
increases with abnormal liver function, at higher doses, and in patients with non–small cell lung 
cancer (NSCLC) who received prior platinum-based therapy receiving docetaxel at 100 mg/m2.
4.1.4.4
Risks of Carboplatin and Paclitaxel Therapy
Details of risks related to carboplatin and paclitaxel therapy are provided in the applicable USPIs.
4.1.4.5
Risks of Pevonedistat and Carboplatin+Paclitaxel as Combination Therapy
The following potential risks, based on the known individual safety profiles of pevonedistat and 
carboplatin+paclitaxel, of combination therapy may apply: bone marrow suppression, 
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hypersensitivity/anaphylaxis reactions, and hepatotoxicity. Renal effects of nephrotoxic 
compounds [1] (see Appendix E) may be potentiated by carboplatin. 
Given limited existing clinical experience, it is not known whether patients will benefit from 
participation in this study. However, a number of patients with solid tumors treated with 
pevonedistat as a single agent did demonstrate clinical benefit based primarily on prolonged SD. In 
addition, it is anticipated that the SOC therapies used in Part B of this study may provide additional 
clinical benefit to patients. Forty-eight patients have been treated with pevonedistat in combination 
with docetaxel, carboplatin, or carboplatin+paclitaxel. On the basis of preliminary data, these 
combinations have shown evidence of clinical benefit in the form of multiple PRs, limited CRs, 
and extended durations of SD.
4.2
Rationale for the Proposed Study
The primary objective of this study is to evaluate the effects of rifampin, a strong metabolic 
enzyme inducer, on the PK of pevonedistat. Pevonedistat is predominantly cleared via 
metabolism, based on in vitro and nonclinical in vivo data, and is also a substrate for the drug 
transporters Pgp and breast cancer resistance protein (BCRP). Strong inducers of metabolic 
enzymes and transporters, such as rifampin may be expected to result in decrease pevonedistat 
exposures and reduced efficacy. Current clinical studies prohibit use of strong enzyme inducers 
(eg, rifampin, carbamazepine, phenytoin). The results of this study will inform the risk assessment 
for potential DDIs with concomitant use of strong metabolic enzyme inducers during the clinical 
development of pevonedistat.
4.2.1
Rationale for Dose and Duration of PK Assessments in Part A
The pevonedistat dose of 50 mg/m2 selected to be evaluated in this study is based on the 
consideration of 50 mg/m2 as the RP2D of pevonedistat in the monotherapy setting and dose-linear 
PK of pevonedistat that should permit translation of the results of this study (ie, estimated 
magnitude of DDI) to lower doses such as those used in combination settings (eg, 20 mg/m2 in 
combination with azacitidine). Approximately 12 evaluable patients will be required to provide 
the protocol-specified dosing and PK data in order to permit adequate assessment of the effects of 
rifampin on single-dose pevonedistat PK.
The elimination half-life of pevonedistat is approximately 9 hours. Serial PK sampling up to 
48 hours following pevonedistat single dosing on Day 1 and Day 10 permits characterization of 
PK profiles of pevonedistat in the absence (Day 1) and in the presence (Day 10) of rifampin. 
Patients will begin to receive once daily (QD) doses of oral capsules of 600 mg rifampin on 
Days 3 through 11 in order to achieve steady-state of enzyme induction. The duration of PK 
assessment in Part A is approximately 12 days.
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4.2.2
Rationale for Continued Treatment With Pevonedistat in Combination With 
Chemotherapy in Optional Part B
After completing Part A, patients will have the option to continue in the study by participating in 
Part B, where they will receive combination treatment with pevonedistat and chemotherapy. Two 
chemotherapy regimens, docetaxel and carboplatin+paclitaxel, which have been previously 
studied as combination partners with pevonedistat, will be used in this study. On the basis of the 
MTDs determined in Study C15010, patients will receive pevonedistat 25 mg/m2 in combination 
with docetaxel 75 mg/m2 or pevonedistat 20 mg/m2 in combination with carboplatin 
AUC5+paclitaxel 175 mg/m2.
Docetaxel is indicated as a single agent for locally advanced or metastatic breast cancer and for 
locally advanced or metastatic NSCLC after platinum therapy failure. 
Paclitaxel is indicated for the treatment of breast cancer after failure of combination chemotherapy 
for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Paclitaxel is also 
indicated for the second-line treatment of acquired immunodeficiency syndrome–related Kaposi’s 
sarcoma. In addition, paclitaxel in combination with cisplatin is indicated for the first-line 
treatment of NSCLC in patients who are not candidates for potentially curative surgery and/or 
radiation therapy.
Carboplatin is indicated for the initial treatment of advanced ovarian carcinoma in combination 
with other approved chemotherapeutic agents (1 established combination regimen consists of 
carboplatin and cyclophosphamide). Carboplatin is also indicated for the palliative treatment of 
patients with ovarian carcinoma recurrent after prior chemotherapy, including patients who have 
been previously treated with cisplatin.
Docetaxel and paclitaxel+carboplatin are also approved in combination with other 
chemotherapeutic agents to treat other indications; refer the applicable USPIs.
In addition to the approved indications outlined above, these agents are widely used to treat a 
variety of malignancies in patients for whom prior therapies have failed. Paclitaxel+carboplatin is 
also widely used to treat patients with newly diagnosed NSCLC.
For a detailed description of each of these medications, see Section 8.9. 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+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.
The MTD and RP2Ds have been determined for the combination of pevonedistat+docetaxel and 
pevonedistat+carboplatin/paclitaxel.
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Therefore, it is considered that the above chemotherapy agents will serve as reasonable partners in 
combination with pevonedistat for investigations in patients with various solid tumors in this 
study.
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5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objectives
The primary objective is to assess the effect of multiple-dose administration of rifampin on the 
single-dose PK of pevonedistat in adult patients with advanced solid tumors (Part A).
5.1.2
Secondary Objectives
The secondary objectives are as follows:
Part A

To further characterize pevonedistat PK following a single dose at 50 mg/m2 in the absence 
or presence of rifampin.
Part B

To evaluate disease response that may be observed following treatment with pevonedistat 
in combination with either docetaxel or carboplatin+paclitaxel in patients with advanced 
solid tumors.
5.1.3
Safety Objectives
The safety objective for Part A is to evaluate the safety and tolerability of pevonedistat in patients 
with advanced solid tumors following a single IV dose at 50 mg/m2 in the absence or presence of 
rifampin.
The safety objective for Part B is to evaluate the safety and tolerability of pevonedistat in 
combination with either docetaxel or carboplatin+paclitaxel in patients with advanced solid 
tumors.
5.1.4
Exploratory/Additional Objectives
None.
5.2
Endpoints
5.2.1
Primary Endpoint
The primary endpoint of the study is the ratios of geometric mean pevonedistat maximum 
observed plasma concentration (Cmax), area under the plasma concentration-time curve from time 
0 to time of the last quantifiable concentration (AUClast), and area under the plasma concentration 
versus time curve from time 0 to infinity (AUC∞) in the presence of rifampin in reference to Cmax, 
AUClast, and AUC∞in the absence of rifampin and associated 90% confidence intervals (CIs).
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5.2.2
Secondary Endpoints
The secondary endpoints are as follows:
Part A

PK parameters: CL, volume of distribution at steady-state after intravenous administration 
(Vss), and t1/2z of pevonedistat following a single dose administration of 50 mg/m2 on 
Day 1 (in the absence of rifampin) and Day 10 (in the presence of rifampin).
Part B

Measures of disease response based on the investigator’s assessment using the Response 
Evaluation Criteria in Solid Tumors (RECIST, Version 1.1) guideline.
5.2.3
Safety Endpoints
The safety endpoints for Part A of this study is AEs, serious adverse events (SAEs), assessments of 
clinical laboratory values, and vital signs measurements following a single-dose IV administration 
of pevonedistat at 50 mg/m2 in the absence or presence of rifampin. The safety endpoint for Part B 
of this study is AEs, SAEs, assessments of clinical laboratory values, and vital signs measurements 
following administration of pevonedistat in combination with either docetaxel or 
carboplatin+paclitaxel.
5.2.4
Exploratory/Additional Endpoints
There are no exploratory or additional endpoints in this study.
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6.0
STUDY DESIGN
6.1
Overview of Study Design
This is a 2-part, open-label, DDI study in 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+paclitaxel in Part B of this study, 
or have progressed, despite standard therapy, or for whom conventional therapy is not considered 
effective. Approximately 20 patients will be enrolled to obtain approximately 12 PK-evaluable 
patients.
Eligible patients will receive a single dose of 50 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 48 hours 
(Day 3) following the single dose of pevonedistat. Patients will then receive an oral dose of 600 mg 
rifampin QD starting from Day 3 (after collecting the 48-hour PK sample) through Day 11. There 
will be no pevonedistat doses from Day 2 through Day 9. On Day 10, a single dose of 50 mg/m2
pevonedistat will be administered, and plasma samples will be collected at predetermined time 
points up to 48 hours (Day 12) following the second single dose of pevonedistat. Study drug will 
be discontinued early if a patient experiences study drug‒related toxicities.
Patients may discontinue therapy at any time, for any reason. Patients in Part A who do not
continue to the optional Part B will attend an End of Study (EOS) visit 30 (+10) days after 
receiving their last dose of study drug in Part A.
Both doses of pevonedistat (Days 1 and 10) will be administered in the clinic, followed by the 
required PK sampling. Serial blood plasma samples for determination of the plasma concentration 
of pevonedistat will be obtained during Part A at prespecified time points as described in 
Appendix A, Table A. The first dose of rifampin will be given orally in the clinic on the morning 
of Day 3 after collection of the 48-hour PK sample. Patients will self-administer rifampin (oral 
capsules) QD on Days 4, 5, 6, 7, 8 and 9 at home. Patients are encouraged to take rifampin at 
approximately the same time each day (± 2 hours from the time of first rifampin dose). On Days 10 
and 11, patients will report to the clinic to continue to receive oral 600 mg rifampin 
co-administered with pevonedistat on Day 10, and at the time of the 24-hour pevonedistat PK 
sampling on Day 11. The last PK sampling is on Day 12 (48-hour post pevonedistat infusion on 
Day 10). There will be no pevonedistat dosing on Days 11 and 12. There will be no rifampin 
dosing on Day 12.
All doses of rifampin will be administered on an empty stomach with patients taking 
nothing-by-mouth (NPO) except for water and prescribed medications for 2 hours before and at 
least 1 hour after each rifampin dose. Patients who miss any rifampin doses on Days 3 to 9 will not 
be considered evaluable; hence, pevonedistat dosing and PK sampling on Day 10 will not be 
required for these patients. Patients will have a washout period from the last dose of rifampin for at 
least 1 week to allow reversal of metabolic enzyme induction before the start of Part B of the study.
After completion of Part A of this study, patients will have the option of participating in Part B. 
Any patient who decides to participate in Part B will need to meet the continuation criteria
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(Section 7.3) of the study before treatment in Part B can begin. Patients will receive pevonedistat 
in combination with either docetaxel or carboplatin+paclitaxel, as recommended by the 
investigator. As in Part A, safety assessments will also be conducted in Part B of the study. In 
addition, Part B will conduct disease assessments using radiological evaluations (computed 
tomography [CT] scan or magnetic resonance imaging [MRI]).
The Schedule of Events (SOEs) for Part A and Part B are provided in Appendix A. Toxicity will be 
evaluated according to National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI CTCAE), Version 4.03, effective date 14 June 2010 [2]. AEs will be assessed, and 
laboratory values and vital signs will be obtained to evaluate the safety and tolerability of 
pevonedistat. See Figure 6.a for an overview of the study design of Parts A and B.
Figure 6.a
Study Overview
D=day.
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6.2
Number of Patients
Approximately 20 patients (for approximately 12 PK-evaluable patients) will be enrolled. A 
patient is considered to be enrolled when the first dose of any study drug has been administered. In 
Part A, patients who are withdrawn from treatment before completing protocol required 
procedures, or are not considered evaluable for Part A will be replaced. Four to 6 study centers in 
the US will are planned to participate in the study.
6.3
Duration of Study
6.3.1
Duration of an Individual Patient’s Study Participation
6.3.1.1
Part A: PK Assessment
It is anticipated that an individual patient will participate in this study for approximately 12 days in 
Part A, with an EOS visit 30 (+10) days after receiving their last dose of study drug to permit the 
detection of any delayed treatment-related AEs. If patients continue to the optional part of the 
study, Part B, they will forgo the EOS visit after Part A and be evaluated per the Part B 
continuation criteria (see Section 7.3). At least 1 week washout will take place before the start of 
Part B.
6.3.1.2
Part B (Optional): Continued Treatment With Pevonedistat in Combination With SOC 
Eligible patients will have the option to continue to receive treatment in Part B of this study until 
discontinuation criteria are met (see Section 9.6). If a patient chooses to continue to Part B, that 
patient may enter Part B after meeting the entry criteria and within approximately 1 week of 
completing Part A; however, patients entering Part B must begin treatment within 1 to 2 weeks of 
completing Part 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 
clinical benefit from continued treatment, the patient may remain on the current combination 
therapy or receive pevonedistat as a single agent beyond 12 cycles.
After completion of at least 6 cycles of treatment, patients will be permitted to take treatment 
breaks, at the investigator’s discretion, that are no longer than 2 weeks in duration (up to 4 weeks 
after consulting with the sponsor); treatment breaks may not be taken consecutively. The 
investigator will confirm patient eligibility for continued treatment (Section 7.3) upon return from 
a treatment break, before resuming treatment.
Patients who have achieved clinical benefit from combination therapy 
(chemotherapy+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 by the sponsor. 
Patients will attend an EOS visit 30 (+10) days (safety follow-up) after the last dose of study drug 
or before the start of subsequent therapy for their indication, if that occurs sooner.
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6.3.2
EOS/Study Completion Definition and Planned Reporting
The analyses for the clinical study report may be conducted after all patients enrolled in the study 
have completed Part A, to meet the primary (PK assessment) objective of the protocol, or have 
discontinued treatment. Patients still on therapy at this point will continue in the study through 
their EOS visit. The estimated time frame for study completion is approximately 18 months for 
Parts A and B combined.
6.3.3
Timeframes for Primary and Secondary Endpoints to Support Disclosures
Please refer to Table 6.a for disclosures information for primary and secondary endpoints for 
Part A and Table 6.b for Part B, respectively.
Table 6.a
Primary and Secondary Endpoints for Disclosures: Part A
Endpoint
Definition
Maximum Time Frame
(per Individual Patient)
Primary: Pevonedistat Cmax, AUClast, and AUC∞geometric 
mean ratios in the presence of rifampin in reference to 
Cmax, AUC0-last, and AUC∞in the absence of rifampin 
(Section 5.2.1)
DDI assessment, ratios of 
geometric mean, 90% CIs.
Up to 12 days.
Secondary: PK parameters: CL, Vss and t1/2z of 
pevonedistat following a single dose administration of 
50 mg/m2 on Day 1 (in the absence of rifampin) and 
Day 10 (in the presence of rifampin) (Section 5.2.2).
DDI assessment, 
descriptive statistics of PK 
parameters.
Up to 12 days.
Table 6.b
Primary and Secondary Endpoints for Disclosures: Part B
Endpoint
Definition
Maximum Time Frame
Primary: not applicable
Not applicable
Not applicable
Secondary: To evaluate disease response that may be 
observed following treatment with pevonedistat in 
combination with either docetaxel or 
carboplatin+paclitaxel in patients with advanced solid 
tumors (Section 5.2.2)
Disease response to 
pevonedistat in 
combination with SOC, 
based on the best overall 
response as determined by 
the investigator using 
RECIST Version 1.1 
guidelines.
Up to 12 months, 
depending on patient 
response.(a)
(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 or receive pevonedistat as a single agent beyond 12 cycles.
6.3.4
Total Study Duration
It is anticipated that this study will last for approximately 18 months for Part A and Part B 
combined. The maximum duration of treatment in Part B will be 12 cycles; however, if it is 
determined, after discussion between the investigator and the sponsor, that a patient would derive 
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benefit from continued treatment, the patient may remain on the current combination therapy or 
receive pevonedistat as a single agent beyond 12 cycles.
Patients who have achieved objective clinical benefit from combination therapy 
(chemotherapy+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 by the sponsor.
6.3.5
Post Trial Access
Currently, there is no post trial access (PTA) protocol available in the pevonedistat development 
program. If during conduct of the Pevonedistat-1015 study, an open-label, rollover PTA study 
should become an option and the investigator and the sponsor agree that a patient would derive 
benefit from continued treatment in Part B or would be harmed without continued access to the 
medication, the patient may be given the opportunity to enroll. Patients who participate in a 
rollover study will be considered to have completed Study Pevonedistat-1015. The patient would 
then be able to continue receiving his/her current study treatment (combination or single-agent 
pevonedistat).
6.3.6
Duration of PTA
In the event of a rollover PTA study, continued access to pevonedistat for participants will be 
terminated for those individuals who no longer benefit from treatment (eg, they have completed 
the recommended course of therapy or their disease has improved or resolved), the benefit-risk no 
longer favors the individual, or an appropriate alternative therapy becomes available. PTA may be 
terminated in a country or geographical region where the development of pevonedistat has been 
suspended or stopped by the sponsor, or pevonedistat can no longer be supplied.
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7.0
STUDY POPULATION
The patient population for this study will be 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+paclitaxel in 
Part B of this study, or have progressed, despite standard therapy, or for whom conventional 
therapy is not considered effective. Confirmation of eligibility must be obtained before the patient 
can enter the study. After completion of Part A, patients who elect to continue into the optional 
Part B must meet the criteria for continuation listed in Section 7.3.
7.1
Inclusion Criteria
Each patient must meet all the following inclusion criteria to be enrolled in the study:
1. Male or female patients 18 years or older.
2. 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+paclitaxel in Part B of this study, or have progressed despite 
standard therapy, or for whom conventional therapy is not considered effective.
3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 (Appendix D).
4. Expected survival of at least 3 months from the date of enrollment in the study.
5. Recovered (ie, ≤Grade 1 toxicity) from the effects of prior antineoplastic therapy.
6. Clinical laboratory values as specified below:

Hemoglobin ≥9 g/dL. Patients may be transfused to achieve this value.

Total bilirubin ≤ upper limit of normal (ULN).

Alanine aminotransferase (ALT), AST, and ALP ≤2.5×ULN.
–
For patients to be treated with pevonedistat+docetaxel in Part B, AST and ALT must be 
≤1.5×ULN, and total bilirubin should be within the normal range.

Calculated CrCl ≥50 mL/min (CrCl is defined in Section 9.4.13).

Absolute neutrophil count (ANC) ≥1,500/mm3.

Platelet count ≥100,000/mm3.

Prothrombin time and aPTT ≤1.5×ULN.

Albumin ≥2.7 g/dL.
7. Suitable venous access for the study-required blood sampling (including PK sampling).
8. Female patients who meet any of the following:

Are postmenopausal for at least 1 year before the screening visit (see Appendix F).
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
Are surgically sterile.

If they are of childbearing potential, they and their male partners agree to practice 1 highly 
effective method of contraception (see Appendix G) and 1 additional effective (barrier) 
method at the same time, from the time of signing the informed consent through 4 months 
after the last dose of study drug, or

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle 
of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 
methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable 
methods of contraception. Female and male condoms should not be used together.)
9. Male patients, even if surgically sterilized (ie, status postvasectomy), who meet either of the 
following:

Agree to practice effective barrier contraception during the entire study treatment period 
and through 4 months after the last dose of study drug, or

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle 
of the 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.)
10. Patients who are willing to refrain from donating blood for at least 90 days after their last dose 
of pevonedistat and (for male patients) willing to refrain from donating semen for at least 
4 months after their last dose of pevonedistat.
11. Voluntary written consent must be given before performance of any study-related procedure 
not part of standard medical care, with the understanding that consent may be withdrawn by 
the patient at any time without prejudice to future medical care.
7.2
Exclusion Criteria
Patients meeting any of the following exclusion criteria are not to be enrolled in the study:
1. Inability to comply with study visits and procedures including required inpatient confinement.
2. Treatment with any systemic antineoplastic therapy or any investigational products within 
21 days before the first dose of study treatment.
3. Major surgery within 14 days before the first dose of study treatment or scheduled surgery 
during Part A of the study. 
4. Prior treatment with radiation therapy involving ≥25% of the hematopoietically active bone 
marrow.
5. Use of strong CYP3A inducers within 2 weeks before the first dose of study drug. (The 
non-exhaustive list of clinically significant strong CYP3A inducers is provided in Appendix K.
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6. 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+docetaxel; history of 
hypersensitivity to carboplatin for patients to be treated with pevonedistat+ 
carboplatin+paclitaxel; or history of severe hypersensitivity to paclitaxel (Cremophor-based 
formulations) for patients to be treated with pevonedistat+carboplatin+ paclitaxel.
7. Life-threatening illness or serious (acute or chronic) medical or psychiatric illness unrelated to 
cancer that may increase the risk associated with trial participation or investigational product 
administration or may interfere with the interpretation of trial results or, in the investigator’s 
opinion, could potentially interfere with the completion of treatment according to this protocol.
8. Active, uncontrolled infection or severe infectious disease, such as severe pneumonia, 
meningitis, septicemia, or methicillin-resistant Staphylococcus aureus infection within 
2 weeks before dosing.
9. Known human immunodeficiency virus seropositive or 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.
10. Persistent diarrhea (≥Grade 2) lasting >3 days within 2 weeks before the first dose of study 
treatment.
11. Known hepatic cirrhosis or severe pre-existing hepatic impairment.
12. Uncontrolled high BP (ie, systolic BP >180 mm Hg, diastolic BP >95 mm Hg).
13. 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 at 
screening.
14. Patients with ischemic heart disease who have had acute coronary syndrome, myocardial 
infarction, or revascularization (eg, coronary artery bypass graft, stent) in the past 6 months are 
excluded. However, patients with ischemic heart disease who have had acute coronary 
syndrome, myocardial infarction, or revascularization greater 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 and patients with 
severe pulmonary arterial hypertension (see Appendix J) are excluded.
15. Arrhythmia (eg, history of polymorphic ventricular fibrillation or torsade de pointes, 
permanent atrial fibrillation defined as continuous atrial fibrillation for ≥6 months, and 
persistent atrial fibrillation, defined as sustained atrial fibrillation lasting 7 days and/or 
requiring cardioversion in the last 4 weeks before screening). However, patients with <Grade 3 
atrial fibrillation for a period of at least 6 months may enroll. Grade 3 atrial fibrillation is 
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defined as symptomatic and incompletely controlled medically, or controlled with device (eg, 
pacemaker) or ablation, and is excluded. Patients with paroxysmal atrial fibrillation are 
permitted to enroll.
16. Prolonged rate corrected QT interval (QTc) ≥500 msec, calculated according to institutional 
guidelines.
17. Implantable cardioverter defibrillator.
18. Patients with a cardiac pace maker whose heart rate is set at a fixed rate and patients on 
concomitant medication that may limit increase in heart rate in response to hypotension (eg, 
high-dose beta blocker).
19. Moderate to severe aortic stenosis, moderate to severe mitral stenosis, or other valvulopathy 
(ongoing).
20. Known moderate to severe chronic obstructive pulmonary disease, interstitial lung disease, 
pulmonary fibrosis, or pulmonary arterial hypotension.
21. Female patients who are lactating and breastfeeding or who have a positive serum pregnancy 
test during the screening period or a positive urine pregnancy test on Day 1 before the first dose 
of study drug.
22. Female patients who intend to donate eggs (ova) during the course of this study or 4 months 
after receiving their last dose of study drug.
23. Male patients who intend to donate sperm during the course of this study or 4 months after 
receiving their last dose of study drug.
24. Patient requiring chronic treatment with BCRP inhibitors. Refer to Table 8.b for the list of 
known BCRP inhibitors.
7.3
Criteria for Continuation into Optional Part B
After completing Part A of the study, patients may choose to enter the optional part of the study, 
Part B. To be eligible for Part B, patients must have completed Part A and be reassessed to 
determine if they meet the continuation criteria for Part B. Only patients who meet the following 
criteria may continue into Part B:
1. ECOG performance status of 0 to 1.
2. ANC ≥1500/mm3.
3. Platelet count ≥100,000/mm3.
4. Laboratory values for hemoglobin, total bilirubin, ALT, AST, ALP, and serum creatinine or 
calculated/measured CrCl, as specified in Inclusion Criterion #6.
5. Diarrhea symptoms resolved to Grade 1 or better.
6. QTc interval <500 msec.
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7. CT scan or MRI of the chest, abdomen, and pelvis within 28 days of Cycle 1 Day 1.
Radiological evaluations (CT scan or MRI) of the chest, abdomen, and pelvis are required as entry 
criteria for Part B to assess the status of the patient’s underlying disease. If the patient has had 
appropriate imaging scans performed within 28 days before Cycle 1 Day 1 of Part B, the results of 
those scans may be used. During the study, CT scans or MRIs encompassing the known sites of 
disease will be performed at the end of Cycle 2 and every 3 cycles thereafter. An EOS/early 
termination CT scan does not need to be completed/repeated if a scan was performed within the 
previous 28 days.
For patients to begin dosing in optional Part B, their predose Cycle 1 Day 1 assessments in Part B 
must return to the baseline values of Part A or Grade ≤1 or to a level considered acceptable by the 
investigator, after discussion with the project clinician or designee, and must meet all the 
continuation criteria specified in this section (Section 7.3).
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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).
8.1.1
Part A: Pevonedistat and Rifampin Administration
8.1.1.1
Pevonedistat Administration
Patients will receive a single dose of 50 mg/m2 pevonedistat via an approximate 1-hour 
(60±5 minutes) IV infusion on Day 1. Plasma PK samples will be collected at a series of 
predetermined time points up to 48 hours (Day 3) following the single dose of pevonedistat. The
start and end times of the IV infusion should be recorded accurately. If the IV infusion is 
interrupted, 2 additional PK samples (1 sample drawn when the infusion is stopped and 1 sample 
drawn when the infusion is restarted) should be collected so that the patient may be considered 
evaluable. The exact date and time of each additional sample collection and the actual start and 
stop times of the infusion should be recorded accurately. Patients will not be considered evaluable 
and need to be replaced if, in the assessment of the Takeda clinical pharmacologist, the infusion 
interruption compromises PK evaluability. All infusion times must be recorded. Refer to the 
Pharmacy Manual for the preparation of the IV infusion. 
There will be no pevonedistat doses from Day 2 through Day 9. On Day 10, a single dose of 
50 mg/m2 pevonedistat will be administered via a 1-hour IV infusion, and plasma samples will be 
collected at predetermined time points up to 48 hours (Day 12) following the second single dose of 
pevonedistat.
Both doses of pevonedistat (Days 1 and 10) will be administered in the clinic, followed by the 
required PK sampling. There will be no pevonedistat dosing on Days 11 and 12.
8.1.1.2
Rifampin Administration
The first dose of rifampin 600 mg will be given orally in the clinic on the morning of Day 3 after 
collection of the 48-hour PK sample. Patients will self-administer rifampin (oral capsules) QD on 
Days 4, 5, 6, 7, 8 and 9 at home. Patients are encouraged to take rifampin at approximately the 
same time each day (±2 hours from the time of first rifampin dose). On Days 10 and 11, patients 
will report to the clinic to continue to receive oral 600 mg rifampin co-administered with 
pevonedistat on Day 10, and at the time of the 24-hour pevonedistat PK sampling on Day 11. 
There will be no rifampin dosing on Day 12.
All doses of rifampin will be administered on an empty stomach with patients taking NPO except 
for water and prescribed medications for 2 hours before and at least 1 hour after each rifampin 
dose. Patients who miss any rifampin doses on Days 3 to 9 will not be considered evaluable; hence, 
pevonedistat dosing and PK sampling on Day 10 will not be required. Patients will have a washout 
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period from the last dose of rifampin for at least 1 week to allow reversal of metabolic enzyme 
induction before the start of Part B of the study.
8.1.2
Part B (Optional): Pevonedistat in Combination With SOC Chemotherapy Agents
Patients will be re-evaluated per the entry criteria before treatment in Part B can begin. Patients 
opting to continue into Part B will receive combination therapy with pevonedistat and SOC 
chemotherapy. Two SOC chemotherapy regimens, docetaxel and carboplatin+paclitaxel, will be 
used in this study in combination with pevonedistat, as recommended by the investigator. 
Study drug(s) will be administered only to eligible patients under the supervision of the 
investigator or identified subinvestigator(s). 
8.1.2.1
Pevonedistat Administration
Patients will receive pevonedistat diluted with 5% dextrose in a 250 mL bag via an approximate 
1-hour (60±5 minutes) IV infusion. 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 dilution 
in 5% dextrose to the end of infusion must not exceed 6 hours.
The entire contents of the pevonedistat IV bag will be infused at a constant rate over approximately 
60 minutes. The start and end times of IV infusion should be recorded accurately. To ensure that 
all the pevonedistat is administered, the infusion line will be flushed with saline or 5% dextrose 
immediately after administration. The volume used for line flushing is not considered part of the 
volume of the pevonedistat IV bag to be documented.
On Day 1 of a 21-day cycle, patients will receive either pevonedistat 25 mg/m2 in combination 
with docetaxel or pevonedistat 20 mg/m2 in combination with carboplatin+paclitaxel. A time-out 
of approximately 15 minutes is required between the end of infusion of the chemotherapy regimen 
and the start of infusion of pevonedistat. On Days 3 and 5, patients will receive pevonedistat alone. 
8.1.2.2
Docetaxel Administration
On Day 1 of each cycle, when all study drugs are administered together, docetaxel 75 mg/m2 will 
be administered first as a 1-hour IV infusion. After a mandatory approximately 15-minute time-out 
(pevonedistat-free period), pevonedistat will be administered IV. On Days 3 and 5, only 
pevonedistat will be given. The duration of each cycle will be 21 days. Refer to the applicable 
USPI for further details regarding docetaxel administration.
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Premedication for Docetaxel-Associated Hypersensitivity or Other Acute Reactions Guidelines
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.
8.1.2.3
Carboplatin+Paclitaxel Administration
On Day 1 of each cycle, when all study drugs are administered together, paclitaxel will be given 
first as an IV infusion over approximately 3 hours, followed by carboplatin as an approximately 
30-minute IV infusion. After a mandatory approximately 15-minute time-out (pevonedistat-free 
period), pevonedistat will be administered IV. On Days 3 and 5, only pevonedistat will be given. 
The duration of each cycle will be 21 days.

Refer to the applicable USPI for further details regarding carboplatin administration.

If a patient’s glomerular filtration rate (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 caused by 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=5, the maximum dose is 5150=750 mg.

For a target AUC=4, the maximum dose is 4150=600 mg.

Refer to the applicable USPI for further details regarding paclitaxel administration.
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
No reference or placebo treatment will be used in this study. All eligible patients will receive 
treatment with pevonedistat in Part A. Participation in Part B of the study is optional.
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8.3
Dose Modification Guidelines (Part B)
8.3.1
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.
Patients will receive pevonedistat in combination with chemotherapy on a dose regimen that has 
been established from Study C15010. If dosing with pevonedistat is held for toxicity during any 
given cycle, dosing may resume within that same cycle when toxicity is resolved (ALT/AST to 
Grade ≤1 or bilirubin within normal range). 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.
In Part B only, Day 1 dosing may be delayed by up to 2 days (of any cycle) to accommodate 
inclement weather, holidays, vacations, or other administrative reasons.
8.3.2
Criteria for Dose Interruption During a Cycle

In Part B, the infusion may be slowed or stopped and restarted for any associated 
infusion-related reactions; however, this should be avoided in Part A. The exact date and time 
of each additional sample collection and the actual start and stop times of the infusion should 
be recorded accurately.
8.3.3
Criteria for Dose Reduction
When a dose modification is warranted for safety, consider dose reductions for chemotherapy first, 
if appropriate. Dose modification of pevonedistat (by 1 dose level=5 mg/m2) may also be 
considered for events judged by the investigator to be directly related to pevonedistat or for 
chemotherapy related toxicities that may have been exacerbated by pevonedistat in the 
combination setting.
Alopecia of any duration will not lead to dose modification or treatment delay.
Patients receiving pevonedistat+docetaxel may have a maximum of 2 docetaxel dose 
modifications. Docetaxel is initially dosed at 75mg/m2, dose reductions up to 60 mg /m2 and 
45 mg/m2 may be considered (if applicable) or modification of pevonedistat (see above).
Patients receiving pevonedistat+carboplatin+paclitaxel may have no more than 1 dose 
modification (if applicable) of chemotherapy agents, as outlined below, or modification of 
pevonedistat (see above). Paclitaxel is initially dosed at 175 mg/m2. One dose reduction to 
135 mg/m2 may be considered. Carboplatin is initially dosed at AUC5. One dose reduction to 
AUC4 may be considered.
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.
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Table 8.a outlines the dose modification guidelines for specific toxicities. Treatment cannot be 
withheld for longer than 3 weeks for any toxicity Grade >1, as indicated in Section 8.3.4.
Table 8.a
Dose Modification Guidelines for Specific Toxicities
Pathologic Condition
Severity
Action on Study Drug
Hematologic:
ANC
Febrile neutropenia
Hold dosing on Day 1 of Cycles ≥2 up to 3 weeks (see Section 8.3.4) 
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 (see 
Section 8.3.4) 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 (see 
Section 8.3.4) 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 8.3.4). 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 8.7.3).
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 (see Section 8.3.4) 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 (see Section 8.3.4) 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 
with moderate or strong CYP3A inhibitors/inducers should be avoided.
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 (see Section Section 8.3.4). 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.
8.3.4
Criteria for Discontinuation of Study Drug
Patients receiving pevonedistat+docetaxel may have a maximum of 2 dose modifications (if 
applicable) or modification of pevonedistat (see Section 8.3.3). Patients who require more than 
2 dose modifications will be discontinued from the study.
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Patients receiving pevonedistat+carboplatin+paclitaxel may have no more than 1 dose 
modification (if applicable) of chemotherapy agents or modification of pevonedistat (see 
Section 8.3). Patients who require additional dose modifications will be discontinued from the 
study.
Patients with unresolved toxicities Grade >1 lasting 3 weeks or longer from the date of the next 
scheduled treatment will be discontinued from the study.
For further details on discontinuation criteria for specific toxicities, see Section 8.7.
8.4
Excluded Concomitant Medications and Procedures
8.4.1
Part A
Table 8.b lists the medications and procedures that are prohibited during Part A of the study.
Table 8.b
Excluded Concomitant Medications and Procedures During Part A
Drug Class/Therapy
Comment
Acetaminophen and acetaminophen-containing 
products
May be used judiciously and should not exceed a dose of 2 g in 
24 hours
Any investigational agent other than pevonedistat
Excluded during the study
Known BCRP inhibitors
Examples: cyclosporine and eltrombopag
Strong CYP3A4 inducers 
See Appendix K.
8.4.2
Part B
Table 8.c lists the medications and procedures that are prohibited in Part B.
Table 8.c
Excluded Concomitant Medications and Procedures During Part B
Drug Class/Therapy
Comment
Acetaminophen and acetaminophen-containing products
May be used judiciously and should not exceed a dose 
of 2 g in 24 hours
Any investigational agent other than pevonedistat
Excluded during the study
Known BCRP inhibitors (eg, cyclosporine and eltrombopag)
Generally excluded during the study but may be used 
as specified in Table 8.e
Systemic antineoplastic therapy, unless specified in the 
protocol as part of the combination with pevonedistat
Strong CYP3A4 inducers 
See Appendix K.
This list is not all-inclusive; consult the docetaxel, carboplatin, and paclitaxel applicable USPIs for additional 
information regarding precautions, warnings, and contraindications.
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8.5
Permitted Concomitant Medications and Procedures
8.5.1
Part A
Medications and procedures that are specifically permitted during Part A are listed in Table 8.d. 
Other supportive care medications are also permitted, unless specifically excluded in 
Section 8.4.1.
Table 8.d
Permitted Concomitant Medications and Procedures During Part A
Therapy
Comment/Exceptions
Nephrotoxic medications, 
including nonsteroidal 
anti-inflammatory drugs
Caution should be used with nephrotoxic concomitant medications (see Appendix E). 
Alternative concomitant nonnephrotoxic medications should be used whenever possible. 
Antiemetic agents
Antiemetic agents may be administered at the discretion of the investigator, but 
prophylactic antiemetic agents should not be administered if nausea or vomiting is not 
observed. 
RBC transfusion
For all patients with anemia, and especially for patients with hemoglobin values <9 g/dL 
during the conduct of the study, consideration should be given for RBC transfusions based 
on the patient’s risk of inadequate oxygenation, underlying cardiopulmonary status, 
clinical judgment, and hospital guidelines.
RBC transfusions must be administered at least 1 day before administration of study drug. 
Each transfusion episode, including the type of transfusion (RBC), should be recorded.
8.5.2
Part B
Medications and procedures that are specifically permitted during Part B are listed in Table 8.e. 
Other supportive care medications are also permitted, unless specifically excluded in 
Section 8.4.2.
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Table 8.e
Permitted Concomitant Medications and Procedures During Part B
Therapy
Comment/Exceptions
Antiemetic agents
Antiemetic agents, including for prophylactic use, may be administered at the discretion 
of the investigator. 
Known BCRP inhibitors 
(eg, cyclosporine and 
eltrombopag)
Limited use is permitted only if clinically necessary and no suitable alternative exists. The 
patient may receive a BCRP inhibitor from 24 hours after the last pevonedistat dose to 
72 hours before the next pevonedistat dose. For example, if a patient receives pevonedistat 
on a Monday (Day 1), Wednesday (Day 3), and Friday (Day 5) schedule, then a BCRP 
inhibitor may be administered (if clinically necessary and no suitable alternative exists) 
from the Saturday after the Day 5 dose (Day 6) up to the Friday (Day 19) before the 
Monday dose of the next cycle.
Nephrotoxic medications, 
including nonsteroidal 
anti-inflammatory drugs
Caution should be used with nephrotoxic concomitant medications (see Appendix E). 
Alternative concomitant nonnephrotoxic medications should be used whenever possible.
RBC transfusion
For all patients with anemia, and especially for patients with hemoglobin values <9 g/dL 
during the conduct of the study, consideration should be given for RBC transfusions based 
on the patient’s risk of inadequate oxygenation, underlying cardiopulmonary status, 
clinical judgment, and hospital guidelines.
RBC transfusions must be administered at least 1 day before administration of study drug. 
Each transfusion episode, including the type of transfusion (RBC), should be recorded.
8.6
Precautions and Restrictions
Concomitant medications and procedures that are excluded or must be used with caution are 
described in Sections 8.4.1and 8.4.2 and Sections 8.5.1 and 8.5.2, 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.
8.6.1
Pevonedistat
It is not known what effects pevonedistat has on human pregnancy or development of the embryo 
or fetus. Therefore, female patients participating in this study should avoid becoming pregnant, 
and male patients should avoid impregnating a female partner. Nonsterilized female patients of 
reproductive age and male patients should use highly effective methods of contraception through 
defined periods during and after study treatment, as specified below.
Use only contraceptive methods that are locally approved in each country. 
Female patients must meet any of the following:

Postmenopausal for at least 1 year before the screening visit (see Appendix F).

Surgically sterile.

If they are of childbearing potential (as defined in Section 9.4.7), they and their male 
partners agree to practice 1 highly effective method and 1 additional effective (barrier) 
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method of contraception (see Appendix G) at the same time, from the time of signing the 
informed consent form (ICF) through 4 months after the last dose of study drug.

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, and 
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 4 months after receiving 
their last dose of study drug.
Male patients, even if surgically sterilized (ie, status postvasectomy), must agree to any of the 
following:

Practice effective barrier contraception during the entire study treatment period and 
through 4 months after the last dose of study drug. (If barrier methods are not locally 
approved to be used by males, then their female partners should use effective contraceptive 
methods, as described in above.)

Practice true abstinence, when this is in line with the preferred and usual lifestyle of the 
subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, and postovulation 
methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable 
methods of contraception. Female and male condoms should not be used together.)

Donate sperm during the course of this study or 4 months after receiving their last dose of 
study drug.
8.6.2
Rifampin
8.6.2.1
Pregnancy
There are no adequate and well-controlled studies of rifampin in pregnant women. Refer to the 
applicable USPI for additional information regarding pregnancy.
8.6.2.2
Geriatric Use
In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency 
of decreased hepatic function and of concomitant disease or other drug. Refer to the applicable 
USPI for further details relating to use with geriatric patients.
8.6.3
Docetaxel
8.6.3.1
Pregnancy
Docetaxel is a pregnancy Category D drug. There are no adequate and well-controlled studies in 
pregnant women using docetaxel. If docetaxel is used during pregnancy, or if the patient becomes 
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pregnant while receiving this drug, the patient should be apprised of the potential hazard to the 
fetus. Refer to the applicable docetaxel USPI for more information.
8.6.3.2
Geriatric Use
In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency 
of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.
Refer to the applicable docetaxel USPI for information relating to use in the geriatric population 
with different types of cancer.
8.6.4
Carboplatin
8.6.4.1
Pregnancy
Carboplatin is a pregnancy Category D drug. Carboplatin injection may cause fetal harm when 
administered to a pregnant woman. Refer to the applicable carboplatin injection USPI for more 
information.
8.6.4.2
Geriatric Use
Because renal function is often decreased in the elderly, renal function should be considered in the 
selection of carboplatin dosage. Refer to the applicable carboplatin USPI for additional 
information on geriatric use.
8.6.5
Paclitaxel
8.6.5.1
Pregnancy
Paclitaxel is a pregnancy Category D drug. Paclitaxel injection can cause fetal harm when 
administered to a pregnant woman. Refer to the applicable paclitaxel injection USPI for more 
information.
8.6.5.2
Geriatric Use
Refer to the applicable paclitaxel USPI for information regarding use in the geriatric population.
8.7
Management of Clinical Events
The most common adverse drug reactions for docetaxel and for paclitaxel+carboplatin are 
described in Section 4.1.4. Refer to the applicable USPIs for additional details regarding the 
management of clinical events attributed to these agents.
Patients who experience an AE with pevonedistat should be followed closely for a recurrence of 
similar or other AEs upon subsequent dosing of pevonedistat.
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8.7.1
Guidance for Clinical Assessment and Management of Hemodynamic Compromise 
(Part A and Part B)
It is essential that the patient is carefully evaluated at screening and before each pevonedistat dose 
for early symptoms and signs of hemodynamic compromise and/or active infection. Particular 
attention should be paid to unexplained fever, tachycardia, hypotension, orthostasis, tachypnea, 
recent nausea and vomiting, and clinical evidence of dehydration. 
For those patients for whom there is a concern of dehydration, the following guidance for 
rehydration before pevonedistat dosing may be considered: 500 mL/hour of 0.5 N saline given 
over 2 to 4 hours for a total of 1 to 2 L of fluid as clinically appropriate; each infusion of IV fluids 
should be recorded in the electronic case report forms (eCRFs).
For all patients with anemia, and especially for patients with hemoglobin values <9 g/dL at 
screening or during the conduct of the study, RBC transfusions should be considered before 
pevonedistat dosing on the basis of the patient’s risk of inadequate oxygenation, underlying 
cardiopulmonary status, clinical judgment, and/or hospital guidelines; each RBC transfusion 
should 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. 
Patients who experience an untoward reaction with pevonedistat should be followed closely on 
subsequent dosing.
8.7.2
Guidance for Use of Granulocyte-Colony Stimulating Factor
Use of growth factors such as granulocyte-colony stimulating factor are permitted at the 
investigator’s discretion.
8.7.3
Guidance for Clinical Assessment and Management of Anemia
Transfusion and/or erythropoietin may be given as clinically indicated for the treatment of anemia. 
These should be recorded in the eCRFs.
For all patients with anemia, and especially for patients with hemoglobin values <9 g/dL at 
screening or during the conduct of the study, RBC transfusions should be considered before 
pevonedistat dosing on the basis of the patient’s risk of inadequate oxygenation, underlying 
cardiopulmonary status, clinical judgment, and/or hospital guidelines; each RBC transfusion 
should be recorded in the eCRFs.
Use of erythropoietin may be considered at the investigator’s discretion and according to 
institutional guidelines.
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8.7.4
Guidance for Management of Extravasation
Based on nonclinical findings as detailed in the IB, pevonedistat is considered a nonvesicant drug. 
Although no published guidelines are available for extravasation of nonvesicants, the investigator 
is encouraged to follow institutional guidelines. Some general advice in case of extravasation 
includes immediately stopping drug infusion and elevating the affected limb to minimize swelling.
8.8
Blinding and Unblinding
This is an open-label study. 
8.9
Description of Investigational Agents
8.9.1
Pevonedistat
Pevonedistat Concentrate for Solution for Infusion formulation consists of 10 mg/mL (as free 
base) of pevonedistat HCl in an aqueous solution containing citric acid (anhydrous), trisodium 
citrate dihydrate, and betadex sulfobutyl ether sodium (Captisol) at pH 3.3. Each United States 
Pharmacopeia (USP) Type I glass vial contains 5 mL compounded sterile solution, sealed with a 
fluoropolymer-coated butyl rubber stopper, and oversealed with an aluminum seal and a plastic 
cap. Pevonedistat Concentrate for Solution for Infusion needs to be diluted in 5% dextrose for 
administration.
8.9.2
Rifampin
Rifampin is a semisynthetic antibiotic derivative of rifamycin SV. Rifampin capsules for oral 
administration contain 300 mg of rifampin per capsule.
For precautions, warnings, contraindications, and AEs associated with rifampin therapy, refer to 
the applicable rifampin USPI. For this study, all doses of rifampin should be administered on an 
empty stomach, with patients remaining NPO except water from 2 hours before until at least 
1 hour after rifampin dosing. Additionally, antacids should not be administered from 2 hours 
before rifampin dosing until at least 2 hours after dosing.
8.9.3
Docetaxel
Docetaxel is obtained from commercial sources according to local practice standards and is 
provided as a commercially available dose formulation. Additional details are provided in the 
applicable USPI for docetaxel.
8.9.4
Carboplatin
Carboplatin is obtained from commercial sources according to local practice standards and is 
provided as a commercially available dose formulation. Additional details are provided in the 
applicable USPI for carboplatin.
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8.9.5
Paclitaxel
Paclitaxel is obtained from commercial sources according to local practice standards, and it is 
provided as a commercially available dose formulation. Additional details are provided in the 
applicable USPI for paclitaxel.
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.
Docetaxel, paclitaxel, and carboplatin are anticancer drugs, and as with other potentially toxic 
compounds, caution should be exercised when handling pevonedistat and these chemotherapy 
agents.
8.10.1 Pevonedistat
For a detailed preparation of the infusion, refer to the Pharmacy Manual. The bag, needle, and 
syringe must be disposed of in a proper biohazard container.
8.10.2 Docetaxel, Carboplatin, Paclitaxel and Rifampin
For instructions and precautions regarding preparation, refer to the applicable USPIs for docetaxel, 
paclitaxel, carboplatin, and rifampin.
8.11
Packaging and Labeling
8.11.1 Pevonedistat
The drug product is labeled Pevonedistat (TAK-924/MLN4924) Concentrate for Solution for 
Infusion.
Pevonedistat Concentrate for Solution for Infusion will be provided in USP Type I glass vials. 
Each Pevonedistat Concentrate for Solution for Infusion vial contains 50 mg Pevonedistat, as free 
base.
Pevonedistat Concentrate for Solution for Infusion will be supplied by the sponsor as detailed in 
the Study/Pharmacy Manual.
8.11.2 Docetaxel, Carboplatin, and Paclitaxel
Docetaxel, paclitaxel, carboplatin may be sourced locally by the clinical site when arrangements 
have been made and agreed to by Takeda 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.
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8.11.3 Rifampin
Rifampin will be provided by the sponsor as oral capsules. 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 pharmacy manual.
8.12
Storage, Handling, and Accountability
8.12.1 Pevonedistat
Pevonedistat injection is an investigational anticancer drug. As with other potentially toxic 
compounds, caution should be exercised when handling pevonedistat. Refer to institutional 
guidelines regarding the proper handling and disposal of toxic agents.
Pevonedistat Concentrate vials should be stored at 2°C to 8°C. The vials are suitable for use up to 
6 hours after removal from the storage condition of 2°C to 8°C. If the drug product vial is not to be 
used within the 6-hour time frame, the vial should be returned to storage. Each vial is for single use 
only.
Once Pevonedistat Concentrate is diluted in 5% dextrose, the prepared pevonedistat IV bag must 
be used within 6 hours if stored at ambient temperature or else must be discarded. Alternatively, 
the prepared pevonedistat IV bag may be stored for up to 18 hours at 2°C to 8°C, after which the 
prepared IV bag can be used within 3 hours upon removal from 2°C to 8°C storage or must be 
discarded.
The vial must not be shaken at any time during dose preparation.
Discard bags, needles, and syringes 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.
8.12.2 Docetaxel, Carboplatin, Paclitaxel and Rifampin
For instructions and precautions regarding preparation, refer to the applicable USPIs for docetaxel, 
paclitaxel, carboplatin, and rifampin.
8.13
Other Protocol-Specified Materials
Refer to the Pharmacy Manual for any other protocol-specified materials to be used in the study.
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9.0
STUDY CONDUCT
This trial will be conducted in compliance with the protocol, GCP, applicable regulatory 
requirements, and ICH guidelines.
9.1
Study Personnel and Organizations
The contact information for the project clinician for this study, the central laboratory and any 
additional clinical laboratories, the coordinating investigator for each member state/country, the 
interactive voice response system/interactive web response system provider, and the contract 
research organization (CRO) team may be found in the Study Manual. A full list of investigators is 
available in the sponsor’s investigator database. For 24-hour contact information, refer to the 
Project Management Plan.
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). Any other arrangements will be described in the Study 
Manual.
9.3
Treatment Group Assignments
All patients will receive the same study treatment in Part A.
In optional Part B, patients will be assigned, as recommended by the investigator, to pevonedistat 
25 mg/m2 in combination with docetaxel 75 mg/m2 or pevonedistat 20 mg/m2 in combination with 
carboplatin AUC5+paclitaxel 175 mg/m2.
9.4
Study Procedures
Refer to the SOE (Appendix A) for timing of assessments. Additional details are provided as 
necessary in the sections that follow.
9.4.1
Informed Consent
Each patient must provide written informed consent before any study-required procedures are 
conducted, unless those procedures are performed as part of the patient’s standard care.
9.4.2
Patient Demographics
The date of birth, race, ethnicity, and sex of the patient are to be recorded during screening.
9.4.3
Medical History
During the screening period, a complete medical history, including prior therapy, will be compiled 
for each patient. The history will emphasize the background and progress of the patient’s 
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malignancy and include a description of prior therapies for it. In addition, concomitant 
medications will be recorded as specified in Section 9.4.8.
9.4.4
Physical Examination
A complete physical examination or symptom-directed physical examination will be completed 
per SOC at the times specified in the SOE (Appendix A).
9.4.5
Patient Height
Height will be measured only during screening.
9.4.6
Vital Signs
Vital signs, including diastolic and systolic BP, heart rate, weight, and body temperature, will be 
collected as indicated in the SOE (Appendix A) and as clinically indicated.
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).
9.4.7
Pregnancy Test
A serum pregnancy test will be performed for women of childbearing potential at screening. In 
Part A, a serum or urine pregnancy test will be performed on Day 1 predose, Day 10 predose, and 
at the EOS visit (Appendix A). In Part B, a serum or urine pregnancy test must also be performed 
for women of childbearing potential at every cycle (typically performed on Day 1 predose of each 
cycle; however, if a serum pregnancy test is used, this may be performed up to 3 days before 
Day 1), with negative results available before the first dose is administered in the respective cycle. 
A serum or urine pregnancy test will also be performed for women of childbearing potential at the 
EOS/Early Termination visit in Part B. 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 (Appendix F) 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).
9.4.8
Concomitant Medications and Procedures
Concomitant medications, therapies, and procedures will be recorded in the eCRF from the time of 
the first dose of any study drug through 30 (+10) days after the last dose of study drug(s). See 
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Sections 8.4 and Section 8.5 for additional details regarding excluded and permitted concomitant 
medications and procedures.
9.4.9
AEs
Monitoring of AEs, serious and nonserious, will be conducted throughout the study as specified in 
the SOEs (Appendix A). Refer to Section 10.1 for details regarding definitions, documentation, 
and reporting of pretreatment events (PTEs), AEs, and SAEs.
For Part B only, refer to Table 8.a for dose modifications related to AEs.
9.4.10
Enrollment
Enrollment is achieved when the first dose of any study drug has been administered. Procedures 
for completing the enrollment information are described in the Pharmacy and Study Manuals.
9.4.11
Electrocardiogram
A 12-lead electrocardiogram (ECG) will be administered at screening (Part A only), on Day 1 
(predose), and at the EOS visit.
9.4.12
Echocardiogram
If no historical data for LVEF within 6 months prior to study enrollment are available, LVEF 
should be assessed by echocardiography at screening.
9.4.13
Clinical Laboratory Evaluations
Clinical laboratory evaluations will be performed locally. Handling and shipment of clinical 
laboratory samples will be outlined in the Study Manual. Clinical laboratory evaluations will be 
performed as outlined below.
For Part B only, refer to Table 8.a for dose modifications related to abnormal laboratory 
evaluations.
Blood samples for analysis of the clinical chemistry and hematologic parameters shown in 
Table 9.a and urine samples for analysis of the parameters shown in Table 9.b will be obtained as 
specified in the SOE (Appendix A).
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Table 9.a
Clinical Chemistry and Hematology Tests
Hematology
Serum Chemistry
Hemoglobin
Hematocrit
Leukocytes (white blood cells) with differential
Neutrophils (ANC)
Platelet (count)
ALT
Albumin
ALP
AST
Bilirubin (total)
Blood urea nitrogen
Creatinine
Direct bilirubin
Glucose 
Lactate dehydrogenase
Phosphate 
Potassium
Sodium
Urate
Calcium
Chloride
Carbon dioxide/bicarbonate
Magnesium
Part A Screening: 
aPTT
Coagulation panel (a)
Prothrombin time international normalized ratio
D-dimer
Fibrinogen
Parts A and B:
Coagulation panel, if applicable (a)
(a) If the initial coagulation screen is positive (ie, results are outside the laboratory’s normal range) in Part A, 
coagulation studies in Part B should include a full coagulation panel. If the initial coagulation screen is negative 
(ie, results are within the laboratory’s normal range) in Part A, no further coagulation studies need to be done.
Table 9.b
Clinical Urinalysis Tests
Urinalysis
Leukocytes
Nitrite
Occult blood
Microscopic assessment 
pH
Protein
Specific gravity
If CrCl is to be estimated, the Cockroft-Gault formula will be employed as follows:
For female patients, the result of the formula above should be multiplied by 0.85. 
9.4.14
Disease Assessment
Computed tomography scans with IV contrast (unless medically contraindicated), or MRI, of the 
chest, abdomen, and pelvis will be performed as entry criteria for Part B. 
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CT scans with IV contrast encompassing the known sites of disease will also be performed at the 
end of Cycle 2 and as specified in the Schedules of Events thereafter. A scan should be taken at the 
EOS visit if a scan has not been completed within the past 28 days. 
If CT scan does not provide adequate imaging, MRI may be used to evaluate sites of disease. If the 
patient has had appropriate imaging scans performed within 28 days of Cycle 1 Day 1, then the 
results of those scans may be used to satisfy the entry criteria for Part B. For each site of disease, 
the imaging modality (CT scan or MRI) used at entry for Part B must be used throughout the study. 
Tumor response will be assessed by the investigator at these times using the RECIST guideline 
(Version 1.1) [3].
9.4.15
Biomarker, Pharmacodynamic, and PK Samples
9.4.15.1 Primary Specimen Collection
Specimen Name is
Schedule of Procedures
Primary Specimen
Description of Intended Use
Sample Collection
Plasma Sample for Pevonedistat PK
Plasma
PK measurements
Mandatory
9.4.16
PK Measurements
Details regarding the preparation, handling, and shipping of samples are provided in the Study and 
Laboratory Manuals. 
As shown in the table in Appendix A, serial blood samples (approximately 3 mL each) for PK 
analysis of pevonedistat will be collected in Part A predose and prespecified time points on Day 1 
and Day 10 and over a 48-hour period on Days 1, 2 (24 hours after the Day 1 dose) and 3 (48 hours 
after the Day 1 dose), 10, 11 (24 hours after the Day 10 dose) and 12 (48 hours after the Day 10 
dose).
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 
that occur close to the infusion. If the IV infusion is interrupted, 2 additional PK samples (1 sample 
drawn when the infusion is stopped and 1 sample drawn when the infusion is restarted) should be 
collected so that the patient may be considered evaluable. The exact date and time of each 
additional sample collection and the actual start and stop times of the infusion should be recorded 
accurately.
There is no protocol-specified PK sampling for Part B.
The primary purpose of PK sampling in this study is to measure pevonedistat concentrations in 
plasma. However, these PK samples may also be used for the exploratory measurement of plasma 
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concentrations of metabolites of pevonedistat, if technically feasible and considered necessary for 
further understanding the metabolism of pevonedistat in patients with cancer.
To ensure that the measurements are representative of plasma exposure, blood draws will be 
conducted in the arm opposite to the patient’s IV infusion. If only a single arm is available, blood 
should be drawn as distal to the site of the IV infusion as feasible, and the site of the blood draw 
should be documented.
9.4.17
Pharmacodynamic Measurements
Not applicable to this study.
9.4.18
DNA Measurements 
Not applicable to this study.
9.4.19
Banked Tumor Specimen Measurements
Not applicable to this study.
9.4.20
Immunogenicity Sample Collection
Not applicable to this study.
9.5
Completion of Study Treatment (for Individual Patients)
9.5.1
Part A
Patients will be considered to have completed Part A of the study if they have completed the 
protocol-specified dose requirement and PK assessments to provide data necessary for assessment 
of effects of rifampin on pevonedistat PK within Part A of the protocol.
An EOS visit is needed in Part A only if the patient does not continue into Part B for any reason. 
The EOS visit will include physical examination (including ECOG performance status, vital signs, 
and weight); pregnancy test; laboratory assessments (hematology, chemistry, and urinalysis); 
12-lead ECG; monitoring of concomitant mediations, therapies, and procedures; and recording of 
AEs/SAEs. The EOS visit will be conducted 30 (+10) days after the last dose of study drug in Part 
A. If the EOS visit occurs earlier than 30 days after the last dose of pevonedistat, the patient should 
be contacted via telephone on Day 30 to assess for any new or ongoing AEs or SAEs that may 
have occurred since the previous visit.
9.5.2
Part B
Patients will be considered to have completed Part B of the study if they have completed 12 cycles 
of treatment with study drug, or if treatment is discontinued for any of the reasons outlined in 
Section 9.6. Patients who have completed Part A and participate in a rollover study (see 
Section 6.3.5) will be considered to have completed Study Pevonedistat-1015. If the patient 
continues into Part B, the EOS visit will occur 30 (+10) days after the last dose of study drug(s) in 
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Part B or before the start of subsequent therapy for the patient’s indication, if that occurs sooner. If 
the EOS visit occurs earlier than 30 days after the last dose of pevonedistat, the patient should be 
contacted via telephone on Day 30 to assess for any new or ongoing AEs or SAEs that may have 
occurred since the previous visit. Patients in Part B may also be considered to have completed 
Study Pevonedistat-1015 if they a enter roll-over or PTA study (see Section 6.3.5).
9.6
Discontinuation of Treatment With Study Drug and Patient Replacement
Study drug may be permanently discontinued for patients meeting any of the following criteria:

AE.

Protocol deviation.

Progressive disease (PD)

Symptomatic deterioration.

Unsatisfactory therapeutic response.

Study terminated by sponsor.

Withdrawal by subject.

Lost to follow-up.

Other (to be specified).
Once study drug has been discontinued, all study procedures outlined for the EOS visit will be 
completed as specified in the SOE (Appendix A). The primary reason for study drug 
discontinuation will be recorded in the eCRF. In Part A of the study, patients who are not PK 
evaluable will be replaced. 
Note: In optional Part B of the study, patients may receive pevonedistat until they experience PD 
or unacceptable pevonedistat-related toxicities or discontinue treatment for any reason. 
Patients who have achieved objective clinical benefit from combination therapy 
(chemotherapy+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.
9.7
Withdrawal of Patients From Study
A patient may be withdrawn from the study for any of the following reasons:

Lost to follow-up.

Study terminated by sponsor.

Withdrawal by subject.

Completed study.
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
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.
9.8
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.
The clinical team and the clinical research associate will review treatment compliance during 
investigational visits and at the completion of the study. Tests and procedures should be performed 
on schedule, but unless otherwise specified, occasional changes are allowable within a 2-day 
window for holidays, vacations, and other administrative reasons. If the study schedule is shifted, 
both assessments and dosing must be shifted to ensure that collection of assessments is completed
before dosing. This 2-day window is allowed for Part B but does not apply for Part A.
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10.0
ADVERSE EVENTS
10.1
Definitions
10.1.1 PTE Definition
A PTE is any untoward medical occurrence in a patient or subject who has signed informed 
consent to participate in a study but before administration of any study medication; it does not 
necessarily have to have a causal relationship with study participation.
10.1.2 AE Definition
AE means any untoward medical occurrence in a patient or subject administered a pharmaceutical 
product; the untoward medical occurrence does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product whether or not it is related to the medicinal product. This includes any 
newly occurring event, or a previous condition that has increased in severity or frequency since the 
administration of study drug.
An abnormal laboratory value will not be assessed as an AE unless that value leads to 
discontinuation or delay in treatment, dose modification, therapeutic intervention, or is considered 
by the investigator to be a clinically significant change from baseline.
10.1.3 SAE Definition
SAE means any untoward medical occurrence that at any dose:

Results in death.

Is life-threatening refers to an AE in which the patient was at risk of death at the time of the 
event. It does not refer to an event which hypothetically might have caused death if it were 
more severe).

Requires inpatient hospitalization or prolongation of an existing hospitalization (see 
clarification in the paragraph in Section 10.2 on planned hospitalizations).

Results in persistent or significant disability or incapacity. Disability is defined as a substantial 
disruption of a person’s ability to conduct normal life functions.

Is a congenital anomaly/birth defect.

Is a medically important event. This refers to an AE that may not result in death, be 
immediately life threatening, or require hospitalization, but may be considered serious when, 
based on appropriate medical judgment, may jeopardize the patient, require medical or 
surgical intervention to prevent 1 of the outcomes listed above, or involves suspected 
transmission via a medicinal product of an infectious agent. Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at home, 
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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 4.03, effective date 14 June 2010 [2]. Clarification should be made between 
an SAE and an AE that is considered severe in intensity (Grade 3 or 4), because the terms serious 
and severe are NOT synonymous. The general term severe is often used to describe the intensity 
(severity) of a specific event; the event itself, however, may be of relatively minor medical 
significance (such as a Grade 3 headache). This is NOT the same as serious, which is based on 
patient/event outcome or action criteria described above, and is usually associated with events that 
pose a threat to a patient’s life or ability to function. A severe AE (Grade 3 or 4) does not 
necessarily need to be considered serious. For example, a white blood cell count of 1000/mm3 to 
less than 2000 is considered Grade 3 (severe) but may not be considered serious. Seriousness (not 
intensity) serves as a guide for defining regulatory reporting obligations.
10.2
Procedures for Recording and Reporting AEs and SAEs
All AEs spontaneously reported by the patient and/or in response to an open question from study 
personnel or revealed by observation, physical examination, or other diagnostic procedures will be 
recorded on the appropriate page of the eCRF (see Section 10.3 for the period of observation). Any 
clinically relevant deterioration in laboratory assessments or other clinical finding is considered an 
AE. When possible, signs and symptoms indicating a common underlying pathology should be 
noted as 1 comprehensive event.
Regardless of causality, SAEs and serious PTEs (as defined in Section 10.1) must be reported (see 
Section 10.3 for the period of observation) by the investigator to the Takeda Global 
Pharmacovigilance department or designee within 24 hours of becoming aware of the event.
This will be done by transmitting an electronic data capture (EDC) SAE report. If transmission of 
an EDC SAE report is not feasible, then a facsimile of the completed Takeda paper-based SAE 
form will be sent. A sample of the paper-based SAE form and processing directions are in the 
Study Manual. Information in the SAE report or form must be consistent with the data provided on 
the eCRF.
If information not available at the time of the first report becomes available at a later date, the 
investigator will transmit a follow-up EDC SAE report (or a paper-based SAE form if an EDC 
SAE report is not feasible) or provide other documentation immediately within 24 hours of receipt. 
Copies of any relevant data from the hospital notes (eg, ECGs, laboratory tests, discharge 
summary, postmortem results) should be sent to the addressee, if requested.
All SAEs and serious PTEs should be followed up until resolution or permanent outcome of the 
event. The timelines and procedure for follow-up reports are the same as those for the initial report.
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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 4.03, effective date 14 June 2010 [2]. The criteria are provided in the Study 
Manual.
Relationship of the event to study drug administration (ie, its causality) will be determined by the 
investigator responding yes (related) or no (unrelated) to this question: “Is there a reasonable 
possibility that the AE is associated with the study drug?” If the event is considered “not related” 
to study drug administration, an alternate etiology must be provided.
10.3
Monitoring of AEs and Period of Observation
AEs, both nonserious and serious, will be monitored throughout the study.

AEs will be reported from the start of study drug administration through 30 days (+10 days) 
days after administration of the last dose of study drug and recorded in the eCRFs.

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) 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 faxing a completed Pregnancy Form to the Takeda Global 
Pharmacovigilance department or designee (see Section 10.2). The pregnancy must be followed 
for the final pregnancy outcome.
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If a female partner of a male patient becomes pregnant during the male patient’s participation in 
this study, the sponsor must also be contacted immediately by faxing a completed Pregnancy Form 
to the Takeda Global Pharmacovigilance department or designee (see Section 10.2). Every effort 
should be made to follow the pregnancy for the final pregnancy outcome.
10.5
Procedures for Reporting Product Complaints or Medication Errors (Including 
Overdose)
A product complaint is a verbal, written, or electronic expression that implies dissatisfaction 
regarding the identity, strength, purity, quality, or stability of a drug product. Individuals who 
identify a potential product complaint situation should immediately report this via the phone 
numbers or e-mail addresses provided below.
A medication error is a preventable event that involves an identifiable patient and that leads to 
inappropriate medication use, which may result in patient harm. Whereas overdoses and 
underdoses constitute medication errors, doses missed inadvertently by a patient do not. 
Individuals who identify a potential medication error (including overdose) situation should 
immediately report this via the phone numbers or e-mail addresses provided below.
Call center
Phone number
E-mail
Fax
Product complaints in and of themselves are not AEs. If a product complaint results in an SAE, an 
SAE form should be completed and sent to 
 (refer to Section 10.2)
10.6
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, investigators, and IRBs or 
IECs, as applicable, in accordance with national regulations in the countries where the study is 
conducted. Relative to the first awareness of the event by/or further provision to the sponsor or 
sponsor’s designee, SUSARs will be submitted to the regulatory authorities as an expedited report
within 7 days for fatal and life-threatening events and 15 days for other serious events, unless 
otherwise required by national regulations. The sponsor will also prepare an expedited report for 
other safety issues where these might materially alter the current benefit-risk assessment of an 
investigational medicinal product or that would be sufficient to consider changes in the 
investigational medicinal product’s administration or in the overall conduct of the trial. The 
investigational site also will forward a copy of all expedited reports to his or her IRB or IEC in 
accordance with national regulations.
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11.0
STUDY-SPECIFIC COMMITTEES
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 cross
functional reviews will include a global safety lead from the study team, and other representation 
from other departments at Millennium such as Clinical Research, Pharmacovigilance, 
Biostatistics, Clinical Pharmacology, and Clinical Operations.
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12.0
DATA HANDLING AND RECORDKEEPING 
The full details of procedures for data handling will be documented in the Data Management Plan. 
If selected for coding, AEs, PTEs, medical history, and concurrent conditions will be coded using 
the Medical Dictionary for Regulatory Activities. Drugs will be coded using the World Health 
Organization Drug Dictionary.
12.1
eCRFs 
Completed eCRFs are required for each subject who signs an ICF.
The sponsor or its designee will supply investigative sites with access to eCRFs and will make 
arrangements to train appropriate site staff in the use of the eCRF. These forms are used to transmit 
the information collected in the performance of this study to the sponsor, CRO partners, and 
regulatory authorities. Investigative sites must complete eCRFs in English.
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site.
Any change of, modification of, or addition to the data on the eCRFs should be made by the 
investigator or appropriate site personnel. Corrections to eCRFs are recorded in an audit trail that 
captures the old information, the new information, identification of the person making the 
correction, the date the correction was made, and the reason for change.
The principal investigator must review the eCRFs for completeness and accuracy and must sign 
and date the appropriate eCRFs as indicated. Furthermore, the principal investigator must retain 
full responsibility for the accuracy and authenticity of all data entered on the eCRFs.
eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The sponsor or its designee will be permitted to review the subject’s medical 
and hospital records pertinent to the study to ensure accuracy of the eCRFs. The completed eCRFs 
are the sole property of the sponsor and should not be made available in any form to third parties, 
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 copy of eCRFs, including the 
audit trail, and detailed records of drug disposition to enable evaluations or audits from regulatory 
authorities, the sponsor or its designees. Any source documentation printed on degradable thermal 
sensitive paper should be photocopied by the site and filed with the original in the subject’s chart 
to ensure long term legibility. Furthermore, ICH E6 Section 4.9.5 requires the investigator to retain 
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essential documents specified in ICH E6 (Section 8) until at least 2 years after the last approval of 
a marketing application for a specified drug indication being investigated or, if an application is 
not approved, until at least 2 years after the investigation is discontinued and regulatory authorities 
are notified. In addition, ICH E6 Section 4.9.5 states that the study records should be retained until 
an amount of time specified by applicable regulatory requirements or for a time specified in the 
Clinical Study Site Agreement between the investigator and sponsor.
Refer to the Clinical Study Site Agreement for the sponsor’s requirements on record retention. The 
investigator should contact and receive written approval from the sponsor before disposing of any 
such documents.
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13.0
STATISTICAL METHODS
13.1
Statistical and Analytical Plans
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.
13.1.1 Analysis Sets
The populations used for analysis will include the following:

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:
–
Receive the protocol-specified single pevonedistat dose in Part A.
–
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.
13.1.2 Analysis of Demographics and Other Baseline Characteristics
Demographic and baseline characteristics will be summarized, including sex, age, race, ethnicity, 
weight, height, BSA, baseline disease characteristics, and other parameters as appropriate.
13.1.3 Efficacy Analysis
Analysis of all efficacy measures collected during Part B will be descriptive. Disease response to 
pevonedistat in combination with SOC will be based on the best overall response as determined by 
the investigator using RECIST Version 1.1 guidelines (Appendix H). The duration of response 
will be defined in patients with disease response (CR or PR) as the time between the first 
documentation of response and PD. Responders without PD will be censored at the last clinical
assessment of response.
13.1.4 PK Analysis
Individual values and summary descriptive statistics of pevonedistat plasma concentration time 
data and PK parameters will be listed and tabulated as follows:

Day 1 (pevonedistat [in the absence of rifampin])
–
Pevonedistat Cmax, AUClast, AUC∞, CL, Vss, and t1/2z.

Day 10 (pevonedistat in the presence of rifampin)
–
Pevonedistat Cmax, AUClast, AUC∞, CL, Vss, and t1/2z.
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For pevonedistat-rifampin DDI assessment, the ratios of geometric mean Cmax, AUClast, and AUC∞
of pevonedistat in the presence of rifampin versus Cmax, AUClast, and AUC∞in the absence of 
rifampin and associated 90% CIs will be calculated based on mixed-model analysis of variance.
13.1.5 Safety Analysis
A safety analysis will be conducted separately for Part A and Part B to respectively characterize 
the safety profile of pevonedistat in combination with SOC. 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 study drug 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 first dose of study treatment in Part A and up through 30 days after the last 
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 Medical Dictionary for Regulatory Activities 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.

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 
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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 World Health Organization 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 and Criteria for Early Termination
No interim analysis is planned.
13.3
Determination of Sample Size
The sample size calculation is based on the expected two-sided 90% CI for the difference in the 
paired, log-transformed AUC (or Cmax) means of pevonedistat co-administered with rifampin and 
pevonedistat administered alone. Based on the preliminary data obtained from Study C15011, the 
within-subject coefficient of variation was estimated to be 13% for AUC and 58% for Cmax, 
respectively. Assuming the AUC (or Cmax) ratio is 1.0, with a sample size of 12 evaluable patients, 
the 90% CI of the ratio of geometric means is expected to be (0.907, 1.102) for AUC and (0.671, 
1.49) for Cmax based on the previously discussed variance assumptions. If the ratio is X, the 90% 
CI of the ratio of geometric means is expected to be within (0.907X, 1.102X) and (0.671X, 1.49X), 
respectively. Patients who are not PK evaluable may be replaced to ensure availability of 
approximately 12 PK-evaluable patients for the final analysis.
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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.
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 primary study 
assessment.
14.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, including 
those of foreign governments (eg, the FDA, the United Kingdom Medicines and Healthcare 
products Regulatory Agency, the Pharmaceuticals and Medical Devices Agency of Japan). If the 
study site is contacted for an inspection by a regulatory body, the sponsor should be notified 
immediately. The investigator and institution guarantee access for quality assurance auditors to all 
study documents as described in Section 14.1.
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15.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will conduct 
the study according to applicable local or regional regulatory requirements and align his or her 
conduct in accordance with the “Responsibilities of the Investigator” that are listed in Appendix B. 
The principles of Helsinki are addressed through the protocol and through appendices containing 
requirements for informed consent and investigator responsibilities.
15.1
IRB and/or IEC Approval
IRBs and IECs must be constituted according to the applicable state and federal/local requirements 
of each participating region. The sponsor or designee will require documentation noting all names 
and titles of members who make up the respective IRB or IEC. If any member of the IRB or IEC 
has direct participation in this study, written notification regarding his or her abstinence from 
voting must also be obtained. Those American sites unwilling to provide names and titles of all 
members because of privacy and conflict of interest concerns should instead provide a Federal 
Wide Assurance Number or comparable number assigned by the Department of Health and 
Human Services.
The sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the IB, a copy of the ICF, and, if 
applicable, subject recruitment materials and/or advertisements and other documents required by 
all applicable laws and regulations, must be submitted to a central or local IRB or IEC for 
approval. The IRB’s or IEC’s written approval of the protocol and subject informed consent must 
be obtained and submitted to the sponsor or designee before commencement of the study (ie, 
before shipment of the sponsor-supplied drug or study specific screening activity). The IRB or IEC 
approval must refer to the study by exact protocol title, number, and version date; identify versions 
of other documents (eg, ICF) reviewed; and state the approval date. The sponsor will ship 
drug/notify site once the sponsor has confirmed the adequacy of site regulatory documentation 
and, when applicable, the sponsor has received permission from competent authority to begin the 
trial. Until the site receives [drug/notification] no protocol activities, including screening may 
occur.
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the ICF, recruitment 
materials intended for viewing by subjects, local safety reporting requirements, reports and 
updates regarding the ongoing review of the study at intervals specified by the respective IRB or 
IEC, and submission of the investigator’s final status report to IRB or IEC. All IRB and IEC 
approvals and relevant documentation for these items must be provided to the sponsor or its 
designee.
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and sponsor.
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15.2
Subject Information, Informed Consent, and Subject Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The ICF, subject authorization form (if applicable), and subject 
information sheet (if applicable) describe the planned and permitted uses, transfers, and 
disclosures of the subject’s personal and personal health information for purposes of conducting 
the study. The ICF and the subject information sheet (if applicable) further explain the nature of 
the study, its objectives, and potential risks and benefits, as well as the date informed consent is 
given. The ICF will detail the requirements of the participant and the fact that he or she is free to 
withdraw at any time without giving a reason and without prejudice to his or her further medical 
care.
The investigator is responsible for the preparation, content, and IRB or IEC approval of the ICF 
and if applicable, the subject authorization form. The ICF, subject authorization form (if 
applicable), and subject information sheet (if applicable) must be approved by both the IRB or IEC 
and the sponsor before use.
The ICF, subject authorization form (if applicable), and subject information sheet (if applicable) 
must be written in a language fully comprehensible to the prospective subject. It is the 
responsibility of the investigator to explain the detailed elements of the ICF, subject authorization 
form (if applicable), and subject information sheet (if applicable) to the subject. Information 
should be given in both oral and written form whenever possible and in the manner deemed 
appropriate by the IRB or IEC. In the event the subject is not capable of rendering adequate written 
informed consent, then the subject’s legally acceptable representative may provide such consent 
for the subject in accordance with applicable laws and regulations.
The subject, or the subject’s legally acceptable representative, must be given ample opportunity to: 
(1) inquire about details of the study and (2) decide whether or not to participate in the study. If the 
subject, or the subject’s legally acceptable representative, determines he or she will participate in 
the study, then the ICF and subject authorization form (if applicable) must be signed and dated by 
the subject, or the subject’s legally acceptable representative, at the time of consent and before the 
subject entering into the study. The subject or the subject’s legally acceptable representative 
should be instructed to sign using their legal names, not nicknames, using blue or black ballpoint 
ink. The investigator must also sign and date the ICF and subject authorization (if applicable) at 
the time of consent and before subject entering into the study; however, the sponsor may allow a 
designee of the investigator to sign to the extent permitted by applicable law.
Once signed, the original ICF, subject authorization form (if applicable), and subject information 
sheet (if applicable) will be stored in the investigator’s site file. The investigator must document 
the date the subject signs the informed consent in the subject’s medical record. Copies of the 
signed ICF, the signed subject authorization form (if applicable), and subject information sheet (if 
applicable) shall be given to the subject.
All revised ICFs must be reviewed and signed by relevant subjects or the relevant subject’s legally 
acceptable representative in the same manner as the original informed consent. The date the 
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revised consent was obtained should be recorded in the subject’s medical record, and the subject 
should receive a copy of the revised ICF.
15.3
Subject Confidentiality
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or date 
of birth, and subject initials may be used to verify the subject and accuracy of the subject’s unique 
identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the sponsor 
requires the investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (eg, FDA, Medicines and Healthcare products Regulatory Agency, 
Pharmaceuticals and Medical Devices Agency), the sponsor’s designated auditors, and the 
appropriate IRBs and IECs to review the subject’s original medical records (source data or 
documents), including, but not limited to, laboratory test result reports, ECG reports, admission 
and discharge summaries for hospital admissions occurring during a subject’s study participation, 
and autopsy reports. Access to a subject’s original medical records requires the specific 
authorization of the subject as part of the informed consent process (see Section 15.2).
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s [e]CRF).
15.4
Publication, Disclosure, and Clinical Trial Registration Policy
15.4.1 Publication 
The investigator is obliged to provide the sponsor with complete test results and all data derived by 
the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the sponsor.
The sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 
this section and the Clinical Study Site Agreement.
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15.4.2 Clinical Trial Registration
In order 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 in Takeda Policy/Standard. 
Takeda contact information, along with investigator’s city, state (for Americas investigators), 
country, and recruiting status will be registered and available for public viewing. 
As needed Takeda and Investigator/site contact information may be made public to support 
participant access to trials via registries. In certain situations/registries, Takeda may assist 
participants or potential participants to find a clinical trial by helping them locate trial sites closest 
to their homes by providing the investigator name, address, and phone number via email/phone or 
other methods callers requesting trial information. Once subjects receive investigator contact 
information, they may call the site requesting enrollment into the trial. The investigative sites are 
encouraged to handle the trial inquiries according to their established subject screening process. If 
the caller asks additional questions beyond the topic of trial enrollment, they should be referred to 
the sponsor. 
Any investigator who objects to Takeda providing this information to callers must provide Takeda 
with a written notice requesting that their information not be listed on the registry site. 
15.4.3 Clinical Trial Results Disclosure
Takeda will post the results of clinical trials on ClinicalTrials.gov or other publicly accessible 
websites (including the Takeda corporate site) and registries, as required by Takeda 
Policy/Standard, applicable laws and/or regulations. 
Data Sharing:
The sponsor is committed to responsible sharing of clinical data with the goal of advancing 
medical science and improving patient care. Qualified independent researchers will be permitted 
to use data collected from patients during the study to conduct additional scientific research, which 
may be unrelated to the study drug or the patient’s disease. The data provided to external 
researchers will not include information that identifies patients personally.
15.5
Insurance and Compensation for Injury
Each subject in the study must be insured in accordance with the regulations applicable to the site 
where the subject is participating. If a local underwriter is required, then the sponsor or sponsor’s 
designee will obtain clinical study insurance against the risk of injury to clinical study subjects. 
Refer to the Clinical Study Site Agreement regarding the sponsor’s policy on subject 
compensation and treatment for injury. If the investigator has questions regarding this policy, he or 
she should contact the sponsor or sponsor’s designee.
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16.0
REFERENCES
1. Naughton CA. Drug-induced nephrotoxicity. American Family Physician 2008;78(6):743-50.
2. Common Terminology Criteria for Adverse Events (CTCAE). National Cancer Institute, 
National Institutes of Health, U.S. Department of Health and Human Services  Series v4.03. 
June 14, 2010. Publication No. 09-5410.
3. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response 
evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 
2009;45(2):228-47.
4. Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and 
response criteria of the Eastern Cooperative Oncology Group. American Journal of Clinical 
Oncology 1982;5(6):649-55.
5. CARBOPLATIN - carboplatin injection, solution [package insert]. Princeton, NJ: Sandoz Inc, 
2011.
6. du Bois A, Luck HJ, Meier W, Adams HP, Mobus V, Costa S, et al. A randomized clinical trial 
of cisplatin/paclitaxel versus carboplatin/paclitaxel as first-line treatment of ovarian cancer. J 
Natl Cancer Inst 2003;95(17):1320-9.
7. The Criteria Committee of New York Heart Association. Nomenclature and Criteria for 
Diagnosis of Diseases of the Heart and Great Vessels. 9 ed. Boston, MA: Little, Brown & Co; 
1994.
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CONFIDENTIAL
Appendix A
Schedules of Events
SOE for Treatment Part A (DDI)
Screening (a)
Day 1
Predose
Day 1
Day 2
Day 3 
(b)
Day 4 
(b)
Day 10
Predose
Day 10
Day 11
Day 12
EOS (c)
Study Drug Administration
Pevonedistat IV solution administration 
(d)
X
X
Rifampin administration (e)
Day 3 through Day 11
Study Procedures
Informed consent
X
Inclusion/exclusion criteria
X
Demographics
X
Complete medical history
X
Physical examination
X
X
Symptom-directed physical 
examination
X (f)
X
ECOG performance status
X
X
Height
X
Weight
X
X (f)
X
X
Vital signs (g)
X
X
X
X
X
X
X
X
X
X
12-Lead ECG
X
X
X
Echocardiogram (h)
X
Pregnancy test (i)
X
X
X
X
Hematology
X
X (f)
X
X
X
X
Chemistry
X
X (f)
X
X
X
X
X
Urinalysis
X
X
Plasma sample for pevonedistat PK(j)
X
X
X
X
X
X
X
X
Monitoring of concomitant medications 
and procedures
To be recorded in the eCRF from the time of the first dose through 30 (+10) days after the last dose of study drug.
AE/SAE reporting
Treatment-emergent AEs will be reported from administration of the first dose through 30 (+10) days after the last dose of study drug.
Serious PTEs will be reported from the signing of the ICF up to the first dose of study drug. In addition, related and unrelated 
treatment-emergent SAEs will be reported from the first dose of study drug through 30 (+10) days after administration of the last dose of 
study drug. After this period, only related SAEs must be reported.
Footnotes are on the last table page.
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CONFIDENTIAL
(a) Unless otherwise noted, the screening visit must occur within 28 days before the day of the first dose of study drug in Part A. Screening clinical laboratory values must be as 
specified in Inclusion Criterion #6 for patients to be eligible for the study.
(b) Patients can be discharged from clinic any time after all Day 3 PK samples have been collected (Days 3-4) and return to the clinic on Day 10.
(c) An EOS visit is needed in Part A only if the patient does not continue into Part B. The EOS visit will occur 30 days (+10 days) after the last dose of study drug or before the start 
of subsequent therapy for the patient’s indication, if that occurs sooner.
(d) Patients will receive a single dose of pevonedistat 50 mg/m2 (equivalent to approximately 86 mg for a typical individual of 1.73 m2 BSA) given as an approximate 1-hour (60±5 
minutes) IV infusion on Day 1 and Day 10.
(e) The first dose of rifampin 600 mg will be given orally in the clinic on the morning of Day 3 after collection of the 48-hour PK sample. Patients will self-administer rifampin oral 
capsules QD on Days 4, 5, 6, 7, 8, and 9 at home. Patients are encouraged to take rifampin at approximately the same time each day (±2 hours from the time of first rifampin dose). On 
Days 10 and 11, patients will report to the clinic to continue to receive oral 600 mg rifampin co-administered with pevonedistat on Day 10, and at the time of the 24-hour pevonedistat 
PK sampling on Day 11.
(f) Procedures conducted during screening that are performed within 3 days of Day 1 can also be used as the Day 1 predose evaluation and do not need to be repeated. Predose clinical 
laboratory values must be as specified in Inclusion Criterion #6 to administer the Day 1 dose of pevonedistat.
(g) On days when pevonedistat is administered, vital signs are to be measured predose (20 minutes [±10 min]) before the infusion of pevonedistat; 30 minutes (±10 min) after the start 
of pevonedistat dosing; and 1 hour (±10 min) and 3 hours (±30 min) after the completion of pevonedistat dosing. When the timing of vital signs assessment coincides with the timing 
of a blood draw, vital signs will be measured before blood sample collection.
(h) Echocardiography will be performed at screening to determine LVEF only for patients who have no historical LVEF data within 6 months prior to study enrollment.
(i) In Part A, a serum pregnancy test will be performed for women of childbearing potential at screening, and a serum or urine pregnancy test be performed on Day 1 predose, Day 10 
predose, and at the EOS visit.
(j) Time points for blood samples for PK analysis will be collected as specified in Table A.
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CONFIDENTIAL
Eligible patients may continue into optional Part B, which can begin within approximately 2 weeks of the patient completing Part A 
(ie, when the patient has met the discharge criteria).
SOE for Optional Continued Treatment With Pevonedistat+Chemotherapy, Part B
Pevonedistat+Chemotherapy Treatment
21-Day Cycle
EOS/
Early Termination (b)
Day 1 Predose (a)
Day 1
Day 3
Day 5
Study Drug Administration
Chemotherapy administration (c)
X
Pevonedistat administration (c)
X
X
X
Study Procedures
Part B entry criteria/retreatment (d)
X
Full physical examination
X (e)
X
Symptom-directed physical 
examination (e)
X
ECOG performance status (f)
X 
X
Weight
X
X
Vital signs (g)
X
X
X
X
X
12-Lead ECG (f)
X
X
Tumor assessment for solid tumors 
by RECIST, version 1.1 (h)
To be completed before dosing in Part B, end of Cycle 2, Cycle 5, and every 6 cycles thereafter
X
Monitoring of concomitant 
medications, therapies, and 
procedures
To be recorded from start of study administration in Part A through 30 days (+10 days) after the last dose of study drug in Part B
AE/SAE reporting (i)
Treatment-emergent AEs will be recorded from start of study administration in Part A through 30 days (+10 days) after the last dose of 
study drug in Part B.
SAEs (regardless of causality) will be reported from signing of the ICF in Part A through 30 days (+10 days) after the last dose of study drug in 
Part B. After this period, only related SAEs must be reported.
Samples/Laboratory Assessments
Pregnancy test (j)
X
X
Hematology (k)
X
X predose
X predose
X
Chemistry (l)
X
X predose
X predose
X
Urinalysis
X
X
Footnotes are on the following page.
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CONFIDENTIAL
Tests and procedures should be performed on schedule, but occasional changes are allowable (±2 days) for holidays, vacations, and other administrative reasons.
(a) For patients to be eligible for dosing with pevonedistat+chemotherapy (Part B), they must meet certain entry criteria (see Section 7.3). 
(b) If the patient continues into Part B, the EOS visit will occur 30 days (+10 days) after the last dose of study drug(s) in Part B or before the start of subsequent therapy for the 
patient’s indication, if that occurs sooner.
(c) The investigator will select which chemotherapy (docetaxel or carboplatin+paclitaxel) that each patient will receive in combination with pevonedistat. On Day 1, when 
pevonedistat and chemotherapy agents are both administered, chemotherapy will be administered first, followed by pevonedistat. The infusion of pevonedistat may be slowed or 
stopped and restarted for any associated infusion-related reactions. The dose of pevonedistat may be reduced because of toxicities in accordance with Section 8.3.3. The 
chemotherapeutic agent may be dose reduced because of toxicities in accordance with Section 8.3.3. See Section 8.1 for the details of study drug administration. NOTE: a time-out 
of approximately 15 minutes is required between the end of infusion of the chemotherapy regimen and the start of infusion of pevonedistat.
(d) For patients to be eligible for dosing with pevonedistat+chemotherapy (Part B), they must meet certain entry criteria (see Section 7.3). For Cycle 2 and beyond, patients must meet 
the criteria for beginning a new cycle of treatment (Section 8.3.1).
(e) A full physical examination is required on Day 1 (predose) of Cycle 1. For Cycle 2 and beyond, a symptom-directed physical examination is to be performed on Day 1 predose.
(f) Predose assessment may be performed 1 day in advance if necessary.
(g) On days when study drug is administered, vital signs are to be measured predose (20 minutes [±10 min]) before the infusion of chemotherapy (when pevonedistat and 
chemotherapy agents are both administered) or pevonedistat; 30 minutes (±10 min) after the start of pevonedistat dosing; and 1 hour (±10 min) after the completion of pevonedistat 
dosing. When the timing of vital signs assessment coincides with the timing of a blood draw, vital signs will be measured before blood sample collection. 
(h) Radiological imaging (as CT scan or MRI) will be required as entry criteria for Part B to assess the status of the patient’s underlying disease. If the patient has had appropriate 
imaging scans performed within 28 days of Cycle 1 Day 1 of Part B, then the results of those scans may be used; otherwise, the first assessment will take place before Cycle 1 Day 1. 
Tumor assessment will be performed before the start of Part B and at the completion of Cycle 2, Cycle 5, and every 6 cycles thereafter. 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 9.4.14. Response will be determined according to RECIST version 1.1.
(i) Including serious PTEs in Part A; see Section 10.1.1.
(j) In Part B, a serum or urine pregnancy test must also be performed for women of childbearing potential at every cycle (typically performed on Day 1 predose of each cycle; 
however, if a serum pregnancy test is used, this may be performed up to 3 days before Day 1), with negative results available before the first dose is administered in the respective 
cycle. A serum or urine pregnancy test will also be performed for women of childbearing potential at the EOS/Early Termination visit in Part B. Pregnancy tests may also be repeated 
during the study if requested by an IEC/IRB or if required by local regulations.
(k) Hematology samples will be collected as part of the entry criteria for Part B and before dosing with study drug on Days 1, 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. In addition, a sample will be taken at the EOS visit.
(l) Clinical chemistry samples will be collected as part of the entry criteria for Part B and before dosing with study drug on Days 1, 3, and 5. On Days 1, 3, and 5, samples may be 
drawn up to 1 day before dosing. In addition, a sample will be taken at the EOS visit.
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Table A
Blood Sampling Schedule (Part A)
Study Day
Time Point (hour)
Plasma Sample Collection
Matrix
Plasma (PK)
Day 1
Predose(a)
X
Day 1
EOI (b) (5 to 1 min)
X
Day 1
0.5 hour postinfusion (c) (±5 min)
X
Day 1
1 hour postinfusion (c) (15 min)
X
Day 1
2 hours postinfusion (c) (15 min)
X
Day 1
3 hours postinfusion (c) (30 min)
X
Day 1
4 hours postinfusion (c) (45 min)
X
Day 1
8 hours postinfusion (c) (1 hour)
X
Day 1
10 hours postinfusion (c) (1 hour)
X
Day 2
24 hours postdose (d) (1 hour)
X
Day 3
48 hours postdose (d) (1 hours)
X
Day 10
Predose(e)
X
Day 10
EOI (f) (5 to 1 min)
X
Day 10
0.5 hour postinfusion (g) (±5 min)
X
Day 10
1 hour postinfusion (g) (15 min)
X
Day 10
2 hours postinfusion (g) (15 min)
X
Day 10
3 hours postinfusion (g) (30 min)
X
Day 10
4 hours postinfusion (g) (45 min)
X
Day 10
8 hours postinfusion (g) (1 hour)
X
Day 10
10 hours postinfusion (g) (1 hour)
X
Day 11
24 hours postdose (h) (1 hour)
X
Day 12
48 hours postdose (h) (1 hours)
X
EOI=end of infusion.
(a) The sample is to be collected within 1 hour before the start of pevonedistat infusion on Day 1.
(b) The window for collection of the EoI time point is between 5 minutes before completion of infusion and 1 minute after 
completion of infusion. If, during Part A, IV infusion of study drug is interrupted or slowed, contact the project clinician or designee 
as soon as possible for consideration of patient replacement, as appropriate. If the IV infusion is interrupted, 2 additional PK 
samples (1 sample drawn when the infusion is stopped and 1 sample drawn when the infusion is restarted) should be collected so 
that the patient may be considered evaluable. The exact date and time of each additional sample collection and the actual start and 
stop times of the infusion should be recorded accurately.
(c) Time points listed on Day 1 are in reference to the end of pevonedistat IV infusion on Day 1.
(d) Time points listed on Day 2 and Day 3 are in reference to the initiation of the pevonedistat IV infusion on Day 1.
(e) The sample is to be collected within 1 hour before the start of pevonedistat infusion on Day 10.
(f) The window for collection of the EoI time point is between 5 minutes before completion of infusion and 1 minute after 
completion of infusion. If, during Part A, IV infusion of study drug is interrupted or slowed, contact the project clinician or designee 
as soon as possible for consideration of patient replacement, as appropriate. If the IV infusion is interrupted, 2 additional PK 
samples (1 sample drawn when the infusion is stopped and 1 sample drawn when the infusion is restarted) should be collected so 
that the patient may be considered evaluable. The exact date and time of each additional sample collection and the actual start and 
stop times of the infusion should be recorded accurately.
(g) Time points listed on Day 10 are in reference to the end of pevonedistat IV infusion on Day 10.
(h) Time points listed on Day 11 and Day 12 are in reference to the initiation of the pevonedistat IV infusion on Day 10.
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Appendix B
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 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 
study-related duties and functions, the investigator/institution should ensure that this 
individual or party is qualified to perform those study-related duties and functions and should 
implement procedures to ensure the integrity of the study-related duties and functions 
performed and any data generated.
4. Ensure that study related procedures, including study specific (non routine/non standard panel) 
screening assessments are NOT performed on potential subjects, before the receipt of written 
approval from relevant governing bodies/authorities.
5. Ensure that all colleagues and employees assisting in the conduct of the study are informed of 
these obligations.
6. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform to 
21 CFR Part 56, ICH, and local regulatory requirements.
7. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and approval 
of the protocol. Promptly report to the IRB/IEC all changes in research activity and all 
anticipated risks to subjects. Make at least yearly reports on the progress of the study to the 
IRB/IEC, and issue a final report within 3 months of study completion.
8. Ensure that requirements for informed consent, as outlined in 21 CFR Part 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 
contact and receive written approval from the sponsor before disposing of any such 
documents.
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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 C
Investigator Consent to Use of Personal Information
Takeda will collect and retain personal information of investigator, including his or her name, 
address, and other personally identifiable information. In addition, investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, United States, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
Investigator’s personal information may be retained, processed, and transferred by Takeda and 
these other parties for research purposes including the following:

Assessment of the suitability of investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may contain 
the same chemical compound present in the study medication.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of study records.

Posting investigator site contact information, study details and results on publicly accessible 
clinical trial registries, databases, and websites.
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in investigator’s own 
country.
Investigator acknowledges and consents to the use of his or her personal information by Takeda 
and other parties for the purposes described above.
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Appendix 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, et al, 1982 [4].
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Appendix E
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 [1].
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Appendix F
Definition of Postmenopausal
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. Refer to the 
following sources for additional information: European Heads of Medicines Agencies Clinical 
Trial Facilitation Group and 
hma.eu/fileadmin/dateien/Human_Medicines/01-About_HMA/Working_Groups/CTFG/2014_09
_HMA_ CTFG_Contraception.pdf.
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Pevonedistat (TAK924/MLN4924)
Study No. Pevonedistat-1015
Page 91 of 102
Protocol Incorporating Amendment 02
04 September 2018
Appendix G
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).
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Pevonedistat (TAK924/MLN4924)
Study No. Pevonedistat-1015
Page 92 of 102
Protocol Incorporating Amendment 02
04 September 2018
(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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Pevonedistat (TAK924/MLN4924)
Study No. Pevonedistat-1015
Page 93 of 102
Protocol Incorporating Amendment 02
04 September 2018
Appendix H
Response Criteria
Disease Response Criteria for Target and Nontarget Lesions
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.
PR
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 PR 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 1 or more nontarget lesion(s) or/and maintenance of tumor marker level above the normal 
limits.
PD
Appearance of 1 or more new lesions and/or unequivocal progression of existing nontarget lesions.
Source: Eisenhauer, et al, 2009 [3].
Overall Disease Response Criteria
Target Lesions
Nontarget Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/Non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all evaluated
No
PR
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, et al, 2009 [3].
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Pevonedistat (TAK924/MLN4924)
Study No. Pevonedistat-1015
Page 94 of 102
Protocol Incorporating Amendment 02
04 September 2018
Appendix I
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 [5].
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+paclitaxel or paclitaxel+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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Pevonedistat (TAK924/MLN4924)
Study No. Pevonedistat-1015
Page 95 of 102
Protocol Incorporating Amendment 02
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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 et al, 2003 [6].
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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Pevonedistat (TAK924/MLN4924)
Study No. Pevonedistat-1015
Page 96 of 102
Protocol Incorporating Amendment 02
04 September 2018
Appendix J
New York Heart Association Classification of Cardiac Disease
The following table presents the New York Heart Association classification of cardiac disease. 
Class
Functional Capacity
Objective Assessment
I
Patients with cardiac disease but without resulting limitations of physical 
activity. Ordinary physical activity does not cause undue fatigue, 
palpitation, dyspnea, or anginal pain.
No objective evidence of 
cardiovascular disease
II
Patients with cardiac disease resulting in slight limitation of physical 
activity. They are comfortable at rest. Ordinary physical activity results in 
fatigue, palpitation, dyspnea, or anginal pain.
Objective evidence of minimal 
cardiovascular disease
III
Patients with cardiac disease resulting in marked limitation of physical 
activity. They are comfortable at rest. Less than ordinary activity causes 
fatigue, palpitation, dyspnea, or anginal pain.
Objective evidence of 
moderately severe 
cardiovascular disease
IV
Patients with cardiac disease resulting in inability to carry on any physical 
activity without discomfort. Symptoms of heart failure or the anginal 
syndrome may be present even at rest. If any physical activity is 
undertaken, discomfort is increased.
Objective evidence of severe 
cardiovascular disease
Source: The Criteria Committee of New York Heart Association, 1994 [7].
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Pevonedistat (TAK924/MLN4924)
Study No. Pevonedistat-1015
Page 97 of 102
Protocol Incorporating Amendment 02
04 September 2018
Appendix K
Excluded Strong CYP3A Inducers
Use of the CYP3A inducers listed in the table below should be avoided during pevonedistat 
therapy unless otherwise noted in the protocol.
In Vivo Inducers of CYP3A
Strong Inducers ≥80% Decrease in AUC
Carbamazepine
Phenytoin
Phenobarbital
Primidone
Rifabutin
Rifampin
Rifapentine
St. John’s Wort
This is not an exhaustive list; refer to the following sources: medicine.iupui.edu/flockhart/table.htm and 
fda.gov/CDER/drug/drugInteractions/tableSubstrates.htm for additional information.
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Pevonedistat (TAK924/MLN4924)
Study No. Pevonedistat-1015
Page 98 of 102
Protocol Incorporating Amendment 02
04 September 2018
Appendix L
Detailed Description of Amendments to Text
The primary section(s) of the protocol affected by the changes in Amendment 02 are indicated. 
The corresponding text has been revised throughout the protocol.
Change 1: Clarify the exclusion criterion regarding the assessment of LVEF.
The primary change occurs in Section 7.2, Exclusion Criteria.
Initial 
wording:
13. Left ventricular ejection fraction <50% as assessed by echocardiogram or 
radionuclide angiography.
Amended 
or new 
wording:
13. Left ventricular ejection fraction (LVEF) <50% as assessed by echocardiogram
or radionuclide angiography within 6 months prior to study enrollment. If a result 
within this time frame is unavailable, LVEF must be determined by 
echocardiography at screening.
Rationale for Change:
The intent of the protocol has been to allow sites to use historical LVEF data, if available, or 
perform an echocardiogram, if needed, to determine patient eligibility for the study. This point has 
been clarified in this protocol amendment.
The following sections also contain this change:

Section 9.4.12 Echocardiogram.

Appendix A
Schedules of Events (SOE for Treatment Part A [DDI]).
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Study No. Pevonedistat-1015
Page 99 of 102
Protocol Incorporating Amendment 02
04 September 2018
Change 2: Delete the requirement that, for inclusion in the study, patients must have a tumor that 
is radiographically or clinically evaluable and/or measurable.
The change occurs in Section 7.1, Inclusion Criteria.
Deleted 
text:
2.
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+paclitaxel in Part B of this 
study, or have progressed despite standard therapy, or for whom conventional 
therapy is not considered effective. The tumor must be radiographically or 
clinically evaluable and/or measurable.
Rationale for Change:
As this is a phase 1 DDI study, the requirement for measurable disease is not considered essential.
Change 3: Change serious adverse event reporting from a paper-based system to electronic data 
capture.
The change occurs in Section 10.2, Procedures for Recording and Reporting AEs and SAEs.
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Pevonedistat (TAK924/MLN4924)
Study No. Pevonedistat-1015
Page 100 of 102
Protocol Incorporating Amendment 02
04 September 2018
Initial
wording:
All AEs spontaneously reported by the patient and/or in response to an open question 
from study personnel or revealed by observation, physical examination, or other 
diagnostic procedures will be recorded on the appropriate page of the eCRF (see 
Section 10.3 for the period of observation). Any clinically relevant deterioration in 
laboratory assessments or other clinical finding is considered an AE. When possible, 
signs and symptoms indicating a common underlying pathology should be noted as 1 
comprehensive event.
Regardless of causality, SAEs and serious PTEs (as defined in Section 10.1) must be 
reported (see Section 10.3 for the period of observation) by the investigator to the 
Takeda Global Pharmacovigilance department or designee (contact information 
provided below). This should be done by faxing the SAE Form within 24 hours after 
becoming aware of the event. The SAE Form, created specifically by Takeda, will be 
provided to each clinical study site. A sample of the SAE Form may be found in the 
Study Manual. Follow-up information on the SAE or serious PTE may be requested 
by Takeda. SAE report information must be consistent with the data provided on the 
eCRF.
SAE Reporting Contact Information*
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nd Subject to the Applicable Terms of Use
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Pevonedistat (TAK924/MLN4924)
Study No. Pevonedistat-1015
Page 101 of 102
Protocol Incorporating Amendment 02
04 September 2018
Amended 
or new 
wording:
All AEs spontaneously reported by the patient and/or in response to an open question 
from study personnel or revealed by observation, physical examination, or other 
diagnostic procedures will be recorded on the appropriate page of the eCRF (see 
Section 10.3 for the period of observation). Any clinically relevant deterioration in 
laboratory assessments or other clinical finding is considered an AE. When possible, 
signs and symptoms indicating a common underlying pathology should be noted as 1 
comprehensive event.
Regardless of causality, SAEs and serious PTEs (as defined in Section 10.1) must be 
reported (see Section 10.3 for the period of observation) by the investigator to the 
Takeda Global Pharmacovigilance department or designee (contact information 
provided below). within 24 hours of becoming aware of the event.This should be 
done by faxing the SAE Form within 24 hours after becoming aware of the event. The 
SAE Form, created specifically by Takeda, will be provided to each clinical study site. 
A sample of the SAE Form may be found in the Study Manual. Follow-up information 
on the SAE or serious PTE may be requested by Takeda. SAE report information must
be consistent with the data provided on the eCRF.
SAE Reporting Contact Information*
This will be done by transmitting an electronic data capture (EDC) SAE report. 
If transmission of an EDC SAE report is not feasible, then a facsimile of the 
completed Takeda paper-based SAE form will be sent. A sample of the 
paper-based SAE form and processing directions are in the Study Manual. 
Information in the SAE report or form must be consistent with the data 
provided on the eCRF.
If information not available at the time of the first report becomes available at a 
later date, the investigator will transmit a follow-up EDC SAE report (or a 
paper-based SAE form if an EDC SAE report is not feasible) or provide other 
documentation immediately within 24 hours of receipt. Copies of any relevant 
data from the hospital notes (eg, ECGs, laboratory tests, discharge summary, 
postmortem results) should be sent to the addressee, if requested.
All SAEs and serious PTEs should be followed up until resolution or permanent 
outcome of the event. The timelines and procedure for follow-up reports are the 
same as those for the initial report.
Property of Takeda: For Non-Com
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one by
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based
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Pevonedistat (TAK924/MLN4924)
Study No. Pevonedistat-1015
Page 102 of 102
Protocol Incorporating Amendment 02
04 September 2018
Rationale for Change:
SAEs are being reported by EDC in this study; the amended text reflects only a change in 
procedure for reporting SAEs.
Change 4: Clarify the timing of chemistry and hematology laboratory assessments before 
administration of the Day 1 dose of pevonedistat in Part A (drug-drug interaction) of the study.
The primary change occurs in Section 7.1 Inclusion Criteria.
Deleted 
text:
3. Clinical laboratory values as specified below within 3 days before the first dose of 
study drug:
Rationale for Change:
To clarify that the clinical laboratory values specified in Inclusion Criterion #6 may be determined 
within the 28-day screening period to determine patient eligibility for the study. If these 
assessments have been performed within 3 days of Day 1, these results can also be used as the 
Day 1 predose evaluation to determine whether the patient can receive study drug and do not need 
to be repeated.
Appendix A
Schedules of Events (SOE for Treatment Part A [DDI]) Footnotes (a) and (f) also 
contain this change. 
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Server Date 
(dd-MMM-yyyy HH:mm ‘UTC’) 
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SAP_001.pdf: 


Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: A Phase 1 Study to Evaluate the Effects of Rifampin on Pharmacokinetics of Pevonedistat 
in Patients with Advanced Solid Tumors
NCT Number: NCT03486314
SAP Approve Date: 11 June 2019
Certain information within this Statistical Analysis Plan has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable (PPD) information 
or company confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.


1.0
TITLE PAGE
STATISTICAL ANALYSIS PLAN
STUDY NUMBER: Pevonedistat-1015
A Phase 1 Study to Evaluate the Effects of Rifampin on Pharmacokinetics of Pevonedistat 
in Patients with Advanced Solid Tumors
TAK-924/MLN4924: Effect of Rifampin (Strong Metabolic Enzyme Inducer)
on 50 mg/m2 dosing of Pevonedistat
PHASE 1
Version: Final
Date: 11 June 2019
Prepared by:
Based on:
Protocol Version: Protocol Amendment No. 02
Protocol Date: 04 September 2018
PPD
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
rmacok
maco
Tumor
Tumo
ng Meta
g Met
Pevoned
evone
HASE 
ASE
Ve
V
D
Protoc
Proto
Pr
For Non
ope


Pevonedistat-1015
Page 2 of 38
Statistical Analysis Plan Draft
11 June 2019
1.1
Approval Signatures
Electronic signatures can be found on the last page of this document.
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Pevonedistat-1015
Page 3 of 38
Statistical Analysis Plan Draft
11 June 2019
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
Safety Objectives.......................................................................................................8
4.4
Exploratory Objectives ..............................................................................................8
4.5
Study Design .............................................................................................................8
4.5.1
Part A: Assessment of the effect of rifampin on pevonedistat 
pharmacokinetics (PK).........................................................................................8
4.5.2
Part B (OPTIONAL): Continued Treatment with Pevonedistat in Combination 
with Standard of Care (SOC)................................................................................9
5.0
ANALYSIS ENDPOINTS.............................................................................................11
5.1
Primary Endpoints ...................................................................................................11
5.2
Secondary Endpoints ...............................................................................................11
5.3
Safety Endpoint .......................................................................................................11
5.4
Exploratory Endpoint...............................................................................................11
6.0
DETERMINATION OF SAMPLE SIZE.......................................................................12
7.0
METHODS OF ANALYSIS AND PRESENTATION...................................................13
7.1
General Principles....................................................................................................13
7.1.1
Study Definitions ...............................................................................................13
7.1.2
Definition of Study Days....................................................................................13
7.1.3
Definition of Baseline Values.............................................................................13
7.1.4
Windowing of Visits ..........................................................................................14
7.1.5
Withdrawals, Dropouts, Loss to Follow-up ........................................................14
7.1.6
Imputations for Missing Dates ...........................................................................14
7.2
Randomization and Stratification.............................................................................15
7.3
Unblinding...............................................................................................................15
7.4
Statistical Software ..................................................................................................15
7.5
Analysis Sets ...........................................................................................................15
7.5.1
Safety Analysis Set/ Population..........................................................................15
7.5.2
Pharmacokinetic (PK)-Evaluable Population......................................................15
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7.5.3
Response-Evaluable Population .........................................................................16
7.6
Disposition of Subjects ............................................................................................16
7.6.1
Patient Disposition.............................................................................................16
7.7
Demographic and Other Baseline Characteristics.....................................................17
7.7.1
Demographics....................................................................................................17
7.7.2
Baseline Disease Characteristics ........................................................................17
7.7.3
Inclusion/Exclusion Criteria...............................................................................18
7.7.4
Medical History .................................................................................................18
7.7.5
Concomitant Medications...................................................................................18
7.8
Study Drug Exposure and Compliance.....................................................................19
7.8.1
Study Drug Exposure.........................................................................................19
7.8.2
Treatment Compliance and Modifications..........................................................20
7.9
Efficacy Analyses (Part B).......................................................................................20
7.10
Pharmacokinetic/ Pharmacodynamic Analysis .........................................................21
7.10.1 Pharmacokinetic Analysis (Part A).....................................................................21
7.10.2 Pharmacodynamic Analysis ...............................................................................23
7.11
Safety Analysis........................................................................................................24
7.11.1 Adverse Events ..................................................................................................24
7.11.2 Overall Summary...............................................................................................25
7.11.3 Serious Adverse Events......................................................................................25
7.11.4 Deaths................................................................................................................25
7.11.5 Adverse Events Resulting in Discontinuation of Study Drug..............................26
7.11.6 Adverse Events Resulting in Dose Reduction.....................................................26
7.11.7 Adverse Events Resulting in Dose Modification.................................................26
7.11.8 Myalgia Events and Musculoskeletal Pain and Discomfort.................................26
7.11.9 Clinical Laboratory Evaluations .........................................................................29
7.11.10
Vital Signs ...................................................................................................32
7.11.11
12-Lead ECGs..............................................................................................32
7.11.12
Eastern Cooperative Oncology Group (ECOG) Performance Status .............32
7.12
Interim Analysis ......................................................................................................32
7.13
Changes in the Statistical Analysis Plan...................................................................32
8.0
REFERENCES..............................................................................................................33
9.0
DATA LISTINGS .........................................................................................................34
10.0
APPENDICES...............................................................................................................36
10.1
APPENDIX 1 ..........................................................................................................36
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10.2
APPENDIX 2 ..........................................................................................................37
LIST OF IN-TEXT TABLES
Table 7.a
Selected Labs.....................................................................................................30
LIST OF IN-TEXT FIGURES
Figure 4.a
Study Overview .................................................................................................10
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3.0
LIST OF ABBREVIATIONS
AE
adverse event
ALL 
acute lymphoblastic leukemia
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AML 
acute myeloid leukemia
ANC 
absolute neutrophil count
AST 
aspartate aminotransferase
AUC 
area under the plasma concentration-time curve
AUC∞
AUC from time zero to infinity
AUClast 
AUC from time zero to time of the last quantifiable concentration
AUCτ
AUC during a dosing interval
BSA 
body surface area
CDL 
cullin-dependent ubiquitin E3 ligases
CFR
Code of Federal Regulations
CLp
Systemic clearance
Cmax 
maximum observed concentration
CR 
complete response
CRO 
contract research organization
CT 
computed tomography
CV 
coefficient of variation
CYP 
cytochrome P450
DDI 
drug-drug interaction
DME 
drug-metabolizing enzyme
ECG 
electrocardiogram
ECOG 
Eastern Cooperative Oncology Group
eCRF 
electronic case report form
EOS 
End-of-Study
FDA (US) 
Food and Drug Administration
FSH 
follicle-stimulating hormone
GCP 
Good Clinical Practice
GFR 
glomerular filtration rate
GI 
gastrointestinal
HIV 
human immunodeficiency virus
IB 
Investigator’s Brochure
ICF 
Informed consent form
ICH 
International Conference on Harmonisation
IDMC 
independent data monitoring committee
IEC 
independent ethics committee
IRB 
institutional review board
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IV 
Intravenous(ly)
Millennium 
Millennium Pharmaceuticals, Inc
pevonedistat 
research name of pevonedistat hydrochloride; TAK-924
MRI 
magnetic resonance imaging
MTD 
maximum tolerated dose
NAE 
NEDD8-activating enzyme
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events
NSCLC 
non-small cell lung cancer
PD 
progressive disease
PK
pharmacokinetics
PR 
partial response
QTc 
rate-corrected QT interval
RECIST 
Response in Evaluation Criteria in Solid Tumors
SAE
serious adverse event
SC 
subcutaneous(ly)
SmPC 
Summary of Product Characteristics
SoC 
standard of care
t1/2z 
terminal disposition phase half-life
TAD
time after dose (actual)
TEAE 
treatment-emergent adverse event
tmax
time of first occurrence of Cmax
TRA 
total radioactivity
ULN 
upper limit of the normal range
US 
United States
USP 
United States Pharmacopeia
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4.0
OBJECTIVES
4.1
Primary Objectives
The primary objective is to assess the effect of multiple-dose administration of rifampin on the 
single-dose PK of pevonedistat in adult patients with advanced solid tumors (Part A).
4.2
Secondary Objectives
The secondary objectives are as follows:
Part A

To further characterize pevonedistat PK following a single dose at 50 mg/m2 in the absence 
or presence of rifampin.
Part B

To evaluate disease response that may be observed following treatment with pevonedistat in 
combination with either docetaxel or carboplatin+paclitaxel in patients with advanced solid 
tumors.
4.3
Safety Objectives
The safety objective for Part A is to evaluate the safety and tolerability of pevonedistat in 
patients with advanced solid tumors following a single IV dose at 50 mg/m2 in the absence or 
presence of rifampin.
The safety objective for Part B is to evaluate the safety and tolerability of pevonedistat in 
combination with either docetaxel or carboplatin+paclitaxel in patients with advanced solid 
tumors.
4.4
Exploratory Objectives
None.
4.5
Study Design
This is a 2-part, open-label, DDI study in 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+paclitaxel in 
Part B of this study, or have progressed, despite standard therapy, or for whom conventional 
therapy is not considered effective. Approximately 20 patients will be enrolled to obtain 
approximately 12 PK-evaluable patients.
4.5.1
Part A: Assessment of the effect of rifampin on pevonedistat pharmacokinetics (PK)
Eligible patients will receive a single dose of 50 mg/m2 pevonedistat via a 1-hour intravenous 
(IV) infusion on Day 1. Plasma PK samples will be collected at a series of predetermined time 
points up to 48 hours (Day 3) following the single dose of pevonedistat. Patients will then 
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receive an oral dose of 600 mg rifampin once daily (QD) starting from Day 3 (after collecting the 
48-hour PK sample) through Day 11. There will be no pevonedistat doses from Day 2 through 
Day 9. On Day 10, a single dose of 50 mg/m2 pevonedistat will be administered, and plasma 
samples will be collected at predetermined time points up to 48 hours (Day 12) following the 
second single dose of pevonedistat. Study drug will be discontinued early if a patient experiences 
study drug‒related toxicities.
Both doses of pevonedistat (Days 1 and 10) will be administered in the clinic, followed by the 
required PK sampling. Serial blood plasma samples for determination of the plasma 
concentration of pevonedistat will be obtained during Part A at prespecified time points. The first 
dose of rifampin will be given orally in the clinic on the morning of Day 3 after collection of the 
48-hour PK sample. Patients will self-administer rifampin (oral capsules) QD on Days 4, 5, 6, 7, 
8, and 9 at home. Patients are encouraged to take rifampin at approximately the same time each 
day (±2 hours from the time of first rifampin dose). On Days 10 and 11, patients will report to 
the clinic to continue to receive oral 600 mg rifampin co-administered with pevonedistat on 
Day 10, and at the time of the 24-hour pevonedistat PK sampling on Day 11. The last PK 
sampling is on Day 12 (48-hour post pevonedistat infusion on Day 10). There will be no 
pevonedistat dosing on Days 11 and 12. There will be no rifampin dosing on Day 12.
All doses of rifampin will be administered on an empty stomach with patients taking nothing by 
mouth (NPO) except for water and prescribed medications for 2 hours before and at least 1 hour 
after each rifampin dose. Patients who miss any rifampin doses on Days 3 to 9 will not be 
considered evaluable and pevonedistat dosing and PK sampling on Day 10 will not be required 
for these patients. Patients will have a washout period from the last dose of rifampin for at least 
1 week to allow reversal of metabolic enzyme induction before the start of Part B of the study.
Patients may discontinue therapy at any time, for any reason. Patients in Part A who do not
continue to the optional Part B will attend an End of Study (EOS) visit 30 (+10) days after 
receiving their last dose of study drug in Part A.
4.5.2
Part B (OPTIONAL): Continued Treatment with Pevonedistat in Combination with 
Standard of Care (SOC)
After completion of Part A of this study, patients will have the option of participating in Part B. 
Any patient who decides to participate in Part B will need to meet the continuation criteria of the 
study before treatment in Part B can begin. Patients will receive pevonedistat in combination 
with either docetaxel or carboplatin+paclitaxel, as recommended by the investigator. As in Part 
A, safety assessments will also be conducted in Part B of the study. In addition, Part B will 
conduct disease assessments using radiological evaluations (computed tomography scan or 
magnetic resonance imaging).
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For an overview of the study design of Parts A and B, refer to Figure 4.a below. 
Figure 4.a
Study Overview
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5.0
ANALYSIS ENDPOINTS
5.1
Primary Endpoints
The primary endpoint of the study is the ratios of geometric mean pevonedistat maximum 
observed plasma concentration (Cmax), area under the plasma concentration-time curve from time 
0 to time of the last quantifiable concentration (AUClast), and area under the plasma 
concentration versus time curve from time 0 to infinity (AUC∞) in the presence of rifampin in 
reference to Cmax, AUClast, and AUC∞in the absence of rifampin and associated 90% confidence 
intervals (CIs).
5.2
Secondary Endpoints
The secondary endpoints are as follows:
Part A

PK parameters: CL, volume of distribution at steady-state after intravenous administration 
(Vss), and t1/2z of pevonedistat following a single dose administration of 50 mg/m2 on Day 1 
(in the absence of rifampin) and Day 10 (in the presence of rifampin).
Part B

Measures of disease response based on the investigator’s assessment using the Response 
Evaluation Criteria in Solid Tumors (RECIST, Version 1.1) guideline.
5.3
Safety Endpoint
The safety endpoints for Part A of this study are AEs, serious adverse events (SAEs), 
assessments of clinical laboratory values, and vital signs measurements following a single-dose 
IV administration of pevonedistat at 50 mg/m2 in the absence or presence of rifampin. The safety 
endpoint for Part B of this study are AEs, SAEs, assessments of clinical laboratory values, and 
vital signs measurements following administration of pevonedistat in combination with either 
docetaxel or carboplatin+paclitaxel.
5.4
Exploratory Endpoint
There are no exploratory or additional endpoints in this study.
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6.0
DETERMINATION OF SAMPLE SIZE
The sample size calculation is based on the expected two-sided 90% CI for the difference in the 
paired, log-transformed AUC (or Cmax) means of pevonedistat co-administered with rifampin and 
pevonedistat administered alone. Based on the preliminary data obtained from Study C15011, the 
within-subject coefficient of variation was estimated to be 13% for AUC and 58% for Cmax, 
respectively. Assuming the AUC (or Cmax) ratio is 1.0, with a sample size of 12 evaluable 
patients, the 90% CI of the ratio of geometric means is expected to be (0.907, 1.102) for AUC 
and (0.671, 1.49) for Cmax based on the previously discussed variance assumptions. If the ratio is 
X, the 90% CI of the ratio of geometric means is expected to be within (0.907X, 1.102X) and 
(0.671X, 1.49X), respectively. Patients who are not PK evaluable will be replaced to ensure 
availability of approximately 12 PK-evaluable patients for the final analysis.
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7.0
METHODS OF ANALYSIS AND PRESENTATION
7.1
General Principles 
In general, summary tabulations will include the number of observations, (arithmetic) mean, 
standard deviation (SD), geometric mean and coefficient of variation (%CV) for PK related 
parameters, median, minimum, and maximum for continuous variables, and the number and 
percent (of non-missing) per category for categorical data, unless specified otherwise. Means and 
medians will be presented to 1 more decimal place than the recorded data. The standard 
deviations (SDs) 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.
Descriptive statistics will be presented with the same precision as the original data. The PK 
parameters will be summarized with a precision of 3 significant digits, while tmax is presented 
with the number of relevant decimal places to specify the sampling time. Percent CV and 
frequency percentages will be presented as integers.
Summary statistics will be calculated by time point, if applicable.
7.1.1
Study Definitions
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. 
7.1.2
Definition of Study Days
Study Day 1 is defined as the date on which a subject is administered their first dose of the study 
drug. Other study days are defined relative to the Study Day 1 with Day 1 being Study Day 1 and 
Day -1 being the day prior to Study Day 1. Study day 1 definition is similarly for part B. 
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 of the 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 which 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.
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7.1.4
Windowing of Visits
All data will be categorized based on the scheduled visit at which they were collected. The 
analysis of PK data and determination of PK parameters will be based on the actual elapsed time 
post dose relative to the first dosing.
7.1.5
Withdrawals, Dropouts, Loss to Follow-up
Patients who are not PK-evaluable will be replaced. Generally no additional patients will be 
enrolled due to withdrawals, dropouts, or loss to follow-up.
7.1.6
Imputations for Missing Dates
Dates of initial diagnosis, prior therapy, surgery or radiation which are partially missing will be 
imputed as follows:

If the date has a month and year but the day is missing, the 15th will be inserted as the day.

If the date has a year but the month and the day are missing, June 30th will be inserted.
7.1.6.1
Analysis of Missing Adverse Event Dates

If the start date has month and year but day is missing, the event will be considered
–
treatment emergent for Part A if both the month and year of the start date of the event are 
on or after the month and year of the date of the first dose of study drug in Part A, and on 
or before the month and year of the date of the last dose of study drugs in Part A plus 30
days for patients who do not continue into Part B or on or before the month and year of 
the date of the first dose of study drugs in Part B for patients who continue into Part B, 
and the end date of the event if not missing is on or after the date of first doseof study 
drug in part A.
–
treatment emergent for Part B if both the month and year of the start date of the event are 
on or after the month and year of the date of the first dose of study drugs in Part B, and 
on or before the month and year of the date of the last dose of study drugs in Part B plus 
30 days, and the end date of the event if not missing is on or after the date of first dose of 
study drug in part B.

If the start date has year, but day and month are missing, the event will be considered.
–
treatment emergent for Part A if the year of the start date of the event is on or after the 
year of the date of the first dose of pevonedistat in Part A, and on or before the year of 
the date of the last dose of study drugs in Part A plus 30 days for patients who do not 
continue into Part B or on or before the year of the date of the first dose of study drugs in 
Part B for patients who continue into Part B, and the end date of the event if not missing 
is on or after the date of first dose of study drug in part A.
–
treatment emergent for Part B if the year of the start date of the event are on or after the 
year of the date of the first dose of study drugs in Part B, and on or before the year of the 
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date of the last dose of study drugs in Part B plus 30 days, and the end date of the event if 
not missing is on or after the date of first dose of study drug in part B.

If the start date of an event is completely missing, the event will be considered.
–
treatment emergent for Part A for patients who do not continue into Part B, and the end 
date of the event if not missing is on or after the date of first dose of study drug in part A.
–
treatment emergent for Part A for patients who continue into Part B if the ending date of 
the event is before the date of the first dose of study drugs in Part B, and the end date of 
the event if not missing is on or after the date of first dose of study drug in part A.
–
treatment emergent for both Part A and Part B for patients who continue into Part B if the 
ending date does not reflect whether the AE ends prior to the first dose of study drug in 
Part B.
7.2
Randomization and Stratification 
No randomization or stratification will be performed in this study.
7.3
Unblinding
As this is an open-label study, no unblinding methodology is required.
7.4
Statistical Software 
SAS version 9.4 (or higher) will be used for all analyses.
7.5
Analysis Sets
7.5.1
Safety Analysis Set/ Population
The safety analysis set for Part A is defined as all enrolled patients who receive at least single 
pevonedistat dose during Part A. All safety analyses in Part A will be performed using the safety 
population for Part A.
The safety population for Part B is defined as all patients who continue to Part B and receive at 
least 1 dose of study drugs administered during Part B. All safety analyses in Part B will be 
performed using the safety population for Part B.
7.5.2
Pharmacokinetic (PK)-Evaluable Population
The PK-evaluable population is defined as a) all enrolled patients who receive the 
protocol-specified single pevonedistat dose in Part A, b) did not receive any excluded 
medications throughout the completion of Part A, and c) have sufficient concentration-time data 
to permit reliable estimation of PK parameters. The patients to be included in the PK-evaluable 
population will be determined by the Takeda Clinical Pharmacologist upon review of the final 
data.
PK analyses during Part A will be performed using the PK-evaluable population.
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7.5.3
Response-Evaluable Population
The response-evaluable population is defined as all patients who receive at least 1 dose of study 
drug in Part B, have measurable disease as entry criteria for Part B, and have at least 
1 post-baseline disease assessment. 
Response analyses for Part B will be performed using the response-evaluable population.
7.6
Disposition of Subjects
7.6.1
Patient Disposition
Separate tabulations of patient disposition data will be generated for Part A (including the 
washout period) and Part B. 
A tabulation of patient disposition data for Part A will include the number of patients for the 
following categories: patients treated (safety population for Part A), patients in the PK-evaluable 
population, patients completing Part A, patients who discontinued study treatment during Part A
the primary reason off study treatment, patients off study during Part A and the primary reason 
off study Patients will be considered to have completed Part A if they have completed the 
protocol-specified dose requirement and PK assessments to provide data necessary for 
assessment of effects of rifampin on pevonedistat PK within Part A of the protocol. The number 
of patients who are continuing into Part B of the study may also be tabulated. Percentages will be 
based on the number of patients in the safety populations for Part A
A tabulation of patient disposition data by SoC treatment and the Part B total for Part B will also 
be generated to include the following categories: patients treated (safety population for Part B), 
patients in the response-evaluable population, patients completing Part B, patients who 
discontinue study treatment from Part B, and the primary reason off study treatment, patients off 
study during Part B and the primary reason off study. Patients will be considered to have 
completed Part B of the study if they have completed 12 cycles of treatment or discontinue 
treatment during Part B for any of the following reasons:

Adverse event.

Lost to follow-up.

Progressive disease.

Protocol violation.

Study terminated by sponsor.

Symptomatic deterioration.

Unsatisfactory therapeutic response.

Withdrawal by subject.

Other (to be specified).
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Percentages in the table of disposition data for Part B will be based on the number of patients in 
the safety populations for Part B.
Summay table for screening failure and Primary Reason Subject Failed Screening will also be 
provided.Data concerning patient disposition (eg, primary reason off study treatment, patient 
population) will be presented in by-patient listings.
7.7
Demographic and Other Baseline Characteristics
7.7.1
Demographics
Demographics will be summarized for the total safety population in Part A, and by SoC 
treatment and total for the safety population in Part B. Demographic data to be evaluated will 
include age at date of informed consent, sex, ethnicity, race, height, weight and body surface area 
(BSA).
BSA is calculated for each patient using the following formula: 
BSA = 
Both Part A and Part B use Height collected at screening. Part A uses weight collected at 
screening. If a weight at screening is not available, the Part A Day 1 pre-dose weight can be 
used. Part B uses weight collected at the visit closest, but prior to the Part B Cycle 1 Day 1 study 
drug administration.
No inferential statistics will be generated.
7.7.2
Baseline Disease Characteristics
Baseline disease characteristics (disease type, disease stage, sites of involvement, time since 
initial diagnosis (months), defined as the time of initial diagnosis to time of informed consent
will be summarized for the safety population in Part A, and by SoC treatment and total for the 
safety population in Part B. ECOG performance status will be summarized similarly in the same 
table.
Information on prior therapies will be summarized for the safety population in Part A. 
Summarized information on prior therapies will include:

Number of patients with prior therapy.

Months from last dose of prior therapy to first dose.

Number of patients with prior radiation.

Months from last prior radiation to first dose.

Number of patients with prior surgery or radiation procedures.

Number of patient with prior transplant.
3600
)
(
)
(
kg
Weight
cm
Height

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Missing dates will be imputed as described in section 7.1.6.
In addition, prior chemotherapy regimens will before Part A. List and categorization of prior 
chemotherapy regimens is described in Appendix 1.
7.7.3
Inclusion/Exclusion Criteria 
All inclusion/exclusion information on enrolled patients will be included in by-patient listings. 
After completing Part A of the study, patients may choose to enter the optional part of the study,
Part B. To be eligible for Part B, patients must have completed Part A and be reassessed to
determine if they meet the continuation criteria for Part B. Only patients who meet the criteria 
may continue into Part B. Eligibility criteria for participation in (optional) Part B for patients 
who continue into Part B will be presented in a separate listing. These listings will include 
whether all criteria were satisfied. Patient pregnancy test results will be included in a separate 
by-patient listing. For patients who did not satisfy the criteria, the criteria number will be listed 
with the deviation. 
In addition, all protocol deviations will be reviewed, and major protocol deviations will be 
identified and summarized by Part A and Part B separately in a table. Any enrolled patients who 
did not meet inclusion or exclusion criteria will be summarized under the category “Not meeting 
study inclusion/exclusion criteria”.
7.7.4
Medical History
Patients with a medical (and/or surgical) history will be presented in a by-patient listing, 
including the medicalhistory and concurrent medical condition, date of onset and the outcome 
status (whether it is resolved or ongoing). 
7.7.5
Concomitant Medications
All concomitant medications will be mapped to generic terms according to the World Health 
Organization (WHO) drug dictionary. The number and percentage of patients taking concomitant 
medications will be tabulated by WHO drug generic term, presented for the safety population in 
Part A, and by SoC treatment and total for the safety population in Part B. Patients are counted 
once for each WHO drug generic term. Concomitant procedures will not be coded.
Concomitant medication for Part A is defined as any medication that occurs after administration 
of the first dose of study treatment during Part A and up through 30 days after the last dose of 
study drug during Part A for patients who do not continue into Part B or up through Part B C1D1 
(pre-dose) for patients who continue into Part B. 
Concomitant medication for Part B is defined as any medication that occurs after administration 
of the first dose of study treatment during Part B and up through 30 days after the last dose of 
study drug during Part B.
Concomitant medications with start or end dates that are completely or partially missing will be 
analyzed using the same imputation rules as adverse events.
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Concomitant medications and procedures will be presented in separate by-patient listings.
7.8
Study Drug Exposure and Compliance
7.8.1
Study Drug Exposure 
There will only be 2 doses scheduled for Part A, therefore the assessment for Extent of Exposure
will be performed for Part B only. The analysis will be done for Part B safety population only
and by SoC treatment.
Part B
The extent of exposure to pevonedistat will be based on the number of cycles received and the 
mean number of doses administered per cycle. The distribution of the number of cycles received 
will be presented by SoC treatment arm for all patients treated in Part B. Patients will be 
considered to have been treated for a cycle if they receive at least one dose during the 21 days of 
that cycle. Percentages will be calculated by SoC treatmentarm, and total for Part B.
For pevonedistat, calculation of Percent Dosing Intensity will use equations as specified below
for Daily Expected Dose (mg), Daily Prepared Dose (mg), and Daily Dose Received (mg). Daily 
Expected Dose and Daily Prepared Dose may differ if there are dose decreases.
BSA will be calculated on Cycle 1, Day 1, 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 percent Dosing Intensity for pevonedistat during 
Part B will be based on the following formulas: 
100
*
 Expected
 Dose
Total
 Received
 Dose
Total
Intensity 
sing
Percent Do
cycles
 treated
of
number 
*
cycle
per 
doses
  
3
*
 Dose
ected
 Daily Exp
 Expected
 Dose
Total
 Part B
in
tion
administra
tat 
 Pevonedis
 with
days
all
on
 Received
e
 Daily Dos
of
Sum
 Received
 Dose
Total



Total dose expected will be calculated based on the BSA measured at baseline for Part B. 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 by treatment arm, and 
total for Part B.
For each of the standard of care drugs, the extent of exposure will be summarized in a similar 
manner as pevonedistat. The number of cycles of standard of care drug administered will also be 
summarized. 
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The mean number of doses per cycle will be calculated for each patient and summarized by SoC 
treatment arm, and total for Part B.
For chemotherapy, Daily Expected Dose, Daily prepared dose, Daily dose received, Total Dose 
Received, Total Dose Expected, and Percent Dosing Intensity for each standard of care drug will 
be based on the following formulas:











Volume
Prepared
(mL)
infused
actually 
bag
IV
of
Volume
*
Dose
Prepared
Daily 
Received
Dose
Daily 
25)
rate
filtration
r 
(Glomerula
*
)
(AUC
Level
Dose
Scheduled
          
(mg)
in)
(Carboplat
Dose
Prepared
Daily 
)
(m
Area
Surface
Body 
*
)
(mg/m
Level
Dose
Scheduled
          
)
Paclitaxel
and
(Docetaxel
Dose
Prepared
Daily 
25)
(mL/min)
rate
filtration
r 
(Glomerula
*
min/mL)
 x 
(mg
Entry 
Study 
at 
AUC
Assigned
Level
Dose
          
=
in)
(Carboplat
Dose
Expected
Daily 
)
(m
Area
Surface
Body 
*
)
(mg/m
Entry 
Study 
at 
Assigned
Level
Dose
          
=
)
Paclitaxel
and
(Docetaxel
Dose
Expected
Daily 
2
2
2
2
AUC is the area under the free carboplatin plasma concentration versus time curve.
7.8.2
Treatment Compliance and Modifications
The actions on study drugs (Dose Held, Dose Reduced, Dose Interrupted, DoseDelayed, or 
Discontinued Permanently) will be summarized for the safety population by SoC treatment and 
total in Part B. For Part B, data will be summarized for all treatment cycles. A patient will count 
only once for each type of action within each cycle.
7.9
Efficacy Analyses (Part B)
Efficacy analysis is only conducted for Part B, where efficacy is not a primary endpoint. A 
summary of the best overall response as determined by the investigator using the RECIST 
version 1.1 guidelines will be presented as a measure of disease response of pevonedistat in 
combination with SoC. The number and percentage of patients in each disease response category 
(e.g., complete response [CR], partial response [PR], stable disease [SD], progressive disease 
[PD]) and in overall response rate (CR + PR, and CR+PR+SD) will be presented by SoC 
treatment arm. Percentages will also be calculated for the total in Part B. Confidence interval will 
be calculated using exact binomial distribution All evaluations of response will be conducted 
using the response-evaluable population.
For each patient, the best percent change (ie, largest reduction) from baseline in the sum of the 
longest diameter will be calculated and displayed in a waterfall plot to show the distribution of 
response in each SoC treatment. Unscheduled visits will also be included in such displays.
The duration of disease response (CR or PR) will be presented in a by-patient listing for all 
response-evaluable patients with CR or PR. Duration of response are the time from the date of 
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first documented response per the investigator response assessment to the date of first 
documentation of PD, or death if no prior PD is documented, or the date of last disease 
assessment if the patient discontinues treatment before PD. The duration of response (in months), 
will be summarized descriptively by SoC treatment arm for all response-evaluable patients.
The duration of SD or better will be presented in a by-patient listing for all response-evaluable 
patients. Duration of SD or better is the time from the date of first dose to the date of first 
documentation of PD, or the date of last disease assessment if the patient discontinues treatment 
before PD. The duration of SD or better (in months) and the number of cycles with SD or better 
will also be summarized descriptively by SoC treatment for all response-evaluable patients.
Results from all disease response assessments and whether there was symptomatic deterioration 
will be presented in by-patient listings. Other measures of response (eg, patients with SD or 
better for ≥5 Cycles) will also be presented in by-patient listings.
Any tumor assessments after the alternate therapies or after disease progression will be excluded 
in the analyses. 
7.10
Pharmacokinetic/ Pharmacodynamic Analysis
7.10.1 Pharmacokinetic Analysis (Part A)
During Part A of the study, serial blood samples (approximately 3 mL each) for PK analysis of 
pevonedistat will be collected in Part A predose and prespecified time points on Day 1 and 
Day 10 and over a 48-hour period on Days 1, 2 (24 hours after the Day 1 dose) and 3 (48 hours 
after the Day 1 dose), 10, 11 (24 hours after the Day 10 dose) and 12 (48 hours after the Day 10 
dose) as indicated below:
Study Day
Time Point (hour)
Plasma Sample Collection
Matrix
Plasma (PK)
Day 1
Predose(a)
X
Day 1
EOI (b) (5 to 1 min)
X
Day 1
0.5 hour postinfusion (c) (±5 min)
X
Day 1
1 hour postinfusion (c) (15 min)
X
Day 1
2 hours postinfusion (c) (15 min)
X
Day 1
3 hours postinfusion (c) (30 min)
X
Day 1
4 hours postinfusion (c) (45 min)
X
Day 1
8 hours postinfusion (c) (1 hour)
X
Day 1
10 hours postinfusion (c) (1 hour)
X
Day 2
24 hours postdose (d) (1 hour)
X
Day 3
48 hours postdose (d) (1 hours)
X
Day 10
Predose(e)
X
Day 10
EOI (f) (5 to 1 min)
X
Day 10
0.5 hour postinfusion (g) (±5 min)
X
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Study Day
Time Point (hour)
Plasma Sample Collection
Matrix
Plasma (PK)
Day 10
1 hour postinfusion (g) (15 min)
X
Day 10
2 hours postinfusion (g) (15 min)
X
Day 10
3 hours postinfusion (g) (30 min)
X
Day 10
4 hours postinfusion (g) (45 min)
X
Day 10
8 hours postinfusion (g) (1 hour)
X
Day 10
10 hours postinfusion (g) (1 hour)
X
Day 11
24 hours postdose (h) (1 hour)
X
Day 12
48 hours postdose (h) (1 hours)
X
EOI=end of infusion.
(a) The sample is to be collected within 1 hour before the start of pevonedistat infusion on Day 1.
(b) The window for collection of the EoI time point is between 5 minutes before completion of infusion and 1
minute after completion of infusion. If, during Part A, IV infusion of study drug is interrupted or slowed, contact the 
project clinician or designee as soon as possible for consideration of patient replacement, as appropriate. If the IV 
infusion is interrupted, 2 additional PK samples (1 sample drawn when the infusion is stopped and 1 sample drawn 
when the infusion is restarted) should be collected so that the patient may be considered evaluable. The exact date 
and time of each additional sample collection and the actual start and stop times of the infusion should be recorded 
accurately.
(c) Time points listed on Day 1 are in reference to the end of pevonedistat IV infusion on Day 1.
(d) Time points listed on Day 2 and Day 3 are in reference to the initiation of the pevonedistat IV infusion on Day 1.
(e) The sample is to be collected within 1 hour before the start of pevonedistat infusion on Day 10.
(f) The window for collection of the EoI time point is between 5 minutes before completion of infusion and 1 minute 
after completion of infusion. If, during Part A, IV infusion of study drug is interrupted or slowed, contact the project 
clinician or designee as soon as possible for consideration of patient replacement, as appropriate. If the IV infusion 
is interrupted, 2 additional PK samples (1 sample drawn when the infusion is stopped and 1 sample drawn when the 
infusion is restarted) should be collected so that the patient may be considered evaluable. The exact date and time of 
each additional sample collection and the actual start and stop times of the infusion should be recorded accurately.
(g) Time points listed on Day 10 are in reference to the end of pevonedistat IV infusion on Day 10.
(h) Time points listed on Day 11 and Day 12 are in reference to the initiation of the pevonedistat IV infusion on 
Day 10.
Individual pevonedistat plasma concentration-time data obtained on Day 1 and Day 10 will be 
analyzed by noncompartmental methods using WinNonlin version 8.1.
The PK-evaluable population will be used for the description of the concentration-time profiles, 
and for the estimation of pevonedistat PK parameters. 
Plasma concentration values below the lower limit of quantification (<BLQ) 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.
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The following plasma PK parameters will be estimated, as permitted by the data:
Parameters
Definition
Units
Cmax
Maximum observed concentration (theoretically end-of-infusion 
concentration)
ng/mL
Tmax
First time at which Cmax occurs
hr
AUClast
Area under the plasma concentration-time curve from time zero to the time 
of the last measurable concentration
hr*ng/mL
AUC0-48hr
Area under the plasma concentration-time curve from time zero to 48
hours post-dose
hr*ng/mL
AUC0-inf
Area under the plasma concentration-time curve extrapolated to infinity
hr*ng/mL
lambdaz
Terminal disposition phase rate constant
1/hr
t1/2
Terminal disposition phase half-life
hr
CLp
Systemic clearance
L/hr
Vss
Volume of distribution at steady-state
L
For pevonedistat-rifampin DDI assessment, the ratios of geometric mean Cmax, AUC0-last and 
AUC0-inf of pevonedistat in the presence of rifampin on Day 10 versus in the absence of rifampin
on Day 1 and associated 90% CIs will be calculated based on mixed-model analysis of variance.
Estimates for each PK parameter were obtained using a mixed effects model of log(PK 
parameter) with fixed terms for the rifampin effect and random terms for patient. Subject will be 
treated as a random effect in the model. Point estimates and adjusted 90% confidence intervals 
for the difference in the log ratios will be constructed. The point estimate and adjusted 90% 
confidence intervals will then be exponentially back transformed to provide point and confidence 
interval estimates for the ratios of interest appropriately (eg, Cmax of pevonedistat with rifampin
vs. Cmax of pevonedistat).
Individual pevonedistat plasma concentration-time data (including nominal, actual and elapsed 
times relative to dosing; TAD) and individual plasma PK parameters will be listed and 
summarized descriptively on Day 1 and Day 10. 
Summary statistics (N, arithmetic mean, standard deviation, geometric mean, coefficient of 
variation [CV], median, minimum, and maximum) will be calculated if there is less than 50% of 
the values missing. The arithmetic mean and geometric mean will be reported on at least 
2 non-missing values; and the median, standard deviation and CV will be reported on at least 
3 non-missing values. For Tmax, only N, median, minimum, and maximum will be calculated.
Individual (single-subject plots with Day 1/Day 10) and mean pevonedistat plasma 
concentration-time data will be plotted against time after the start of the infusion by study Day.
Linear and logarithmic scales will be used. Individual comparison of Cmax and AUCs vs Day 
plots will also be provided. 
7.10.2 Pharmacodynamic Analysis
Not Applicable
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7.11
Safety Analysis
Safety analyses will be conducted separately for Part A and Part B. 
Safety evaluations will be based on the incidence, severity, type of AEs, clinically significant 
changes or abnormalities in the patient’s physical examination, vital signs, ECG, and clinical 
laboratory results. 
These analyses for Part A will be performed using the safety population for Part A. Safety 
analyses for Part B will be performed by SoC treatment using the safety population for Part B
defined in section 7.4.1.
7.11.1 Adverse Events
AEs will be coded according to the Medical Dictionary for Regulatory Activities (MedDRA). 
A treatment-emergent AE for Part A is defined as any AE that occurs after administration of the 
first dose of study treatment during Part A and up through 30 days after the last dose of study 
drug during Part A for patients who do not continue into Part B or up through Part B C1D1 
(pre-dose) for patients who continue into Part B.
A treatment-emergent AE for Part B is defined as any AE that occurs after administration of the 
first dose of study treatment during Part B and up through 30 days after the last dose of study 
drug during Part B.
AEs will be tabulated by system organ class (SOC), high level term (HLT), and preferred term 
(PT). Summary tabulations include the following subsets:

Treatment-emergent AEs.

Drug-related treatment-emergent AEs.

Grade 3 or higher treatment-emergent AEs(presented by grade and overall).

Grade 3 or higher drug-related treatment-emergent AEs (presented by grade and overall).

Treatment-emergent AEs resulting in study drug discontinuation.

SAEs.

Treatment-emergent drug-related SAEs.

On Study Deaths.
A listing of TEAEs resulting in study drug discontinuation will be provided.
By-patient listing of treatment emergent adverse events will be provided.
Most commonly reported (at least 10% of all patients) treatment-emergent AEs will be presented 
by preferred term in part A and separately by SoC treatment in part B. 
All adverse events will include the variable AE onset window (ie, days of onset of AE from first 
and last dose).
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Adverse events with start dates that are completely or partially missing will be analyzed as 
described in 7.1.6:
7.11.2 Overall Summary
The number and percentage of patients who experience any of the following treatment emergent 
adverse events will be summarized 

Any adverse event.

Drug-related adverse event.

Grade 3 or higher adverse event.

Drug-related Grade 3 or higher adverse event.

Serious adverse event.

Drug related serious adverse event.

Adverse events resulting in study drug discontinuation.

Adverse events resulting in study drug dose delayed.

Adverse events resulting in study drug dose reduction.

Adverse events resulting in study drug dose interruption.

On-study deaths.
Percentages will be calculated for the Part A total, by SoC treatment for Part B and the Part B 
total.
7.11.3 Serious Adverse Events
The number and percentage of patients experiencing at least one treatment emergent serious AE 
(SAE) will be summarized by MedDRA SOC, HLT, and PT. Similar summary will be generated 
for treatment emergent drug-related SAEs.
By-patient listings of the SAEs will be presented (the patient listing will contain all SAEs 
regardless of treatment emergent AE status, severity and causality will be indicated) .The 
drug-related SAEs will also be presented.
7.11.4 Deaths
By-subject listings of the deaths will be presented, causality will be indicated. All deaths 
occurring on-study will be displayed. 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.
All deaths will be summarized for Part A, by SoC treatment for Part B, including deaths 
occurring on-study and death during follow-up separately.
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7.11.5 Adverse Events Resulting in Discontinuation of Study Drug
The number and percentage of patients experiencing at least one adverse event resulting in 
discontinuation of study drug will be summarized by MedDRA SOC, HLT, and PT.
By-patient listing of AEs resulting in discontinuation of study drug will be presented, severity 
and causality will be indicated. All AEs resulting in discontinuation of study drug occurring
during the study will be displayed 
7.11.6 Adverse Events Resulting in Dose Reduction
The number and percent of patients experiencing at least one adverse event resulting in dose 
reduction will be summarized by MedDRA MedDRA SOC, HLT, and PT. 
A by-patient listing of AEs resulting in dose reduction of study drug will be presented, severity 
and causality will be indicated. All AEs resulting in dose reduction of study drug occurring on-
study will be displayed.
7.11.7 Adverse Events Resulting in Dose Modification
The number and percent of patients experiencing at least one adverse event resulting in dose 
modification (including dose Reduction, Delay or Permanent Discontinuation) will be 
summarized by MedDRA SOC, HLT, and PT.
A by-patient listing of AEs resulting in dose modification of study drug will be presented, 
severity and causality will be indicated. All AEs resulting in dose reduction of study drug 
occurring on-study will be displayed.
7.11.8 Myalgia Events and Musculoskeletal Pain and Discomfort
A listing of patients who experience treatment emergent myalgia (PT) event or treatment-
emergent musculoskeletal pain and discomfort (PT)will be presented, severity and causality will 
be indicated.
7.11.8.1 Hemorrhages SMQ
By-patient line listing for patients who have Thrombocytopenia/Platelet Count Decreased and 
concurrent Hemorrhages (defined by SMQ Hemorrhages) with both events occurred within 5 
days will be provided.
7.11.8.2 Acute Renal Failure SMQ
A listing of treatment-emergent acute renal failure events will be generated, severity and 
causality will be indicated.
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7.11.8.3 Liver Function Test (LFT) Elevations
A listing of treatment-emergent LFT elevations will be generated, severity and causality will be 
indicated. The corresponding preferred and high level terms are listed as below:

Acute hepatic failure (PT).

Blood alkaline phosphatase (PT).

Blood alkaline phosphatase abnormal (PT).

Blood alkaline phosphatase increased (PT).

Hyperbilirubinemia (PT).

Hepatic function abnormal (PT).

Liver function analyses (HLT).
7.11.8.4 Tachycardia Events
A listing of treatment-emergent tachycardia events will be generated, severity and causality will 
be indicated. The corresponding preferred terms are listed as below:

Heart rate increased.

Rebound tachycardia.

Sinus tachycardia.

Supraventricular tachyarrhythmia.

Tachyarrhythmia.

Tachycardia.

Tachycardia paroxysmal.

Palpitations.
7.11.8.5 Hypotension
A listing of treatment-emergent hypotension will be generated, severity and causality will be 
indicated. The corresponding preferred terms 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.

Hypotension.

Orthostatic hypotension.
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7.11.8.6 Anemia
A listing of treatment-emergent anemia will also be generated, severity and causality will be 
indicated. The corresponding preferred terms are listed as below:

Anemia of chronic disease.

Anemia of malignant disease.

Anemia.

Red blood cell count decreased.

Hemoglobin decreased.

Mean cell hemoglobin decreased.

Hematocrit decreased.
7.11.8.7 Neutropenia
A listing of treatment-emergent neutropenia will also be generated, severity and causality will be 
indicated. The corresponding preferred terms are listed as below:

Agranulocytosis.

Granulocyte count decreased.

Band neutrophil count decreased.

Band neutrophil percentage decreased.

Febrile neutropenia.

Idiopathic neutropenia.

Leukopenia.

Neutropenia.

Neutropenic infection.

Neutropenic sepsis.

Neutrophil count abnormal.

Neutrophil count decreased.

Neutrophil percentage abnormal.

Neutrophil percentage decreased.
By- patient line listing for patients who have Febrile neutropenia and concurrent Infections 
(defined by SOC Infections and Infestations. or HLGT Respiratory Tract Infections, or HLT 
Lower Respiratory Tract Inflammatory and Immunologic Conditions) with both events occurred 
within 5 days will be generated.
By- patient line listing for Patients who have Grade 3 or Higher TEAE of Neutropenia (defined 
by PT Neutropenia, PT Neutrophil Count Decreased, PT White Cell Count Decreased) and 
Infections (defined by SOC Infections and Infestations. or HLGT Respiratory Tract Infections, or 
HLT Lower Respiratory Tract Inflammatory and Immunologic Conditions) with both events 
occurred within 5 days will be generated. 
7.11.8.8 Dose Modifications due to LFT Abnormalities
A listing of patient that required dose modification of due to LFT abnormalities during study to 
display trend over time (Week 1-4, Week 5-8, Week 9-12, and Week 13+) 
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7.11.8.9 Dose Modifications due to Renal Abnormalities
A listing of patients that required dose modification due to renal abnormalities during study to 
display trend over time (Week 1-4, Week 5-8, Week 9-12, and Week 13+) 
7.11.8.10
Dose Modifications due to Myelosuppression
A listing of patient that required dose modification due to myelosuppression during study to 
display trend over time (Week 1-4, Week 5-8, Week 9-12, and Week 13+). +). Corresponding 
PT terms include: 

PTs from section 7.11.7.6 Anaemia.

PTs from section 7.11.7.7. neutropenia.

Thrombocytopenia.

Platelet count decreased.
7.11.9 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 (eg, 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.
If a subject has repeated laboratory values for a given time point, the value from the last 
evaluation will be used.
Shift tables of the change in NCI CTCAE (v4.03: June 14, 2010) from baseline to the post 
baseline worst CTCAE grade will be generated. If necessary, graphical displays will be used to 
show changes in laboratory measures over time for each individual patient; (1) line graphs of 
individual tests over time for each patient; and (2) scatter plots of baseline versus worst 
post-baseline values.
In addition, the lines of mean and median estimates over time may be graphed for a selected list 
of test parameters. The box plots of creatinine and platelet may be graphed too. By patient 
listings of desired lab parameters may be generated, if deemed necessary. For complete list of lab 
analytes, see appendix 2. 
Graphical displays will be used to show changes in laboratory measures over time for patients
separately for Part A and Part B: 

Box graphs of individual tests over time by SoC treatment.

Scatter plots of baseline versus worst post-baseline values for all patients. Separate plotting 
characters will be used for SoC treatment. These will be generated for only selected labs in
Table 7.a.
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Table 7.a
Selected Labs
Panel
Test
CTCAE Shift 
Table
Box Graphs
Scatter 
Plots
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
X
Calcium
X
X
Chloride
X
X
Creatinine
X
X
Creatinine Clearance
X
X
X
Glucose
X
X
Lactate dehydrogenase 
(LDH)
X
X
Magnesium
X
X
Phosphate
X
X
X
Potassium
X
X
X
Sodium
X
X
Urate
X
X
Hematology
Platelets
X
X
X
Hemoglobin
X
X
Hematocrit
X
White Blood Cells
X
X
Lymphocyte Count
X
X
Leukocytes
X
X
Neutrophils (ANC)
X
X
X
Monocytes
X
Basophils
X
Additional
Reticulocyte
X
X
Ferritin
X
X
Creatinine clearance will be derived using one of the Cockcroft-Gault and CKD-epi formulas as 
follows:
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Pevonedistat-1015
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Statistical Analysis Plan Draft
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Cockcroft-Gault equation:
For males:
)
mol/L]
[
creatinine
serum
(
81
.0
[kg]
 weight 
)
age[years]
-
(140
(mL/min)
Clearance
Creatinine




OR 
)
[mg/dL]
creatinine
serum
(
72
[kg]
 weight 
)
age[years]
-
(140
(mL/min)
Clearance
Creatinine



For females:
)
mol/L]
[
creatinine
serum
(
81
.0
[kg]
 weight 
)
age[years]
-
(140
0.85
(mL/min)
Clearance
Creatinine





OR
)
[mg/dL]
creatinine
serum
(
72
[kg]
 weight 
)
age[years]
-
(140
0.85
(mL/min)
Clearance
Creatinine




A cap value of 125 will be set to creatinine clearance (calculated from Cockcroft-Gault equation) 
higher than 125.
CKD-EPI equation (http://nephron.com/epi_equation): 
For males:
  
0.993
 x 
1)
  
9,
max(Scr/0.
 x 
1)
  
9,
min(Scr/0.
 x 
141
)
m
73
(mL/min/1.
GFR
Age
-1.209
-0.411
2 
where Scr = serum creatinine (mg/dL).
For black males:
1.159
 x 
0.993
 x 
1)
  
9,
max(Scr/0.
 x 
1)
  
9,
min(Scr/0.
 x 
141
)
m
/1.73
GFR(mL/min
Age
-1.209
-0.411
2 
where Scr = serum creatinine (mg/dL).
For females:
1.018
 x 
0.993
 x 
1)
  
7,
max(Scr/0.
 x 
1)
  
7,
min(Scr/0.
 x 
141
)
m
73
(mL/min/1.
GFR
Age
-1.209
-0.329
2 
where Scr = serum creatinine (mg/dL).
For black females:
1.159
x 
1.018
 x 
0.993
 x 
1)
  
7,
max(Scr/0.
 x 
1)
  
7,
min(Scr/0.
 x 
141
)
m
73
(mL/min/1.
GFR
Age
-1.209
-0.329
2 
where Scr = serum creatinine (mg/dL).
All chemistry and hematology lab data will also be presented in by-patient listings separately for 
Part A and Part B.
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Statistical Analysis Plan Draft
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7.11.10
Vital Signs
Tables will be used to show changes in vital sign parameters, including oral temperature, heart 
rate, and systolic and diastolic blood pressure, over time.
Change from baseline and by-patient listing will also be presented.
7.11.11
12-Lead ECGs
A 12-lead electrocardiogram (ECG) will be summarized over each time point, separately for Part 
A, and for Part B by SoC treatment arm. 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 Part A, and Part B. Shift 
tables of the change from baseline to the post baseline worst will be generated.
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
Increase from baseline >25% and to a value >200
QRS
Increase from baseline >25% and to a value >110
7.11.12
Eastern Cooperative Oncology Group (ECOG) Performance Status
ECOG shifts from baseline to post-baseline assessment over time will be tabulated for both parts. 
7.12
Interim Analysis
No interim analysis is planned
7.13
Changes in the Statistical Analysis Plan 
Reference materials for this statistical plan include Clinical Study Protocol Pevonedistat-1015
Amend 02 (dated 04 Septermber 2018), and the accompanying data collection documents 
(Annotated Case Report Form [CRF], version 1.0 and 2.0 dated 09 March 2017).
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Pevonedistat-1015
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Statistical Analysis Plan Draft
11 June 2019
8.0
REFERENCES
U.S. Department of Health and Human Services, National Institutes of Health National 
1.
Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE). Version 4.03. 
14 June 2010.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New 
2.
response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J 
Cancer 2009;45(2):228-47. 
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Pevonedistat-1015
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Statistical Analysis Plan Draft
11 June 2019
9.0
DATA LISTINGS
The below subject-level listings will be generated:
Screen Failures.
1.
Subject Disposition (Part A, Part B).
2.
Inclusion/Exclusion Criteria (Part A).
3.
Continuation Criteria (Part B).
4.
Significant protocol deviation (Part A, Part B)).
5.
Analysis Set (Part A, Part B).
6.
Demographics and Baseline Characteristics (Part A, Part B).
7.
Baseline Disease Characteristics (Part A).
8.
Prior Therapy (Part A).
9.
Prior Radiation (Part A).
10.
Prior Transplant (Part A).
11.
Prior Surgery (Part A).
12.
Medical History and Concurrent Medical Condition (Part A).
13.
Concomitant Medications (Part A, Part B).
14.
Concomitant Procedures (Part A, Part B).
15.
Study Drug Administration (Part A, Part B).
16.
Extent of Exposure (Part B).
17.
Plasma Concentration of Pevonedistat (Part A).
18.
PK parameters of Pevonedistat (Part A).
19.
Duration of Disease Response (Part B).
20.
Duration of SD or Better (Part B).
21.
Duration of SD or Better among Subjects with 5 or More Cycles of SD or Better (Part B).
22.
Treatment-Emergent Adverse Events (Part A, Part B).
23.
Serious Adverse Events (Part A, Part B).
24.
Overview Listing of Subject Deaths.
25.
Treatment-Emergent Adverse Events Resulting in Death (Part A. Part B).
26.
Subject Survival Status (Part A. Part B).
27.
Adverse Events Resulting in Discontinuation of Study Drug (Part A, Part B).
28.
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Statistical Analysis Plan Draft
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Adverse Events Resulting in Dose Reduction (Part A, Part B).
29.
Adverse Events Resulting in Dose Modification (Part A, Part B).
30.
Myalgia Events and Musculoskeletal Pain and Discomfort (Part A, Part B).
31.
Acute Renal Failure Events (Part A, Part B).
32.
Liver Function Test Elevations (Part A, Part B).
33.
Tachycardia Events (Part A, Part B).
34.
Hypotension Events (Part A, Part B).
35.
Anaemia Events (Part A, Part B).
36.
Neutropenia Events (Part A, Part B).
37.
Febrile Neutropenia and Concurrent Infections with both events occurred within 5 days (Part 
38.
A, Part B).
Grade 3 or Higher TEAE of Neutropenia and Infections with both events occurred within 5 
39.
days (Part A, Part B).
Thrombocytopenia/ Platelet Count Decreased and concurrent Hemorrhages with both events 
40.
occurred within 5 day (Part A, Part B).
Hydration (Part B).
41.
Dose Modifications due to LFT Abnormalities (Part B).
42.
Dose Modifications due to Renal Abnormalities (Part B).
43.
Dose Modifications due to Myelosupression (Part B).
44.
Hematology Results and Change from Baseline (Part A, Part B).
45.
Chemistry Results and Change from Baseline (Part A, Part B).
46.
Vital Signs (Part A, Part B).
47.
Electrocardiogram Results (Part A, Part B).
48.
Electrocardiogram Interpretation (Part A, Part B).
49.
ECOG Results (Part A, Part B).
50.
Pregnancy Test Results.
51.
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Statistical Analysis Plan Draft
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10.0
APPENDICES
10.1
APPENDIX 1
Prior Chemotherapy Regimens Categories:
Taxane-containing regimens
BEVACIZUMAB+CARBOPLATIN+PACLITAXEL
BEVACIZUMAB+CISPLATIN+DOCETAXEL
BEVACIZUMAB+CISPLATIN+PACLITAXEL
BEVACIZUMAB+PACLITAXEL
CAPECITABINE+DOCETAXEL
CAPECITABINE+PACLITAXEL 
CARBOPLATIN+PACLITAXEL 
CARBOPLATIN+PACLITAXEL+TRASTUZUMAB 
CISPLATIN+DOCETAXEL 
CISPLATIN+DOCETAXEL+FLUOROURACIL 
CISPLATIN+PACLITAXEL 
CYCLOPHOSPHAMIDE+DOCETAXEL 
CYCLOPHOSPHAMIDE+DOCETAXEL+DOXORUBICIN 
CYCLOPHOSPHAMIDE+DOXORUBICIN+PACLITAXEL 
DOCETAXEL (TAXOTERE) 
DOCETAXEL+DOXORUBICIN 
DOCETAXEL+FLUOROURACIL 
DOXORUBICIN+PACLITAXEL 
FLUOROURACIL+PACLITAXEL 
GEMCITABINE+PACLITAXEL 
PACLITAXEL (ABRAXANE FOR INJECTABLE SUSPENSION; APO-
PACLITAXEL)
PACLITAXEL+TRASTUZUMAB
Regimens containing a taxane but 
not a platinum
BEVACIZUMAB+PACLITAXEL 
CAPECITABINE+DOCETAXEL 
CAPECITABINE+PACLITAXEL 
CYCLOPHOSPHAMIDE+DOCETAXEL
CYCLOPHOSPHAMIDE+DOCETAXEL+DOXORUBICIN
CYCLOPHOSPHAMIDE+DOXORUBICIN+PACLITAXEL
DOCETAXEL (TAXOTERE)
DOCETAXEL+DOXORUBICIN 
DOCETAXEL+FLUOROURACIL
DOXORUBICIN+PACLITAXEL 
FLUOROURACIL+PACLITAXEL
GEMCITABINE+PACLITAXEL
PACLITAXEL (ABRAXANE FOR INJECTABLE SUSPENSION; APO-
PACLITAXEL)
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Statistical Analysis Plan Draft
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PACLITAXEL+TRASTUZUMAB
Regimens containing a platinum but 
not a taxane
CAPECITABINE+CISPLATIN 
CAPECITABINE+CISPLATIN+EPIRUBICIN 
CAPECITABINE+EPIRUBICIN+OXALIPLATIN 
CAPECITABINE+OXALIPLATIN 
CARBOPLATIN (PARAPLATIN-AQ) 
CARBOPLATIN+ETOPOSIDE 
CARBOPLATIN+FLUOROURACIL 
CETUXIMAB+CISPLATIN+VINBLASTINE 
CETUXIMAB+CISPLATIN+VINORELBINE 
CISPLATIN (PLATINOL)
CISPLATIN+EPIRUBICIN+FLUOROURACIL 
CISPLATIN+ETOPOSIDE 
CISPLATIN+FLUOROURACIL 
CISPLATIN+FLUOROURACIL+LEUCOVORIN CALCIUM 
CISPLATIN+GEMCITABINE 
CISPLATIN+IRINOTECAN 
CISPLATIN+PEMETREXED 
CISPLATIN+VINBLASTINE 
FLUOROURACIL+LEUCOVORIN CALCIUM+OXALIPLATIN 
FLUOROURACIL+OXALIPLATIN
OXALIPLATIN (ELOXATIN)
Regimens containing both a 
platinum and a taxane
BEVACIZUMAB+CARBOPLATIN+PACLITAXEL 
BEVACIZUMAB+CISPLATIN+DOCETAXEL 
BEVACIZUMAB+CISPLATIN+PACLITAXEL 
CARBOPLATIN+PACLITAXEL 
CARBOPLATIN+PACLITAXEL+TRASTUZUMAB 
CISPLATIN+DOCETAXEL 
CISPLATIN+DOCETAXEL+FLUOROURACIL 
CISPLATIN+PACLITAXEL
10.2
APPENDIX 2
Panel
Test
CTCAE Shift 
Table
MTD Box 
Plots
Spaghetti 
Plots
Scatter
Plots
Chemistry
Albumin
X
X
Alanine aminotransferase 
(SGPT)
X
X
X
Aspartate 
aminotransferase (SGOT)
X
X
X
Alkaline Phosphatase
X
X
X
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Statistical Analysis Plan Draft
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Panel
Test
CTCAE Shift 
Table
MTD Box 
Plots
Spaghetti 
Plots
Scatter
Plots
Carbon Dioxide
X
X
Direct Bilirubin
X
X
X
Total Bilirubin
X
X
X
Blood urea nitrogen
X
X
Blood urea nitrogen 
(mg/dL)/Creatinine 
(mg/dL)
X
X
Calcium
X
X
Chloride
X
X
Creatinine
X
X
X
Creatinine clearance
X
X
Glomerular filtration rate 
(estimated)
X
X
Glucose
X
X
Gamma-glutamyl-
transpeptidase
X
X
X
Lactate dehydrogenase
X
X
Magnesium
X
X
Phosphate
X
X
X
Potassium
X
X
Sodium
X
X
Urate
X
X
Hematology
Platelets
X
X
X
Hematocrit
X
Hemoglobin
X
X
X
White Blood Cells
X
X
X
Lymphocyte Count
X
X
Neutrophils (ANC)
X
X
X
Monocytes
X
Eosinophils
X
Basophils
X
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