A Phase 1 Study to Assess Mass Balance, Pharmacokinetics, and Metabolism of [14C]-Pevonedistat in Patients With Advanced Solid Tumors
Phase: PHASE1
Conditions: Advanced Solid Tumors, Neoplasms, Advanced Solid
Sponsor: Millennium Pharmaceuticals, Inc.

This may include, but is not limited to, redaction of the following: 


•
Title: A Phase 1 Study to Assess Mass Balance, Pharmacokinetics, and Metabolism of [14C]-
Pevonedistat in Patients With Advanced Solid Tumors
NCT Number: NCT03057366
Protocol Approve Date: 29 November 2016
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 or company confidential information. 
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.

1.0 TITLE PAGE
CONFIDENTIAL
PROTOCOL
A Phase 1 Study to Assess Mass Balance, Pharmacokinetics, and Metabolism of 
[14C]-Pevonedistat in Patients With Advanced Solid Tumors
Sponsor:
Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda 
Pharmaceutical Company Limited
40 Lansdowne Street
Cambridge, MA USA 02139
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-1013
Compound:
Pevonedistat (MLN4924; TAK-924)
Date:
29 November 2016
Final
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement by 
the recipient that no information contained herein will be published or disclosed without written authorization from 
Takeda except to the extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. Furthermore, the information is only meant for review and compliance by the recipient, his or her staff, 
and applicable institutional review committee and regulatory agencies to enable conduct of the study.

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CONFIDENTIAL
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 or medication errors. 
Takada Development Center sponsored investigators per individual country requirements will be 
provided with emergency medical contact information cards to be carried by each subject.
General advice on protocol procedures should be obtained through the monitor assigned to the 
study sites. Information on service providers is given in Section 3.1 and relevant guidelines 
provided to the sites.
Contact Type/Role
European 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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CONFIDENTIAL
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 Conference on Harmonisation E6 Good Clinical Practice: 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.
Date
Date
Date
Date
Personally Protected Data
Personally Protected Data
Personally Protected Data
Personally Protected Data

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CONFIDENTIAL
INVESTIGATOR AGREEMENT 
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, package 
insert and any other product information provided by the sponsor. I agree to conduct this study in 
accordance with the requirements of this protocol and also to protect the rights, safety, privacy, 
and well-being of study subjects in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Conference on Harmonisation, E6 Good Clinical Practice: Consolidated 
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting serious adverse events defined in Section 10.0 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/Provence)
Location of Facility (Country)

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TABLE OF CONTENTS
1.0
ADMINISTRATIVE.................................................................................................. 2
1.1
Contacts................................................................................................................ 2
1.2
Approval............................................................................................................... 3
2.0
STUDY SUMMARY ............................................................................................... 11
3.0
STUDY REFERENCE INFORMATION ................................................................. 15
3.1
Study-Related Responsibilities............................................................................ 15
3.2
Principal Investigator/Signatory Coordinating Investigator ................................. 15
3.3
List of Abbreviations .......................................................................................... 16
3.4
Corporate Identification...................................................................................... 18
4.0
INTRODUCTION.................................................................................................... 19
4.1
Background ........................................................................................................ 19
4.1.1
Study Drug.................................................................................................... 19
4.1.2
Nonclinical Background Information ............................................................ 19
4.1.3
Clinical Background Information .................................................................. 20
4.1.4
Potential Risks and Benefits.......................................................................... 21
4.2
Rationale for the Proposed Study........................................................................ 27
4.2.1
Rationale for Dose and Duration of PK/Excretion 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
Exploratory Objective ................................................................................... 30
5.2
Endpoints............................................................................................................ 31
5.2.1
Primary Endpoints ........................................................................................ 31
5.2.2
Secondary Endpoints..................................................................................... 31
5.2.3
Exploratory Endpoint.................................................................................... 31
6.0
STUDY DESIGN..................................................................................................... 32
6.1
Overview of Study Design.................................................................................. 32
6.1.1
Part A: Mass Balance/ADME Assessment .................................................... 32
6.1.2
Part B: Continued Treatment With Pevonedistat in Combination With 
Chemotherapy (OPTIONAL)........................................................................ 33
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..................................................................................... 36
7.0
STUDY POPULATION........................................................................................... 38
7.1
Inclusion Criteria ................................................................................................ 38
7.2
Exclusion Criteria ............................................................................................... 39
8.0
STUDY DRUG ........................................................................................................ 42
8.1
Study Drug Administration................................................................................. 42
8.1.1
Part A ........................................................................................................... 42
8.1.2
Part B............................................................................................................ 42
8.2
Reference/Control Therapy................................................................................. 44
8.3
Dose Modification Guidelines (Part B) ............................................................... 44
8.3.1
Criteria for Beginning or Delaying a Subsequent Treatment Cycle................ 44
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.................................................... 48
8.4
Excluded Concomitant Medications and Procedures ........................................... 48
8.4.1
Excluded Concomitant Medications and Procedures (Part A)........................ 48
8.4.2
Excluded Concomitant Medications and Procedures (Part B) ........................ 48
8.5
Permitted Concomitant Medications and Procedures........................................... 49
8.5.1
Permitted Concomitant Medications and Procedures (Part A)........................ 49
8.5.2
Permitted Concomitant Medications and Procedures (Part B)........................ 49
8.6
Precautions and Restrictions ............................................................................... 50
8.6.1
Pevonedistat.................................................................................................. 50
8.6.2
Docetaxel...................................................................................................... 51
8.6.3
Carboplatin ................................................................................................... 52
8.6.4
Paclitaxel ...................................................................................................... 53
8.7
Management of Clinical Events .......................................................................... 53
8.7.1
Guidance for Clinical Assessment and Management of Hemodynamic 
Compromise (Part A and Part B)................................................................... 54
8.7.2
Guidance for Use of Granulocyte-Colony Stimulating Factor........................ 54
8.7.3
Guidance for Clinical Assessment and Management of Anemia .................... 54
8.8
Blinding and Unblinding..................................................................................... 55

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8.9
Description of Investigational Agents ................................................................. 55
8.9.1
Pevonedistat.................................................................................................. 55
8.9.2
Docetaxel...................................................................................................... 55
8.9.3
Carboplatin ................................................................................................... 55
8.9.4
Paclitaxel ...................................................................................................... 55
8.10
Preparation, Reconstitution, and Dispensation..................................................... 55
8.10.1 Pevonedistat.................................................................................................. 56
8.10.2 Docetaxel, Carboplatin, and Paclitaxel.......................................................... 56
8.11
Packaging and Labeling...................................................................................... 56
8.11.1 Pevonedistat.................................................................................................. 56
8.11.2 Docetaxel, Carboplatin, and Paclitaxel.......................................................... 56
8.12
Storage, Handling, and Accountability................................................................ 56
8.12.1 Pevonedistat.................................................................................................. 56
8.12.2 Docetaxel, Carboplatin, and Paclitaxel.......................................................... 56
8.13
Other Protocol-Specified Materials ..................................................................... 56
9.0
STUDY CONDUCT................................................................................................. 57
9.1
Study Personnel and Organizations..................................................................... 57
9.2
Arrangements for Recruitment of Patients........................................................... 57
9.3
Treatment Group Assignments............................................................................ 57
9.4
Confinement and Overnight Visits...................................................................... 57
9.5
Study Procedures................................................................................................ 57
9.5.1
Informed Consent.......................................................................................... 57
9.5.2
Patient Demographics ................................................................................... 57
9.5.3
Medical History ............................................................................................ 58
9.5.4
Physical Examination.................................................................................... 58
9.5.5
Patient Height ............................................................................................... 58
9.5.6
Vital Signs .................................................................................................... 58
9.5.7
Pregnancy Test.............................................................................................. 58
9.5.8
Concomitant Medications and Procedures..................................................... 59
9.5.9
AEs............................................................................................................... 59
9.5.10 Enrollment .................................................................................................... 59
9.5.11 Echocardiogram............................................................................................ 59
9.5.12 ECG.............................................................................................................. 59
9.5.13 Clinical Laboratory Evaluations .................................................................... 59
9.5.14 Disease Assessment ...................................................................................... 61

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9.5.15 PK Measurements......................................................................................... 61
9.5.16 DNA Measurements...................................................................................... 62
9.5.17 Discharge Criteria for Part A......................................................................... 62
9.5.18 Entry Criteria for Continuation Into Part B.................................................... 62
9.6
Completion of Study Treatment (for Individual Patients) .................................... 63
9.6.1
Part A ........................................................................................................... 63
9.6.2
Part B............................................................................................................ 63
9.7
Completion of Study (for Individual Patients)..................................................... 63
9.7.1
Part A ........................................................................................................... 63
9.7.2
Part B............................................................................................................ 63
9.8
Discontinuation of Treatment With Study Drug and Patient Replacement........... 64
9.9
Withdrawal of Patients From Study .................................................................... 64
9.10
Study Compliance............................................................................................... 65
10.0
ADVERSE EVENTS ............................................................................................... 66
10.1
Definitions.......................................................................................................... 66
10.1.1 Pretreatment Event Definition....................................................................... 66
10.1.2 AE Definition ............................................................................................... 66
10.1.3 SAE Definition ............................................................................................. 66
10.2
Procedures for Recording and Reporting AEs and SAEs..................................... 67
10.3
Monitoring of AEs and Period of Observation .................................................... 68
10.4
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events.... 68
10.5
Procedures for Reporting Product Complaints or Medication Errors (Including 
Overdose) ........................................................................................................... 69
10.6
Safety Reporting to Investigators, IRBs, or IECs and Regulatory Authorities...... 69
11.0
STUDY-SPECIFIC COMMITTEES ........................................................................ 70
11.1
Sponsor Safety Assessments ............................................................................... 70
11.2
Independent Data Monitoring Committee ........................................................... 70
12.0
DATA HANDLING AND RECORDKEEPING....................................................... 71
12.1
eCRFs................................................................................................................. 71
12.2
Record Retention ................................................................................................ 71
13.0
STATISTICAL METHODS..................................................................................... 73
13.1
Statistical and Analytical Plans ........................................................................... 73
13.1.1 Analysis Sets................................................................................................. 73
13.1.2 Analysis of Demographics and Other Baseline Characteristics ...................... 73
13.1.3 Efficacy Analysis.......................................................................................... 73

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13.1.4 PK Analysis .................................................................................................. 73
13.1.5 Safety Analysis ............................................................................................. 74
13.2
Interim Analysis and Criteria for Early Termination ........................................... 75
13.3
Determination of Sample Size............................................................................. 75
14.0
QUALITY CONTROL AND QUALITY ASSURANCE.......................................... 76
14.1
Study-Site Monitoring Visits .............................................................................. 76
14.2
Protocol Deviations............................................................................................. 76
14.3
Quality Assurance Audits and Regulatory Agency Inspections ........................... 76
15.0
ETHICAL ASPECTS OF THE STUDY................................................................... 77
15.1
IRB and/or IEC Approval ................................................................................... 77
15.2
Subject Information, Informed Consent, and Subject Authorization .................... 78
15.3
Subject Confidentiality ....................................................................................... 79
15.4
Publication, Disclosure, and Clinical Trial Registration Policy............................ 79
15.4.1 Publication.................................................................................................... 79
15.4.2 Clinical Trial Registration............................................................................. 79
15.4.3 Clinical Trial Results Disclosure ................................................................... 80
15.5
Insurance and Compensation for Injury............................................................... 80
16.0
REFERENCES......................................................................................................... 81
LIST OF IN-TEXT TABLES
Table 6.a
Primary and Secondary Endpoints for Disclosures ........................................ 36
Table 8.a
Dose Modification Guidelines for Specific Toxicities ................................... 46
Table 8.b
Excluded Concomitant Medications and Procedures During Part A............... 48
Table 8.c
Excluded Concomitant Medications and Procedures During Part B............... 49
Table 8.d
Permitted Concomitant Medications and Procedures During Part A .............. 49
Table 8.e
Permitted Concomitant Medications and Procedures During Part B............... 50
Table 9.a
Clinical Chemistry and Hematology Tests..................................................... 60
Table 9.b
Clinical Urinalysis Tests ............................................................................... 60
LIST OF IN-TEXT FIGURES
Figure 6.a
Study Overview ............................................................................................ 34

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LIST OF APPENDICES
Appendix A
Schedule of Events........................................................................................ 83
Appendix B
Responsibilities of the Investigator................................................................ 91
Appendix C
Investigator Consent to Use of Personal Information..................................... 93
Appendix D
ECOG Scale for Performance Status ............................................................. 94
Appendix E
Response Criteria.......................................................................................... 95
Appendix F
Excluded CYP3A Inhibitors and Inducers..................................................... 96
Appendix G
Hematologic Toxicity of Carboplatin Alone and in Combination With 
Paclitaxel ...................................................................................................... 98
Appendix H
Drugs Associated With Nephrotoxicity ....................................................... 100
Appendix I
New York Heart Association Classification of Cardiac Disease................... 101
Appendix J
Definition of Postmenopausal ..................................................................... 102
Appendix K
Acceptable Methods of Contraception Considered Highly Effective............ 103

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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 (MLN4924; TAK-924)
Title of Protocol: A Phase 1 Study to Assess Mass Balance, Pharmacokinetics, and Metabolism of [14C]-Pevonedistat 
in Patients With Advanced Solid Tumors
Study Number: Pevonedistat-1013
Phase: 1
Study Design:
This is a 2-part, open-label, multicenter, mass balance and absorption, distribution, metabolism, excretion (ADME) 
study in 4 to 6 pharmacokinetics (PK)-evaluable patients with advanced solid tumors.
Part A: Mass Balance/ADME Assessment
Part A represents the period for assessment of the mass balance, PK, metabolism, and elimination of pevonedistat in 
this population. Patients will be required to stay at the Part A study site for approximately 8 days or until the discharge 
criteria are met, with a maximum estimated confinement period of 9 to 14 days.
Patients who meet all inclusion criteria and no exclusion criteria will be assigned a patient number and will be 
admitted to the Part A study site on the morning of Day -1 for predose assessments and to begin confinement. On the 
morning of Day 1, patients will receive a single dose of 25 mg/m2 (equivalent to approximately 43 mg for a typical 
individual of 1.73 m2 body surface area [BSA], up to a absolute maximum dose of 50 mg) [14C]-pevonedistat 
intravenous (IV) solution (containing approximately 60-85 μCi [approximately 2.22-3.145 MBq] of total radioactivity 
[TRA]) via a 1-hour infusion. The actual amount of administered radioactivity and pevonedistat dose will be 
documented for each patient. 
Patients will be closely monitored for adverse events (AEs) throughout the study. Safety will be assessed by 
monitoring vital signs, physical examinations (including weight at Day 1 predose and End of Study [EOS]), 
electrocardiograms, and clinical laboratory tests. 
Blood will be collected at prespecified time points for analyses of pevonedistat and TRA PK and for metabolite 
profiles over the confinement period. Complete urinary and fecal output will be collected throughout the confinement 
period until discharge; urine samples will be analyzed for PK, TRA, and biotransformation and fecal samples will be
analyzed for TRA and products of pevonedistat biotransformation. For patients who experience emesis during the first 
24 hours after drug administration, the vomitus will be collected as much as possible and assayed for TRA. If a subject 
vomits more than once during the period, vomitus corresponding to each vomiting event will be collected in a separate 
labeled container and separately counted. Refer to the Study Manual for further details. To ensure defecation before
release from the Part A study site, two 15 mL doses of oral lactulose will be administered, separated by approximately 
2 hours, on the evening of Day 4; the second dose of lactulose will be withheld if the first dose was not tolerated. 
Patients will be required to stay at the Part A study site for approximately 8 days or until the discharge criteria are met, 
with a maximum estimated confinement period of 9 to 14 days.
 
Part B: Continued Treatment With Pevonedistat in Combination With Chemotherapy (OPTIONAL)
After completion of the mass balance/ADME assessment portion of the study, patients will have the opportunity to 
continue into Part B at a secondary study site, which can begin within approximately 2 weeks of the patient completing 
Part A (ie, when the patient has met the criteria to be discharged from the clinic). Participation in Part B is optional. 
Any patient who continues on to Part B will need to be re-evaluated for entry criteria before treatment in Part B can 
begin. Patients will receive pevonedistat in combination with either docetaxel or carboplatin+paclitaxel as
recommended by the investigator. Safety and disease assessments will be conducted in Part B of the study. Disease 
assessments will be conducted using radiological evaluations (computed tomography scan or magnetic resonance 
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CONFIDENTIAL
imaging as clinically indicated) to assess the status of the patient’s underlying disease and will be part of the entry 
criteria for Part B.
Toxicity will be evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events, 
version 4.03, effective date 14 June 2010. 
Primary Objectives:
The primary objectives are as follows:
!
To assess the mass balance (ie, cumulative excretion of TRA in urine and feces) of pevonedistat following a 
single 1-hour infusion of 25 mg/m2 [14C]-pevonedistat IV solution containing approximately 60 to 85 μCi 
(approximately 2.22-3.145 MBq) of TRA in patients with advanced solid tumors in Part A. 
!
To characterize the PK of pevonedistat in whole blood, plasma, and urine, and of TRA in plasma and whole blood 
following a single 1-hour infusion of 25 mg/m2 [14C]-pevonedistat IV solution containing approximately 60 to 85 
μCi (approximately 2.22-3.145 MBq) of TRA in patients with advanced solid tumors in Part A.
Secondary Objectives:
The secondary objectives are as follows:
!
To collect samples for characterization of the metabolic profile of pevonedistat in plasma, urine, and feces 
following a single 1-hour infusion of 25 mg/m2 [14C]-pevonedistat IV solution containing approximately 60 to 
85 μCi (approximately 2.22-3.145 MBq) of TRA (maximum dose of 50 mg) in patients with advanced solid 
tumors in Part A. 
!
To evaluate the safety and tolerability of pevonedistat in patients with advanced solid tumors after a single dose in 
Part A and in combination with either docetaxel or carboplatin+paclitaxel in Part B.
!
To evaluate disease response that may be observed with the combination of pevonedistat and docetaxel or 
pevonedistat and carboplatin+paclitaxel in patients with advanced solid tumors (Part B).
Exploratory Objectives:
Subject Population: Patients aged 18 years and older with advanced solid tumors.
Number of Subjects:
4 to 6 PK-evaluable patients
Number of Sites: 
Part A: Part A study site
Part B: secondary study site
Dose Level(s):
Part A: A single dose of 25 mg/m2 (equivalent to 
approximately 43 mg for a typical individual of 1.73 m2
BSA, up to a maximum absolute dose of 50 mg) 
[14C]-pevonedistat IV solution (containing approximately 
60-85 ∀Ci [approximately 2.22-3.145 MBq] of TRA) via 
1-hour infusion.
Part B (optional): Pevonedistat will be administered on 
Days 1, 3, and 5 of each cycle at the dose of 25 mg/m2 in 
combination with docetaxel (75 mg/m2) or at the dose of 20 
mg/m2 in combination with carboplatin AUC5+ paclitaxel 
(175 mg/m2) on Day 1. On Days 3 and 5 of each cycle, only 
pevonedistat will be given. The duration of each cycle will 
be 21 days.
Route of Administration:
Part A: 
Pevonedistat IV infusion
Part B (optional): 
Pevonedistat: IV infusion 
Docetaxel, carboplatin, and paclitaxel: IV infusion 
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Duration of Treatment:
Part A: single IV dose 
Part B (optional): Eligible patients may continue to receive 
treatment in Part B of this study until they experience 
symptomatic deterioration or progressive disease; treatment 
is discontinued for another reason; or until the study is 
stopped.
Period of Evaluation:
Screening: within 28 days before the first dose of study 
drug in Part A.
Part A: Patients will be required to stay at the Part A 
study site for approximately 8 days or until the 
discharge criteria are met, with a maximum estimated 
confinement period of 9 to 14 days.
Part B (optional): 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.
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.
Main Criteria for Inclusion:
Male or female patients, aged 18 years or older, who have a histologically or cytologically confirmed metastatic or 
locally advanced and incurable solid tumor that is felt to be appropriate for treatment with one of the 2 chemotherapy 
regimens in Part B of this study (carboplatin+paclitaxel or docetaxel), 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.
Main Criteria for Exclusion:
Subjects who (1) have an inability to comply with study visits and procedures including required inpatient 
confinement; (2) have been treated with any systemic antineoplastic therapy or any investigational products within 21 
days before the first dose of study treatment; (3) had radiotherapy within 14 days preceding the first dose of study 
treatment; (4) have known hypersensitivity, or history of severe intolerance or toxicity to chemotherapeutic agents 
used in Part B; (5) have a 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; (6) have irregular defecation patterns and/or history of urinary 
and/or fecal incontinence; (7) persistent diarrhea (≥Grade 2) lasting >3 days within 2 weeks before the first dose of 
study treatment.
Main Criteria for Evaluation and Analyses:
The primary endpoints for this study are as follows:

Summary statistics of PK parameters of pevonedistat and TRA in plasma and whole blood: maximum observed 
concentration (Cmax), time of first occurrence of Cmax (tmax), and area under the concentration-time curve (AUC) 
from time zero to time of the last quantifiable concentration (AUClast).

Cumulative percentage of urinary recovery, percentage of fecal excretion, and percentage of TRA in urine and 
feces over the entire period of collection.

Summary statistics of PK parameters of pevonedistat in urine: cumulative amount excreted in urine (Aeurine and 
percentage of dose) and renal clearance (CLR).
The secondary endpoints for this study are as follows:

Safety parameters: AEs, serious adverse events, and abnormal laboratory values reported.

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!
Metabolite profiles in plasma, urine, and feces.
!
Measures of disease response based on investigator’s assessment using the Response in Evaluation Criteria in 
Solid Tumors guideline (Version 1.1).
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, 
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.
The following PK parameters will be calculated by noncompartmental analysis and tabulated for each individual:
!
TRA in plasma and whole blood: Cmax, tmax, AUClast, and as permitted by data, terminal disposition phase half-life 
(t1/2z) and AUC from time zero to infinity, calculated using the observed value of the last quantifiable 
concentration (AUC∞).
!
TRA in urine: amount of [14C]-radioactivity excreted into urine per sampling interval (Aeurine,14
C,t1-t2 in ng-eq and 
percentage of dose) and cumulative amount of [14C]-radioactivity excreted in urine up to the last sampling interval 
(Aeurine,14
C in ng-eq and percentage of dose).
!
TRA in feces: amount of [14C]-radioactivity excreted into feces per sampling interval (daily excretion) 
(Aefeces,14
C,t1-t2 in ng-eq and percentage of dose) and cumulative amount of [14C]-radioactivity excreted in feces up
to the last sampling interval (Aefeces,14
C in ng-eq and percentage of dose).
!
The total cumulative excretion of [14C]-radioactivity per interval and over the total collection period will be 
calculated as the sum of the cumulative excretion in urine and feces: total cumulative excretion of 
[14C]-radioactivity from the body (Aetotal,
14
C=Aeurine,
14
C+Aefeces,
14
C) (in ng-eq and percentage of dose).
!
Pevonedistat in whole blood and plasma: Cmax, tmax, AUClast, and as permitted by data, t1/2z, AUC∞, and clearance.
!
Pevonedistat in urine (per sampling interval and total): cumulative amount excreted in urine (Aeurine,t and 
percentage of dose) and CLR.
Additionally, one of the objectives of this study is to collect plasma, urine, and feces for metabolite profiling and 
identification. While the results of PK of pevonedistat and TRA, time course of excretion of TRA in urine and feces, 
and overall mass balance will be included in the clinical study report, the metabolite profiling and identification results 
will be reported separately.
Sample Size Justification: The sample size for this study is not based on statistical considerations. On the basis of the 
ALARA principle (As Low [radioactive burden] As Reasonably Achievable) set forth in the 96/29/EURATOM 
directive, a sample size of 4 to 6 PK-evaluable patients is considered sufficient to provide adequate characterization of 
the mass balance, PK, and metabolism of pevonedistat in patients with cancer. Patients will be replaced if they are not 
evaluable for PK.
Company Confidential Information

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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/Signatory Coordinating Investigator
Takeda will select only 1 principal investigator/signatory coordinating investigator for this study. 
Selection criteria will include having significant knowledge of the study protocol and the study 
medication, expertise in the therapeutic area, and expertise in the conduct of clinical research and
study participation. The principal investigator/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
ADME
absorption, distribution, metabolism, excretion 
AE
adverse event
Aefeces,
14
C
cumulative amount of [14C]-radioactivity excreted in the feces up to the last sampling interval
Aefeces,
14
C,t1-t2
amount of [14C]-radioactivity excreted in feces in a sampling interval
Aetotal,
14
C
total cumulative excretion of [14C]-radioactivity from the body (Aetotal,14
C=Aeurine,14
C+Aefeces,14
C)
Aeurine
cumulative amount of drug excreted in urine
Aeurine,
14
C
cumulative amount of [14C]-radioactivity excreted in the feces/urine up to the last sampling interval
Aeurine,
14
C, t1-t2
amount of [14C]-radioactivity excreted in feces in a sampling interval
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, calculated using the observed value of the last quantifiable 
concentration
AUClast
AUC from time zero to time of the last quantifiable concentration
AUCt
AUC from time zero to time t
AUC
AUC during a dosing interval
BID
twice daily
BSA
body surface area
CDL
cullin-dependent ubiquitin E3 ligases
CFR
Code of Federal Regulations
CLR
renal clearance
Cmax
maximum observed concentration
CR
complete response
CRO
contract research organization
CT
computed tomography
CV 
coefficient of variation
CYP
cytochrome P450 
DCSI
development core safety information
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

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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
IV
Intravenous(ly)
MDS
myelodysplastic syndrome
Millennium
Millennium Pharmaceuticals, Inc
MLN4924
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
pevonedistat 
hydrochloride 
salt form of MLN4924; TAK-924
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
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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3.4
Corporate Identification 
Millennium
Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda Pharmaceutical 
Company Limited
TDC Japan
Takeda Development Center Japan
TDC Asia
Takeda Development Center Asia, Pte Ltd
TDC Europe
Takeda Development Centre Europe Ltd
TDC Americas
Takeda Development Center Americas, Inc
TDC
TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as applicable
Takeda
Millennium Pharmaceuticals, Inc, TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, 
as applicable

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4.0
INTRODUCTION
4.1
Background
4.1.1
Study Drug
Pevonedistat (MLN4924; TAK-924) is a first-in-class, small molecule inhibitor of the 
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 by inhibiting the degradation of a subset of proteins that are regulated 
by the proteasome.
4.1.2
Nonclinical Background Information
Pevonedistat is a potent and selective, mechanism-based inhibitor of NAE activity. Pevonedistat 
also inhibits human carbonic anhydrase II, which may explain the extensive partitioning of 
pevonedistat in red blood cells that has been observed in animal species and humans (see the 
current Investigator’s Brochure [IB]).
Pevonedistat treatment of cultured tumor cells resulted in growth inhibition of a wide variety of 
cell lines and induced phenotypes consistent with NAE inhibition, including a decrease in 
NEDD8-cullin levels and a reciprocal increase in levels of known CDL substrates; DNA 
re-replication; cell cycle arrest; and ultimately death via apoptosis. In vitro experiments with 
pevonedistat administered in combination with hypomethylating agents azacitidine and decitabine 
demonstrated synergistic activity in acute myeloid leukemia (AML) cell lines. 
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 (BID) 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 
models with less frequent treatment, showing that continuous dosing is not necessary for antitumor 
activity.
In vitro assay results indicated a low risk for hERG channel inhibition by pevonedistat (inhibitory 
constant17.3 M) or its 3 major circulating metabolites (half-maximal inhibitory concentration
100 M for all three).

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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
The clinical pharmacokinetics (PK) of pevonedistat has been evaluated in 4 monotherapy phase 1 
studies in 96 patients with solid tumors (C15001 and C15005) and 109 patients with hematologic 
malignancies (C15002 and C15003). These studies have evaluated the single- and multiple-dose 
PK of pevonedistat administered via IV infusion across a range of 25 to 278 mg/m2 given at
various daily or intermittent dosing schedules within 21-day treatment cycles.
Plasma concentrations of pevonedistat declined in a bi-exponential manner at the end of IV 
infusion, with little or no drug accumulation following intermittent dosing or once-daily dosing for 
5 consecutive days of a 21-day cycle. Mean t1/2z was estimated to be approximately 10 hours 
(range 7.7-15.2) across doses and schedules. Consistent with in vitro data, pevonedistat is 
extensively partitioned in human blood (mean blood-to-plasma concentration ratio of 
approximately 65) with whole blood and plasma kinetics declining in parallel over time. 
Pevonedistat generally exhibited linear PK over the dose range studied. Observed interindividual 
variability was generally moderate with 18% to 41% coefficient of variation (CV) for the 
maximum observed concentration (Cmax), 12% to 56% CV for area under the plasma 
concentration-time curve (AUC) from time zero to 24 hours postdose (AUC24), and 15% to 33% 
CV for the AUC during a dosing interval (AUCτ) when pevonedistat was administered on Days 1, 
3, and 5. Body size influences pevonedistat systemic clearance and volume of distribution, thus 
supporting body surface area (BSA)-normalized dosing to reduce variation in systemic exposure 
of pevonedistat in patients with cancer. Pevonedistat clearance tended to gradually decrease in 
elderly patients (by approximately 25% over the 30-90 years age range). There was also no 
apparent effect of renal function status (as assessed by estimated creatinine clearance 
>30 mL/min) on pevonedistat PK. 
Additionally, evaluation of pevonedistat PK is ongoing for 2 studies of pevonedistat in 
combination with different standard-of-care therapies, and for a drug-drug interaction (DDI) study 

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evaluating the effects of cytochrome P450 (CYP)3A-mediated inhibition on pevonedistat. 
Pevonedistat PK was not altered in the presence of azacitidine when compared with historical 
single-agent data. Also, no obvious changes in the PK behavior of pevonedistat in the presence of 
docetaxel or gemcitabine have been observed, whereas a trend toward increasing plasma 
concentrations of pevonedistat in the presence of carboplatin+paclitaxel was evident. This 
apparent drug interaction effect, which cannot be explained at this time, warrants further 
understanding of the disposition properties of pevonedistat in humans. Lastly, multiple doses of 
fluconazole, a moderate CYP3A inhibitor, had minimal effect (13% increase in mean AUC from 
time zero to infinity, calculated using the observed value of the last quantifiable concentration
[AUC]) on the single-dose IV PK of pevonedistat, while pevonedistat systemic exposure 
increased by 23% on average in the presence of the strong CYP3A inhibitor itraconazole.
Additional information on the clinical PK of pevonedistat is provided in the current IB.
4.1.3.2
Clinical Experience
As of 22 January 2016, the clinical development program of pevonedistat includes 8 clinical 
studies in patients with advanced malignancies. Four of the 8 clinical studies are completed phase 
1 monotherapy studies (C15001, C15002, C15003, and C15005), and 2 are ongoing, phase 1b 
studies of pevonedistat in combination with different standard of care (SoC) therapies (C15009 
and C15010). A phase 1 DDI study (C15011) is also evaluating the effects of CYP3A-mediated 
inhibition on pevonedistat. Thus, approximately 390 patients diagnosed with advanced 
malignancies including solid tumors, AML, melanoma, lymphoma, multiple myeloma, higher risk 
myelodysplastic syndrome (MDS), and acute lymphoblastic leukemia (ALL) have been enrolled 
in the overall clinical development program. Further details on these studies are provided in the 
current IB.
4.1.4
Potential Risks and Benefits
Pevonedistat will be administered in Part A as a single 1-hour IV infusion of 25 mg/m2 (equivalent 
to approximately 43 mg for a typical individual of 1.73 m2 BSA, up to a maximum absolute dose 
of 50 mg) [14C]-pevonedistat (containing approximately 60-85 µCi [approximately
2.22-3.145 MBq]) as the radioactive tracer to allow mass balance evaluation and quantitative 
metabolite profiling in plasma, urine, and feces. The safety of the dose of radioactivity is supported 
by dosimetry calculations based on quantitative whole body autoradiography studies in rats 
(Millennium: the Takeda Oncology Company, Report 96N-1213, 2012), while ensuring adequate 
sensitivity for radiometric detection in all biological matrices. Refer to Section 4.2.1 for the risks 
for [14C]-pevonedistat.
It is anticipated that the chemotherapies used in Part B of this study may provide clinical benefit to 
patients. Study C15010 is an ongoing, open-label, dose-finding study to assess safety and 
tolerability of pevonedistat+chemotherapy. Fifty-four patients evaluable for response have been 
treated with pevonedistat in combination with docetaxel (N=22), carboplatin (N=6), or 
carboplatin+paclitaxel (N=26): 3 objective responses were seen in 22 patients treated in Arm 1 
(pevonedistat+docetaxel), and 9 partial responses (PRs)/complete responses (CRs) were seen in 

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32 patients treated in Arm 2 (pevonedistat+carboplatin or pevonedistat+carboplatin/paclitaxel) 
[1,2]. The overall response rate in the intent-to-treat population of Arm 1 was 13% and Arm 2 was 
28%. 
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 (DCSI) (Appendix A of the IB).
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. 
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 trials 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.

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
Renal failure.
–
The events of multi-organ failure (hepatic, renal, and cardiac) with a fatal outcome, and 
renal failure alone, have been reported at doses of pevonedistat ranging from 110 to 
278 mg/m2. 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.

Hypophosphatemia.
Potential Risks Confounded by Underlying Disease or Malignancy
Events have been reported from clinical trials that are confounded by the patient’s underlying 
medical condition, including malignancy. These events are noted in the absence of randomized, 
controlled data:

Fatigue.

Chills.

Decreased appetite.

Neutropenia.

Febrile neutropenia.

GI bleeding.
–
All events were assessed by the investigator as unrelated; the majority occurred in the 
setting of thrombocytopenia.
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, and increased diastolic blood pressure.

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
Enteropathy (including dehydration and electrolyte loss) with secondary sepsis.

Effects on the testes and ovaries that represent a reproductive hazard, including sterility.

Increased developmental risk to the fetus or embryo.

Decreased trabecular bone (graded minimal to moderate) was noted in the femur and in the 
sternum in rats at all dose groups (low, medium, 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.

Local tissue injury when administered SC.
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 (see Section 8.6.1). 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 
Section 8.4 and Section 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.
Patients will be monitored closely when they are receiving this agent and for at least 30 days after 
their last dose for these anticipated and potential toxicities and for unanticipated toxicities. 
Monitoring will include the following: laboratory assessments, physical examinations, serious 
adverse event (SAE) and adverse event (AE) reporting, and safety review (see Section 11.1). In 
addition, an independent data monitoring committee (IDMC) (see Section 11.2) is in place that 
will monitor the safety data from studies within the pevonedistat program. 
This trial will be conducted in compliance with the protocol, Good Clinical Practice (GCP), and
the applicable regulatory requirements (including International Conference on Harmonisation 
[ICH] guidelines).

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4.1.4.2
Risks of Docetaxel Treatment
Treatment-related mortality increases with abnormal liver function, at higher doses, and in patients 
with non-small cell lung cancer (NSCLC) and prior platinum-based therapy receiving docetaxel at 
100 mg/m2.
Severe hypersensitivity, including very rare, fatal anaphylaxis, has been reported in patients who 
received dexamethasone premedication. Severe reactions require immediate discontinuation of 
docetaxel and administration of appropriate therapy. 
Docetaxel is contraindicated if the patient has a history of severe hypersensitivity reactions to 
docetaxel or to drugs formulated with polysorbate 80.
Severe fluid retention may occur despite dexamethasone premedication.
For more details, refer to the docetaxel Summary of Product Characteristics (SmPC) [3]. 
Hepatotoxicity Warning
Docetaxel should not be given if total bilirubin is greater than the upper limit of the normal range 
(ULN) or if aspartate aminotransferase (AST) or alanine aminotransferase (ALT) is greater than 
1.5 times the ULN. Liver function test elevations increase the risk of severe or life-threatening
complications. Liver function tests should be obtained before each treatment cycle.
Hematologic Warning
Docetaxel should not be given if the absolute neutrophil count (ANC) is less than 1500 cells/mm3.
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, hepatoxicity, 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 NSCLC and prior 
platinum-based therapy receiving docetaxel at 100 mg/m2.
4.1.4.4
Risks of Carboplatin and Paclitaxel Therapy
See Appendix H for information on the hematologic toxicity of carboplatin alone and in 
combination with paclitaxel.
Carboplatin
Anaphylaxis-like reactions to carboplatin have been reported and may occur within minutes of 
carboplatin administration. Epinephrine, corticosteroids, and antihistamines have been employed 
to alleviate symptoms.
Vomiting is another frequent drug-related side effect.

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Carboplatin injection is contraindicated in patients with a history of severe allergic reactions to 
cisplatin or other platinum-containing compounds.
Carboplatin injection should not be employed in patients with severe bone marrow depression or 
significant bleeding.
For more details, refer to the carboplatin SmPC [4]. 
Nephrotoxicity Warning
The renal effects of nephrotoxic compounds may be potentiated by carboplatin.
Hematologic Warning
Bone marrow suppression is dose related and may be severe, resulting in infection or bleeding. 
Peripheral blood counts should be frequently monitored during carboplatin treatment and, when 
appropriate, until recovery is achieved.
Anemia may be cumulative and may require transfusion support.
Paclitaxel
Anaphylaxis and severe hypersensitivity reactions characterized by dyspnea and hypotension 
requiring treatment; angioedema; and generalized urticaria have occurred in 2% to 4% of patients 
receiving paclitaxel in clinical trials. Fatal reactions have occurred in patients despite 
premedication. All patients should be pretreated with corticosteroids, diphenhydramine, and H2 
antagonists. Patients who experience severe hypersensitivity reactions to paclitaxel should not be 
rechallenged with the drug.
Severe conduction abnormalities have been documented in less than 1% of patients during 
paclitaxel therapy and, in some cases, require pacemaker placement. If patients develop significant 
conduction abnormalities during paclitaxel infusion, appropriate therapy should be administered, 
and continuous cardiac monitoring should be performed during subsequent therapy with 
paclitaxel.
Paclitaxel is contraindicated in patients who have a history of hypersensitivity reactions to 
paclitaxel or other drugs formulated in Cremophor EL (polyoxyethylated castor oil).
For more details, refer to the paclitaxel SmPC [5]. 
Hematologic Warning
Paclitaxel injection therapy should not be given to patients with solid tumors who have baseline 
neutrophil counts of less than 1500 cells/mm3. To monitor for the occurrence of bone marrow 
suppression, primarily neutropenia, which may be severe and result in infection, it is 
recommended that frequent peripheral blood cell counts be performed on all patients receiving 
paclitaxel injection.

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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, 
hypersensitivity/anaphylaxis reactions, and hepatotoxicity. Renal effects of nephrotoxic 
compounds (see Appendix H) may be potentiated by carboplatin.
4.2
Rationale for the Proposed Study
Pevonedistat is currently in phase 2 of clinical development across multiple solid tumors, AML, 
and higher risk MDS. This study is intended to provide a quantitative characterization of the mass 
balance, rates and routes of excretion, and metabolic pathways of pevonedistat in humans. Such 
definitive characterization will help guide understanding of the potential for patient-specific (eg, 
renal function, hepatic function) or extrinsic (eg, concomitant medications with potential to affect 
drug metabolism) factors to affect pevonedistat PK and, thereby, is important to inform the need 
for future clinical pharmacology studies (eg, special population studies in patients with organ 
impairment).
4.2.1
Rationale for Dose and Duration of PK/Excretion Assessments in Part A 
Pevonedistat will be administered in Part A, the absorption, distribution, metabolism, excretion 
(ADME) portion of this study, as a single 1-hour IV infusion of 25 mg/m2 (equivalent to 
approximately 43 mg for a typical individual of 1.73 m2 BSA, up to a maximum absolute dose of 
50 mg) [14C]-pevonedistat (containing approximately 60-85 µCi [approximately
2.22-3.145 MBq]) as the radioactive tracer to allow mass balance evaluation and quantitative 
metabolite profiling in plasma, urine, and feces. On the basis of the available results from studies 
with SoC therapies, the recommended phase 2 dose of the combinations was determined to be 
20 mg/m2 pevonedistat (plus azacitidine or carboplatin/paclitaxel) or 25 mg/m2 pevonedistat (plus 
docetaxel). These dose levels were chosen to study the highest potential dose of pevonedistat (in 
combination with SoC) to be further investigated in clinical development in any tumor type. On 
the basis of previous clinical observations, it is anticipated that a single IV dose administration of 
25 mg/m2 pevonedistat as single agent will be well tolerated. Additionally, [14C]-pevonedistat will 
be supplied in glass vials, each containing compounded sterile solution, at a concentration of 
1 mg/mL (as free base). It was therefore determined that the maximum absolute dose of 
pevonedistat that can be accurately administered via infusion to a patient from a single vial is 
50 mg; using BSA-adjusted dosing, individuals with BSA values greater than 2 m2 will receive no 
more than 50 mg of pevonedistat in Part A of this study. As the clinical PK of pevonedistat is dose 
linear, this maximum selected dose of 50 mg based on the above described practical considerations 
does not affect the scientific objectives of the study or interpretation of the results.
Furthermore, the safety of the dose of radioactivity is supported by dosimetry calculations based 
on the results of quantitative whole body autoradiography studies in rats, while providing adequate 
sensitivity for radiometric detection in plasma, urine, and feces. [14C]-pevonedistat-derived 
radioactivity in male Long-Evans rats was well distributed at the end of a single 30-minute IV 
infusion of [14C]-pevonedistat, at a target dose of 5 mg/kg, through 4 hours postdose. Tissue 

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concentrations declined steadily over the course of the study, and elimination of radioactivity was 
observed in most tissues (24 of 40 tissues), which were below the lower limit of quantitation at 
72 hours postdose; by 672 hours, all tissue concentrations, except the eye uveal tract, were below 
the lower limit of quantitation. It was estimated that the administration of a 100 μCi (3.70 MBq) IV 
infusion of [14C]-pevonedistat would expose adult male human subjects to a total maximum 
weighted effective dose equivalent of 1.1077 mrem (0.0111 mSv). This is approximately 0.04% of 
the 3000 mrem single dose limit specified for whole-body exposure by the United States (US) 
Code of Federal Regulations (21 CFR: part 361.1, section b, 3i) and 1.1% of the 1 mSv single dose 
limit specified for whole-body exposure by the International Commission on Radiological 
Protection. In conclusion, an excessive individual tissue or whole-body exposure of male human 
subjects to 14C is not expected to occur with a single IV infusion of up to 100 μCi (3.70 MBq) of 
[14C]-pevonedistat. 
The mean t1/2z of pevonedistat as parent drug was estimated to be approximately 10 hours (range 
7.7-15.2 hours) across doses and schedules in adult patients with advanced malignancies. The 
human t1/2z of metabolites of pevonedistat is not known; therefore, the t1/2z of total drug-related 
material (parent drug+metabolites) cannot be accurately estimated. The estimated assessment 
period of 8 days (greater than 5 t1/2z) takes into account potential metabolites that may have t1/2z
that are up to 2 times that of parent drug for characterizing the PK of total radioactivity (TRA) and 
excretion of drug-related material in urine and feces. 
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 
maximum tolerated doses (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 (one established combination regimen consists of 
carboplatin and cyclophosphamide). Carboplatin is also indicated for the palliative treatment of 

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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 to the SmPCs for additional information 
[3-5]. 
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 (all 3 regimens). 

Their 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 recommended phase 2 doses have been determined for the combination of 
pevonedistat+docetaxel or pevonedistat+carboplatin/paclitaxel. 
Therefore, it is thought 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 objectives are as follows:
!
To assess the mass balance (ie, cumulative excretion of total radioactivity [TRA] in urine and 
feces) of pevonedistat following a single 1-hour infusion of 25 mg/m2 [14C]-pevonedistat IV 
solution containing approximately 60 to 85 μCi (approximately 2.22-3.145 MBq) of TRA in 
patients with advanced solid tumors in Part A. 
!
To characterize the PK of pevonedistat in whole blood, plasma, and urine, and of TRA in 
plasma and whole blood following a single 1-hour infusion of 25 mg/m2 [14C]-pevonedistat IV 
solution containing approximately 60 to 85 μCi (approximately 2.22-3.145 MBq) of TRA in 
patients with advanced solid tumors in Part A.
5.1.2
Secondary Objectives
The secondary objectives are as follows:
!
To collect samples for characterization of the metabolic profile of pevonedistat in plasma, 
urine, and feces following a single 1-hour infusion of 25 mg/m2 [14C]-pevonedistat IV solution 
containing approximately 60 to 85 μCi (approximately 2.22-3.145 MBq) of TRA (maximum 
dose of 50 mg) in patients with advanced solid tumors in Part A. 
!
To evaluate the safety and tolerability of pevonedistat in patients with advanced solid tumors 
after a single dose in Part A and in combination with either docetaxel or carboplatin+paclitaxel 
in Part B.
!
To evaluate disease response that may be observed with the combination of pevonedistat and 
docetaxel or pevonedistat and carboplatin+paclitaxel in patients with advanced solid tumors 
(Part B). 
5.1.3
Exploratory Objective
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5.2
Endpoints
5.2.1
Primary Endpoints
The primary endpoints are as follows:
!
Summary statistics of PK parameters of pevonedistat and TRA in plasma and whole blood: 
Cmax, time of first occurrence of Cmax (tmax), and AUC from time zero to time of the last 
quantifiable concentration (AUClast).
!
Cumulative percentage of urinary recovery, percentage of fecal excretion, and percentage of 
TRA in urine and feces over the entire period of collection.
!
Summary statistics of PK parameters of pevonedistat in urine: cumulative amount excreted in 
urine (Aeurine and percentage of dose) and renal clearance (CLR).
5.2.2
Secondary Endpoints
The secondary endpoints are as follows:
!
Safety parameters: AEs, SAEs, and abnormal laboratory values reported.
!
Metabolite profiles in plasma, urine, and feces.
!
Measures of disease response based on investigator’s assessment using the Response 
Evaluation Criteria in Solid Tumors (RECIST) guideline (Version 1.1) [6].
5.2.3
Exploratory Endpoint 
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6.0
STUDY DESIGN
6.1
Overview of Study Design
This is a 2-part, open-label, multicenter, mass balance and ADME study in adult patients with 
advanced solid tumors. It is expected that approximately 4 to 6 PK-evaluable patients will be 
enrolled in this study. Once enrolled into the study, patients will be administered a single dose of 
[14C]-pevonedistat via IV infusion.
In the first part of the study, patients will remain at the Part A study site for approximately 
8 consecutive days (or until the discharge criteria are met, with a maximum estimated confinement 
period of 9-14 days) to measure mass balance and PK, followed by a washout period of 
approximately 2 weeks.
In the optional second part of the study, patients will receive pevonedistat in combination with 
docetaxel or pevonedistat in combination with carboplatin+paclitaxel at a secondary study site. 
Patients may receive pevonedistat combination therapy for 12 cycles, or longer if the investigator 
and sponsor agree that a patient would benefit from continued treatment (see Section 6.3.4), or 
until discontinuation criteria are met (see Section 9.8). Patients will attend the End-of-Study
(EOS) visit 30 days after receiving their last dose of study drug.
6.1.1
Part A: Mass Balance/ADME Assessment
Part A represents the period for assessment of the mass balance, PK, metabolism, and elimination 
of pevonedistat in this population. Patients will be required to stay at the Part A study site for 
approximately 8 days or until the discharge criteria are met (see Section 9.5.17), with a maximum 
estimated confinement period of 9 to 14 days.
Patients who meet all inclusion criteria and no exclusion criteria will be assigned a patient number 
and will be admitted to the Part A study site on the morning of Day -1 for predose assessments and 
to begin confinement. On the morning of Day 1, patients will receive a single dose of 25 mg/m2
(equivalent to approximately 43 mg for a typical individual of 1.73 m2 BSA, with a maximum 
absolute dose of up to 50 mg) [14C]-pevonedistat IV solution (containing approximately 60-85 µCi
[approximately 2.22-3.145 MBq] of TRA) via a 1-hour infusion. The actual amount of 
administered radioactivity will be documented for each patient. 
Patients will be closely monitored for AEs throughout the study. Safety will be assessed by 
monitoring vital signs, physical examinations (including weight at Day 1 predose and EOS), 
electrocardiograms (ECGs), and clinical laboratory tests.
Blood will be collected at prespecified time points in Appendix A for analyses of pevonedistat and 
TRA PK and for metabolite profiles over the confinement period. Complete urinary and fecal 
output will be collected throughout the confinement period until discharge; urine samples will be 
analyzed for PK, TRA, and biotransformation, and fecal samples will be analyzed for TRA and 
products of pevonedistat biotransformation. For patients who experience emesis during the first 
24 hours after drug administration, the vomitus will be collected as much as possible and assayed 

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for TRA. If a subject vomits more than once during the period, vomitus corresponding to each 
vomiting event will be collected in a separate labeled container and separately counted. Refer to 
the Study Manual for further details. To ensure defecation before release from the Part A study 
site, two 15 mL doses of oral lactulose will be administered, separated by approximately 2 hours, 
on the evening of Day 4; the second dose of lactulose will be withheld if the first dose was not 
tolerated. Patients will be required to stay at the Part A study site for approximately 8 days or until 
the discharge criteria are met, with a maximum estimated confinement period of 9 to 14 days. See 
Section 9.5.17 for Part A discharge criteria.
6.1.2
Part B: Continued Treatment With Pevonedistat in Combination With 
Chemotherapy (OPTIONAL)
After completion of the mass balance/ADME assessment portion of the study, patients will have 
the opportunity to continue into Part B at a secondary study site, which can begin within 
approximately 2 weeks of the patient completing Part A (ie, when the patient has met the Part A 
discharge criteria; see Section 9.5.17). Participation in Part B is optional. Any patient who 
continues on to Part B will need to be re-evaluated for entry criteria before treatment in Part B can 
begin. Patients will receive pevonedistat in combination with either docetaxel or 
carboplatin+paclitaxel as recommended by the investigator. On the basis of the MTDs determined 
in Study C15010, patients will receive pevonedistat on Days 1, 3, and 5 at the dose of 25 mg/m2 in 
combination with docetaxel 75 mg/m2 on Day 1 every 3 weeks, or pevonedistat on Days 1, 3, and 
5 at the dose of 20 mg/m2 in combination with carboplatin AUC5+paclitaxel 175 mg/m2 every 
3 weeks on Day 1. Safety and disease assessments will be conducted in Part B of the study. 
Disease assessments will be conducted using radiological evaluations (computed tomography 
[CT] scan or magnetic resonance imaging [MRI] as clinically indicated) to assess the status of the 
patient’s underlying disease and will be part of the entry criteria for Part B (see Section 9.5.18).
Toxicity will be evaluated according to the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE), version 4.03, effective date 14 June 2010 [7]. 
Dose-limiting toxicities are defined in Section 8.3. 
See Figure 6.a for an overview of the study design of Parts A and B. 
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Figure 6.a
Study Overview
(a) Screening assessments will be performed within 28 days before administration of [14C]-pevonedistat.
(b) On the morning of Day 1, following the collection of Day 1 predose assessments, patients will receive a single dose 
of 25 mg/m2 (equivalent to approximately 43 mg for a typical individual of 1.73 m2 BSA up to a maximum absolute 
dose of 50 mg) [14C]-pevonedistat IV solution (containing approximately 60-85 µCi [approximately 2.22-3.145 MBq]
of TRA) via a 1-hour infusion. 
(c) Two 15 mL doses of oral lactulose will be administered, separated by approximately 2 hours, on the evening of 
Day 4; the second dose of lactulose will be withheld if the first dose was not tolerated. Lactulose may also be 
administered as needed.
(d) During Part A, patients will be required to stay at the Part A study site for approximately 8 days or until the 
discharge criteria are met, with a maximum estimated confinement period of 9 to 14 days.
(e) Eligible patients may continue into Part B (optional), which can begin within approximately 2 weeks of the patient 
completing Part A (ie, when the patient has met the discharge criteria). Cycle length is 21 days. Treatment assignment 
in Part B will be based on recommendation by the investigator. 
(f) 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. 
(g) Patients will attend an EOS visit 30 days (+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.
6.2
Number of Patients
In this study, 4 to 6 PK-evaluable patients will be enrolled at the Part A study site in Europe. 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 or are not considered evaluable for PK will be 
replaced.
6.3
Duration of Study
6.3.1
Duration of an Individual Patient’s Study Participation
Patients will be required to stay at the Part A study site for approximately 8 days or until the 
discharge criteria are met, with a maximum estimated confinement period of 9 to 14 days. 

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Eligible patients may have the option to continue to receive treatment at a secondary site in Part B 
of this study until discontinuation criteria are met (see Section 9.8). 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.
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.
Patients will attend an EOS visit 30 days (+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.
It is anticipated that an individual patient will participate in this study for approximately 8 days in 
Part A or a total of approximately 36 weeks for Parts A and B combined for those patients who 
participate in the optional Part B. 
6.3.2
EOS/Study Completion Definition and Planned Reporting
Primary Completion/Study Completion
The analyses for the clinical study report may be conducted after all patients enrolled in the study 
have provided assessments in Part A to meet the primary (ADME) objectives 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 36 weeks for Parts A 
and B combined.
6.3.3
Timeframes for Primary and Secondary Endpoints to Support Disclosures
Refer to Table 6.a for disclosures information for all primary and secondary endpoints.

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Table 6.a
Primary and Secondary Endpoints for Disclosures
Endpoint
Definition
Maximum Time Frame
Primary: Summary statistics of PK 
parameters of pevonedistat and TRA 
in plasma and whole blood 
Maximum observed concentration 
(Cmax)
Time of first occurrence of Cmax (tmax) 
Area under the plasma 
concentration-time curve from time zero 
to time of the last quantifiable 
concentration (AUClast
Up to 168 hours postdose 
(4 hours)
Primary: Cumulative percentage of
urinary recovery, percentage of fecal 
excretion, and percentage of TRA in 
urine and feces over the entire period 
of collection
Cumulative amount of 
[14C]-radioactivity excreted in urine up 
to the last sampling interval (Aeurine,14
C).
Cumulative amount of 
[14C]-radioactivity excreted in feces up 
to the last sampling interval (Aefeces,14
C).
Total cumulative excretion of 
[14C]-radioactivity from the body 
(Aetotal,
14C=Aeurine,
14C+Aefeces,
14C)
Up to 168 hours postdose 
(4 hours)
Primary: Summary statistics of PK 
parameters of pevonedistat in urine: 
cumulative amount excreted in urine 
(Aeurine,t and % of dose) and CLR
Cumulative amount of pevonedistat 
excreted in urine (Aeurine and percent of 
dose)
Renal clearance (CLR)
Up to 168 hours postdose 
(4 hours)
Secondary: Metabolite profiling
Determination of relative percentage of 
circulatory and excretory metabolites
Up to 168 hours postdose 
(4 hours)
Secondary: Safety parameters: AEs, 
SAEs, and abnormal laboratory 
values reported
Abnormal laboratory values are those 
outside of normal range. 
See Section 10.1 for AE and SAE 
definitions.
AEs recorded from start of study 
administration through 30 days 
(+10 days) after the last dose of 
study drug.
This will include serious 
pretreatment events.
SAEs will be reported from 
signing of the informed consent 
form through 30 days (+10 days) 
after the last dose of study drug.
Laboratory tests up to EOS
6.3.4
Total Study Duration
It is anticipated that this study will last for approximately 36 weeks. 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.

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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. 

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7.0
STUDY POPULATION
Confirmation of eligibility must be obtained before the patient can enter the study. After 
completion of Part A, patients who are to continue into Part B must meet the entry criteria listed in 
Section 9.5.18.
7.1
Inclusion Criteria
Each patient must meet all the following inclusion criteria to be enrolled in the study:
1. Male or female patients aged 18 years or older.
2. Patients must have a histologically or cytologically confirmed metastatic or locally advanced 
and incurable solid tumor that is felt to be appropriate for treatment with one of the 
2 chemotherapy regimens in Part B of this study (carboplatin+paclitaxel or docetaxel), or have 
progressed despite prior standard therapy, or for whom conventional therapy is not considered 
effective. The tumor must be radiographically or clinically evaluable and/or measurable.
3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
4. Expected survival longer than 3 months from enrollment in the study.
5. Recovered (ie, ≤Grade 1 toxicity) from the effects of prior antineoplastic therapy.
6. Clinical laboratory values as specified below within 3 days before the first dose of study drug:

Hemoglobin ≥9 g/dL. Patients may be transfused to achieve this value.

Total bilirubin ≤ULN.

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 creatinine clearance ≥50 mL/min (creatinine clearance is defined in 
Section 9.5.13.1).

ANC ≥1,500/mm3.

Platelet count ≥100,000/mm3.

Prothrombin time and activated partial thromboplastin time ≤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:

Are postmenopausal for at least 1 year before the Screening visit (see 

Appendix J), or

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
Are surgically sterile, or

If they are of childbearing potential, they and their male partners agree to practice 1 highly 
effective method and 1 additional effective (barrier) method of contraception (see 
Appendix K) 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:

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 for the female partner] 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 dose of 
pevonedistat and (for male patients) willing to refrain from donating semen for at least 
4 months after their 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. Subject has irregular defecation patterns (less than 1 defecation per 2 days or excessive 
diarrhea) and/or has a history of changes in bowel habits with daily routine or environment 
changes. 
3. Treatment with any systemic antineoplastic therapy or any investigational products within 
21 days before the first dose of study treatment.
4. Major surgery within 14 days before the first dose of study treatment or scheduled surgery 
during Part A of the study.
5. Receiving antibiotic therapy within 14 days before the first dose of study treatment.
6. Radiotherapy within 14 days before the first dose of study treatment.

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7. Prior treatment with radiation therapy involving ≥25% of the hematopoietically active bone 
marrow.
8. Treatment with moderate or strong CYP3A inhibitors or inducers within 14 days before the 
first dose of pevonedistat. Patients must have no history of amiodarone use in the 6 months 
before the first dose of pevonedistat. 
9. Prior treatment with pevonedistat; however, prior treatment with docetaxel, paclitaxel, and 
carboplatin is allowed.
10. 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.
11. 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.
12. Active, uncontrolled infection or severe infectious disease, such as severe pneumonia, 
meningitis, septicemia, or methicillin-resistant Staphylococcus aureus infection within 
2 weeks before dosing.
13. Known human immunodeficiency virus (HIV) 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.
14. History of urinary and/or fecal incontinence.
15. Persistent diarrhea (≥Grade 2) lasting >3 days within 2 weeks before the first dose of study 
treatment. 
16. Clinically significant central nervous system disease defined as newly diagnosed, untreated, 
progressive, or requiring steroids for control of symptoms.
17. Newly diagnosed or uncontrolled cancer-related central nervous system disease.
18. Known hepatic cirrhosis or severe pre-existing hepatic impairment.
19. Uncontrolled high blood pressure (ie, systolic blood pressure >180 mm Hg, diastolic blood 
pressure >95 mm Hg).
20. Left ventricular ejection fraction <50% as assessed by echocardiogram or radionuclide 
angiography. 

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21. 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. In addition, 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 I) may enroll.
22. 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 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.
23. Prolonged rate corrected QT interval (QTc) ≥500 msec, calculated according to institutional
guidelines.
24. Implantable cardioverter defibrillator.
25. 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).
26. Moderate to severe aortic stenosis, moderate to severe mitral stenosis, or other valvulopathy
(ongoing).
27. Known moderate to severe chronic obstructive pulmonary disease, interstitial lung disease,
pulmonary fibrosis, or pulmonary arterial hypotension.
28. 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.
29. 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.
30. Male patients who intend to donate sperm during the course of this study or 4 months after
receiving their last dose of study drug.
31. Patient requiring chronic treatment with BCRP or P-gp inhibitors. Refer to Table 8.b for the list
of known BCRP and P-gp inhibitors.

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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
Patients will receive a single dose of pevonedistat given as an IV infusion on Day 1. The clinic will 
be supplied with vials containing approximately 60 to 98 μCi (approximately 2.22-3.626 MBq) of 
[14C]-pevonedistat as the radioactive tracer.
Patients will receive [14C]-pevonedistat via a 60-minute (±5 minutes) IV infusion. 
[14C]-pevonedistat should be administered through central or peripheral venous access. The start 
and end times of the IV infusion should be recorded accurately. 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. All infusion times must be recorded.
Refer to the Pharmacy Manual for the preparation of the IV infusion.
Samples will continue to be collected at 24-hour intervals until radioactivity in urine and feces 
combined is ≤1% per day of the total administered radioactivity for at least 2 consecutive days or 
the excretion of radioactivity is ≥80% of the administered radioactive dose. When radioactivity 
levels have fallen below these thresholds, patients can be discharged from the Part A study site.
See Section 9.5.17 for Part A discharge criteria. 
8.1.2
Part B
8.1.2.1
Pevonedistat Administration
Patients opting to continue into Part B will receive combination treatment with pevonedistat and 
chemotherapy. Two chemotherapy regimens, docetaxel and carboplatin+paclitaxel, will be used in 
this study as combination partners with pevonedistat. 
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Pevonedistat 
Concentrate is diluted in 5% dextrose for administration.
Patients will receive pevonedistat diluted with 5% dextrose in a 250 mL bag via a 60-minute 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 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.
8.1.2.2
Docetaxel Administration
On Day 1 of each cycle, when all study drugs are administered together, docetaxel 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 most recent 
SmPC for further details regarding docetaxel administration [3].
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 (Decadron, 4 mg BID 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 3 hours followed by carboplatin as a 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 most recent SmPC for further details regarding carboplatin administration [4].
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
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and Drug Administration (FDA) recommends that physicians consider capping the dose of 
carboplatin for desired exposure (AUC) to avoid potential toxicity due to overdosing. Using
the Calvert formula described in the carboplatin label, the maximum doses can be calculated 
as:
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 most recent SmPC for further details regarding paclitaxel administration [5].
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 methylprednisone (solu-Medrol) 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.
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 for each new cycle will be 
delayed until toxicity is reduced to ≤Grade 1 or 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 2 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.

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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. 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.
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 (to 15 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.
The following are dose modification guidelines for specific toxicities:

Alopecia of any duration will not lead to dose modification or treatment delay. 

Patients receiving pevonedistat+docetaxel may have a maximum of 2 dose modifications (if 
applicable) of chemotherapy agents as outlined below or modification of pevonedistat (see 
Section 8.3). 

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 Section 8.3). 
–
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.
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.

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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 
(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 (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 more than 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 
(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 
more than 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 (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 that both chemotherapy and pevonedistat are 
administered, hold all dosing for up to 3 weeks (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 dosing of pevonedistat for up to 
3 weeks (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.

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Table 8.a
Dose Modification Guidelines for Specific Toxicities (continued)
Pathologic Condition
Severity
Action on Study Drug
Stomatitis
Grade 3
Hold treatment for up to 3 weeks until the stomatitis is Grade 
1 (Section 8.3.4). If acute Grade 3 stomatitis occurs at any 
time, the dose of chemotherapy should be reduced 1 level. 
This is a permanent dose reduction.
Hepatic toxicity
ALT/AST Grade 3 at 
any time 
If ALT or AST is Grade 3 at any time, withhold pevonedistat 
dosing until patient has recovered to Grade 1 (see 
Section 8.3 for further details on dose modification of 
pevonedistat; also see Section 8.3.4 for discontinuation).
In addition, if toxicity is felt to be attributable to the 
chemotherapy agent(s), consider dose reduction for 
chemotherapy also by 1 dose level.
Hepatic toxicity
Total bilirubin 
>1.5ULN, regardless of 
ALT/AST
Hold all dosing for up to 3 weeks (Section 8.3.4) until 
bilirubin returns to within normal range and/or dose reduce 
chemotherapy by 1 level and/or modify pevonedistat dose 
(see Section 8.3).
Cardiac toxicity
Symptomatic arrhythmia 
during infusion
Stop infusion and manage arrhythmia according to 
institutional guidelines. Report as AE and discontinue further 
dosing.
Cardiac toxicity
Chest pain and/or 
symptomatic 
hypotension 
(<90/60 mmHg)
Stop infusion. Perform an ECG. Give IV diphenhydramine 
and dexamethasone if hypersensitivity is thought to be the 
etiology. Also, consider epinephrine or bronchodilators if 
chest pain is not thought to be cardiac. If Grade 3, 
discontinue patient from the study.
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 (Section 8.3.4). 
This will be a permanent dose reduction. Carboplatin or 
pevonedistat are not to be dose modified.
Allergic reaction
(paclitaxel or docetaxel 
only
Moderate symptoms
Stop infusion. Give IV diphenhydramine 25 to 50 mg and IV 
dexamethasone 10 mg and/or treatment per institutional 
guidelines. Resume infusion after recovery of symptoms at a 
low infusion rate. If no further symptoms, resume full dose 
rate until infusion is complete. If symptoms recur, stop 
infusion and discontinue patient.
Allergic reaction
(paclitaxel or docetaxel 
only)
Severe symptoms
Stop infusion. Give IV diphenhydramine and dexamethasone 
and/or treatment per institutional guidelines as above. Add 
epinephrine or bronchodilators if indicated. Report as an AE 
and discontinue patient.

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8.3.4
Criteria for Discontinuation of Study Drug
Patients receiving pevonedistat+docetaxel may have a maximum of 2 dose modifications (if 
applicable) of chemotherapy agents or modification of pevonedistat (see Section 8.3). Patients 
who require more than 2 dose modifications will be discontinued from the study.
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
Excluded Concomitant Medications and Procedures (Part A)
Medications and procedures that are prohibited in Part A are listed in Table 8.b.
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
eg, cyclosporine and eltrombopag (Promacta)
Moderate and strong CYP3A4 inhibitors 
and clinically significant CYP3A4 
inducers 
See Appendix F
Known P-gp inhibitors 
eg, azithromycin (Zithromax), captopril, carvedilol, felodipine, quercetin, 
quinidine, ranolazine, ticagrelor
8.4.2
Excluded Concomitant Medications and Procedures (Part B)
Medications and procedures that are prohibited in Part B are listed in Table 8.c.

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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 (ie, cyclosporine and eltrombopag 
[Promacta])
Generally excluded during the study but may be used as 
specified in Table 8.e
Strong CYP3A4 inhibitors and clinically significant CYP3A4 
inducers 
Generally excluded during the study but may be used as 
specified in Appendix F
Systemic antineoplastic therapy unless specified in the 
protocol as part of the combination with pevonedistat
This list is not all-inclusive; consult the docetaxel, carboplatin, and paclitaxel SmPCs [3-5] for additional information 
regarding precautions, warnings, and contraindications.
8.5
Permitted Concomitant Medications and Procedures
8.5.1
Permitted Concomitant Medications and Procedures (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
Whenever possible, caution should be used with nephrotoxic concomitant 
medications (Appendix H). Alternative concomitant non-nephrotoxic 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. 
Red blood cell 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 red blood 
cell transfusions based on the patient’s risk of inadequate oxygenation, underlying 
cardiopulmonary status, clinical judgment, and hospital guidelines.
Red blood cell transfusions must be administered at least 1 day before administration 
of study drug. Each transfusion episode, including the type of transfusion (red blood 
cell), should be recorded.
8.5.2
Permitted Concomitant Medications and Procedures (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
Azole antifungal agents
Limited use of the azole antifungal agent, voriconazole, is permitted (if clinically 
necessary and no suitable alternative exists). The patient may receive voriconazole 
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), Friday (Day 5) schedule, then voriconazole 
may be administered (if clinically necessary and no suitable alternative) from the 
Saturday after the Day 5 dose (Day 6) up to the Friday (Day 19) before the Monday 
dose of the next cycle.
Antiemetic agents
Antiemetic agents, including for prophylactic use, may be administered at the 
discretion of the investigator. 
Known BCRP inhibitors 
(ie, cyclosporine and 
eltrombopag [Promacta])
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
Whenever possible, caution should be used with nephrotoxic concomitant 
medications (Appendix G). Alternative concomitant non-nephrotoxic medications 
should be used whenever possible.
Red blood cell 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 red blood 
cell transfusions based on the patient’s risk of inadequate oxygenation, underlying 
cardiopulmonary status, clinical judgment, and hospital guidelines.
Red blood cell transfusions must be administered at least 1 day before administration 
of study drug. Each transfusion episode, including the type of transfusion (red blood 
cell), 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 8.4.1 and 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 group and male patients should use highly effective methods of contraception 
through defined periods during and after study treatment as specified below.
1. Use only contraceptive methods that are locally approved in each country. 

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2. Female patients must meet 1 of the following:

Postmenopausal for at least 1 year before the Screening visit (see 

Appendix J), or

Surgically sterile, or

If they are of childbearing potential (as defined in Section 9.5.7), they and their male 
partners agree to practice 1 highly effective method and 1 additional effective (barrier) 
method of contraception (see Appendix K) 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.)

Female patients must agree to not donate eggs (ova) during the course of this study or 
4 months after receiving their last dose of study drug.
3. Male patients, even if surgically sterilized (ie, status postvasectomy) must agree to 1 of the 
following:

Agree to practice effective barrier contraception during the entire study treatment period 
and through 4 months after the last dose of study drug, (if barrier methods are not locally 
approved to be used by males, then their female partners should use effective contraceptive 
methods as described in the above) or

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle 
of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 
methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable 
methods of contraception. Female and male condoms should not be used together.)

Male patients must agree to not donate sperm during the course of this study or 4 months 
after receiving their last dose of study drug.
8.6.2
Docetaxel
8.6.2.1
Pregnancy
Docetaxel is a pregnancy Category D drug. Refer to the docetaxel SmPC for more information [3].
Docetaxel can cause fetal harm when administered to a pregnant woman. Docetaxel caused 
embryo-fetal toxicities including intrauterine mortality when administered to pregnant rats and 
rabbits during the period of organogenesis. Embryo-fetal effects in animals occurred at doses as 
low as 1/50 and 1/300 the recommended human dose on a BSA basis.
There are no adequate and well-controlled studies in pregnant women using docetaxel. If 
docetaxel is used during pregnancy, or if the patient becomes pregnant while receiving this drug, 

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the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential 
should be advised to avoid becoming pregnant during therapy with docetaxel [3]. 
8.6.2.2
Geriatric Use
Refer to the docetaxel SmPC for additional information on geriatric use in different types of cancer 
[3].
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 in 
elderly patients.
8.6.3
Carboplatin
8.6.3.1
Pregnancy
Carboplatin is a pregnancy Category D drug. Refer to the carboplatin injection SmPC for more 
information [4].
Carboplatin injection may cause fetal harm when administered to a pregnant woman. Carboplatin 
has been shown to be embryotoxic and teratogenic in rats. There are no adequate and 
well-controlled studies in pregnant women. If this drug is used during pregnancy, or if the patient 
becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard 
to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant [4]. 
8.6.3.2
Geriatric Use
Refer to the carboplatin SmPC for additional information on geriatric use [4].
Of the 789 patients in initial treatment combination therapy studies (National Cancer Institute of 
Canada and Southwest Oncology Group), 395 patients were treated with carboplatin in 
combination with cyclophosphamide. Of these, 141 were aged greater than 65 years and 22 were 
aged 75 years or older. In these trials, age was not a prognostic factor for survival. In terms of 
safety, elderly patients treated with carboplatin were more likely to develop severe 
thrombocytopenia than younger patients. In a combined database of 1942 patients (414 were aged 
65 years) who received single-agent carboplatin for different tumor types, a similar incidence of 
AEs was seen in patients aged 65 years and older and in patients aged less than 65 years. Other 
reported clinical experience has not identified differences in responses between elderly and 
younger patients, but greater sensitivity of some older individuals cannot be ruled out. Because 
renal function is often decreased in the elderly, renal function should be considered in the selection 
of carboplatin dosage.

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8.6.4
Paclitaxel
8.6.4.1
Pregnancy
Paclitaxel is a pregnancy Category D drug. Refer to the paclitaxel injection SmPC for more 
information [5].
Paclitaxel injection can cause fetal harm when administered to a pregnant woman. Administration 
of paclitaxel during the period of organogenesis to rabbits at doses of 3 mg/kg/day (about 0.2 the 
daily maximum recommended human dose on a mg/m2 basis) caused embryo- and fetotoxicity, as 
indicated by intrauterine mortality, increased resorptions, and increased fetal deaths.
Maternal toxicity was also observed at this dose. No teratogenic effects were observed at 
1 mg/kg/day (about 1/15 the daily maximum recommended human dose on a mg/m2 basis); 
teratogenic potential could not be assessed at higher doses due to extensive fetal mortality.
There are no adequate and well-controlled studies in pregnant women. If paclitaxel injection is 
used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient 
should be apprised of the potential hazard to the fetus. Women of childbearing potential should be 
advised to avoid becoming pregnant [5]. 
8.6.4.2
Geriatric Use 
Refer to the paclitaxel SmPC for additional information [5].
Of 2228 patients who received paclitaxel in 8 clinical studies evaluating its safety and 
effectiveness in the treatment of advanced ovarian cancer, breast carcinoma, or NSCLC, and 1570 
patients who were randomized to receive paclitaxel in the adjuvant breast cancer study, 649 
patients (17%) were aged 65 years or older, and 49 patients (1%) were aged 75 years or older. In 
most studies, severe myelosuppression was more frequent in elderly patients; in some studies, 
severe neuropathy was more common in elderly patients. In 2 clinical studies in NSCLC, elderly 
patients treated with paclitaxel had a higher incidence of cardiovascular events. Estimates of 
efficacy appeared similar in elderly patients and in younger patients; however, comparative 
efficacy cannot be determined with confidence because of the small number of elderly patients 
studied. In a study of first-line treatment of ovarian cancer, elderly patients had a lower median 
survival than younger patients, but no other efficacy parameters favored the younger group.
8.7
Management of Clinical Events
Specific recommendations for the management of pevonedistat clinical events that were identified 
from toxicology studies in dogs and rats and from early experience in ongoing clinical studies are 
outlined in the pevonedistat current IB, which includes the DCSI (Appendix A of the IB).
The most common adverse drug reactions for docetaxel and for paclitaxel+carboplatin are 
described in Section 4.1.4. Refer to the applicable SmPC for additional details regarding the 
management of clinical events attributed to these agents [3-5].

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Patients who experience an AE with pevonedistat should be followed closely for a recurrence of 
similar or other AEs upon subsequent dosing of pevonedistat.
8.7.1
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, red blood cell 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 red blood cell 
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. If granulocyte-colony stimulating factor is used, it should be used in 
accordance with the European Society for Medical Oncology guidelines [8]. 
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, red blood cell 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 red blood cell 
transfusion should be recorded in the eCRFs.

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Use of erythropoietin may be considered at the investigator’s discretion and according to
institutional guidelines.
8.8
Blinding and Unblinding
This is an open-label study. 
8.9
Description of Investigational Agents
8.9.1
Pevonedistat
8.9.1.1
Part A
8.9.1.2
Part B
 
 
 
Pevonedistat 
Concentrate is diluted in 5% dextrose for administration.
8.9.2
Docetaxel 
Docetaxel is obtained from commercial sources according to local practice standards and is 
provided as a commercially available dosage formulation. Refer to the docetaxel SmPC [3].
8.9.3
Carboplatin 
Carboplatin is obtained from commercial sources according to local practice standards and is 
provided as a commercially available dosage formulation. Refer to the carboplatin SmPC [4].
8.9.4
Paclitaxel 
Paclitaxel is obtained from commercial sources according to local practice standards and it is 
provided as a commercially available dosage formulation. Refer to the paclitaxel SmPC [5].
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.
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Pevonedistat, docetaxel, paclitaxel, and carboplatin are anticancer drugs, and as with other 
potentially toxic compounds, caution should be exercised when handling pevonedistat and 
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, and Paclitaxel
Refer to the SmPCs for docetaxel, paclitaxel, and carboplatin for instructions and precautions 
regarding preparation [3-5].
8.11
Packaging and Labeling
8.11.1 Pevonedistat
[14C]-pevonedistat will be provided in USP Type I glass vials containing compounded sterile 
solution, at a concentration of 1 mg/mL (as free base), sealed with a coated butyl rubber stopper 
and oversealed with an aluminum seal.
8.11.2 Docetaxel, Carboplatin, and Paclitaxel
Docetaxel, paclitaxel, and carboplatin may be sourced locally by the clinical site when 
arrangements have been made and agreed to by Takeda and the clinical site and when regulations 
allow for clinical site sourcing, appropriate labeling, and compliance with local and regional 
regulations. As required by local regulations, any modifications to the plan for drug supply or 
storage will be communicated to the investigator and detailed in the Study Manual.
8.12
Storage, Handling, and Accountability
8.12.1 Pevonedistat
[14C]-pevonedistat will be provided in USP Type I glass vials containing 1 mg/mL of compounded 
sterile solution sealed with a coated butyl rubber stopper and oversealed with an aluminum seal. 
Vials should be stored at 5°C until use, allowed to reach room temperature (1 hour) before use, and 
used within 72 hours of manufacture.
8.12.2 Docetaxel, Carboplatin, and Paclitaxel
Refer to the SmPCs for the docetaxel, paclitaxel, and carboplatin for instructions and precautions 
regarding preparation [3-5]. 
8.13
Other Protocol-Specified Materials
Refer to the Pharmacy Manual.

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9.0
STUDY CONDUCT
This trial will be conducted in compliance with the protocol, 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 contract research organization (CRO) team, and other vendors 
can be found in the Project Management Plan. 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). 
9.3
Treatment Group Assignments
All patients will receive the same study treatment in Part A.
In optional Part B, patients will be assigned 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 as recommended by the investigator.
9.4
Confinement and Overnight Visits
In Part A, patients will check into the clinic on Day -1 and be confined from Day -1 to Day 7 as 
specified in the Schedule of Events (Appendix A). Patients will be required to stay at the Part A 
study site for approximately 8 days or until the discharge criteria are met (Section 9.5.17), with a 
maximum estimated confinement period of 9 to 14 days. 
9.5
Study Procedures
Refer to the Schedule of Events (Appendix A) for timing of assessments. Additional details are 
provided as necessary in the sections that follow.
9.5.1
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.
9.5.2
Patient Demographics
The date of birth, race, ethnicity, and sex of the patient are to be recorded during Screening.

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9.5.3
Medical History
During the Screening period, a complete medical history will be compiled for each patient. The 
history will emphasize the background and progress of the patient’s malignancy and include a 
description of prior therapies for it. In addition, concomitant medications will be recorded as 
specified in Section 8.5. 
9.5.4
Physical Examination
Full and symptom-driven physical examinations will be completed per SoC at the times specified 
in the Schedule of Events (Appendix A).
9.5.5
Patient Height
Height will be measured only during Screening.
9.5.6
Vital Signs
Vital signs, including diastolic and systolic blood pressure, heart rate, weight, and body 
temperature, will be collected as indicated in the Schedule of Events (Appendix A) and as 
clinically indicated. All vital signs will be taken in the sitting position, as noted in the Schedule of 
Events (Appendix A).
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 Schedule 
of Events (Appendix A).
9.5.7
Pregnancy Test
A serum pregnancy test will be performed for women of childbearing potential at Screening, 
Day -1, and the EOS visit in Part A (Appendix A). In Part B, a pregnancy test must also be 
performed for women of childbearing potential at every cycle (typically performed on Day 1 of the 
cycle; however, if a serum pregnancy test is used, this may be performed up to 3 days before 
Day 1), with negative results available before the first dose is administered in that cycle. A 
pregnancy test will also be performed for women of childbearing potential at the 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:
1. Those who have not undergone hysterectomy or bilateral oophorectomy, and 
2. Those who have not had natural menopause (Appendix J) for 12 consecutive months or longer 
(eg, 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).

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9.5.8
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 days (+10 days) after the last dose of study drug(s). See 
Sections 0 and 8.4 for additional details regarding excluded and permitted concomitant 
medications and procedures.
9.5.9
AEs
Monitoring of AEs, serious and nonserious, will be conducted throughout the study as specified in 
the Schedule of Events. Refer to Section 10.0 for details regarding definitions, documentation, and 
reporting of pretreatment events, AEs, and SAEs.
For Part B only, refer to Table 8.a for dose modifications related to AEs. 
9.5.10
Enrollment
Enrollment is achieved when the first dose of any study drug has been administered.
Procedures for completion of the enrollment information are described in the Pharmacy and Study 
Manuals.
9.5.11
Echocardiogram
An echocardiogram will be performed at Screening as indicated in the Schedule of Events 
(Appendix A).
9.5.12
ECG
A 12-lead ECG will be performed as indicated in the Schedule of Events (Appendix A). When the 
timing of ECG assessment coincides with the timing of a blood draw, ECG assessments will be 
completed before the collection of the blood sample unless otherwise noted in the Schedule of 
Events (Appendix A). 
For Part B only, refer to Table 8.a for dose modifications related to cardiotoxicity. 
9.5.13
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.

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9.5.13.1 Clinical Chemistry, Hematology, and Urinalysis
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 Schedule of Events (Appendix A).
Table 9.a
Clinical Chemistry and Hematology Tests
Hematology
Serum Chemistry
Hemoglobin
Hematocrit
Leukocytes with differential
Neutrophils (ANC)
Platelet (count)
ALT
ALP
AST
Bilirubin (total)
Blood urea nitrogen (BUN)
Creatinine
Direct bilirubin
Glucose 
Lactate dehydrogenase (LDH)
Phosphate Albumin
Potassium
Sodium
Urate
Calcium
Chloride
Carbon dioxide (CO2)/Bicarbonate
Magnesium
Part A Screening: 
Activated partial thromboplastin 
time
Coagulation panel (a)
Prothrombin time (PT) international 
normalized ratio (INR)
Part A Screening: 
D-dimer
Fibrinogen
Parts A and B:
Coagulation panel, if applicable (a)
(a) If the initial coagulation screen is positive (ie, results are outside of 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, then no further coagulation studies need to be done.
Table 9.b
Clinical Urinalysis Tests
Urinalysis
Bilirubin
Glucose
Ketones
Leukocytes
Nitrite
Occult blood
Microscopic assessment
pH
Protein
Specific gravity
Turbidity and color
Urobilinogen

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If creatinine clearance 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.
9.5.14
Disease Assessment
CT scans with IV contrast (unless medically contraindicated), or MRI, of the chest, abdomen, and 
pelvis will be performed as entry criteria for Part B. 
CT scans with IV contrast encompassing the known sites of disease will also be performed at the 
end of Cycle 2 and every 3 cycles 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) [6].
9.5.15
PK Measurements
Details regarding the preparation, handling, and shipping of samples are provided in the Study and 
Laboratory Manuals.
9.5.15.1 Blood Sampling
During Part A, blood samples (approximately 3 mL each) for TRA and PK assessments in whole 
blood and plasma will be drawn at the time points specified in Table A (Appendix A). Additional 
blood samples (approximately 5 mL) will be collected at each time point for metabolite profiling in 
plasma. 
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.
To ensure that the measurements are representative of plasma exposure, blood draws will be 
conducted in the arm opposite to a patient’s IV infusion. 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.

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9.5.15.2 Urine and Fecal Sampling
Urine and fecal output will be collected over the 7-day period or until discharge. Urine samples 
will be analyzed for PK, TRA, and biotransformation as specified in Table B (Appendix A), and 
fecal samples will be analyzed for TRA and products of pevonedistat biotransformation as 
specified in Table B (Appendix A). 
9.5.15.3 Vomitus Sampling
For patients who experience emesis during the first 24 hours after drug administration, the vomitus 
will need to be collected as much as possible and assayed for TRA. If a subject vomits more than 
once during the period, vomitus corresponding to each vomiting event will be collected in a 
separate labeled container and separately counted. Refer to the Study Manual for further details. 
9.5.16
DNA Measurements 
9.5.17 Discharge Criteria for Part A
Samples will continue to be collected at 24-hour intervals until radioactivity in urine and feces 
combined is ≤1% per day of the total administered radioactivity for at least 2 consecutive days or 
the excretion of radioactivity is ≥80% of the administered radioactive dose. When radioactivity 
levels have fallen below these thresholds, patients can be discharged from the Part A study site. 
If on Day 7 the criteria for discharge are not met, subjects will be required to remain confined for a 
maximum estimated period of 4 additional days (until Day 11) until the criteria are met (daily 
check by quick counts).
9.5.18
Entry Criteria for Continuation Into Part B
To be eligible for Part B, patients must meet the following entry criteria:
!
ECOG performance status of 0 to 1.
!
Laboratory values for hemoglobin, ANC, platelets, total bilirubin, ALT, AST, ALP, and serum 
creatinine or calculated/measured creatinine clearance as specified in Section 8.6.1.
!
Diarrhea symptoms resolved to Grade 1 or better.
!
QTc interval <500 msec.
!
CT scan or MRI of the chest, abdomen, and pelvis within 28 days of Cycle 1 Day 1.
In addition, patients will require at least a 2-week (may be extended up to 8 weeks) washout period 
after their last dose of [14C]-pevonedistat. For patients to begin dosing in 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 
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to a level considered acceptable by the investigator after discussion with the project clinician or 
designee. If, after a maximum of 8 weeks from the last dose in Part A (eg, up to 8 weeks after the 
Day 1 visit), the predose Cycle 1 Day 1 assessments in Part B have not returned to Part A baseline 
values (or ≤Grade 1), the patient will not be eligible for Part B, and all assessments required for the 
EOS visit should be completed. The predose Cycle 1 Day 1 assessments for Part B do not need to 
be repeated if the Day 24 Part A results confirm that the patient is eligible for dosing in Part B 
AND Cycle 1 Day 1 occurs within 5 days from Part A Day 24; however, the liver function tests 
will need to be repeated within 3 days of Cycle 1 Day 1.
9.6
Completion of Study Treatment (for Individual Patients)
9.6.1
Part A
Patients will be considered to have completed Part A of the study if they have completed the 
protocol-specified assessments to provide data necessary for evaluation of mass balance and PK 
within Part A of the protocol.
9.6.2
Part B
Patients will be considered to have completed Part B of the study if they complete 12 cycles of 
treatment with study drug. 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.
9.7
Completion of Study (for Individual Patients)
9.7.1
Part A
Patients will be considered to have completed Part A of the study if they have completed the 
protocol-specified assessments to provide data necessary for evaluation of mass balance and 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 and vitals), 
laboratory assessments (hematology, chemistry, urinalysis), and 12-lead ECG. The EOS visit will 
be conducted 30 days (+10 days) after the last dose of study drug in Part A. If the EOS visit occurs 
before 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.
9.7.2
Part B
Patients will be considered to have completed Part B of the study if they complete 12 cycles of 
treatment with study drug or if treatment is discontinued for any of the reasons outlined in 
Section 9.8. The EOS visit will be conducted 30 days (+10 days) after the last dose of study drug in 

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Part B. If the EOS visit occurs before 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.
9.8
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.

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 Schedule of Events (Appendix A). The primary reason for study drug 
discontinuation will be recorded on the eCRF. In Part A of the study, patients who are not PK 
evaluable will be replaced. 
Note: In Part B of the study, patients may receive pevonedistat until they experience progressive 
disease (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 by the sponsor.
9.9
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.

Death. 

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
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.
9.10
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 Pretreatment Event Definition
A pretreatment event 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 [7]. 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 pretreatment events (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 of the 2 clinical study sites. A sample of 
the SAE Form may be found in the Study Manual. Follow-up information on the SAE or serious 
pretreatment event may be requested by Takeda. SAE report information must be consistent with 
the data provided on the eCRF.
SAE Reporting Contact Information
Cognizant
All Other Countries (Rest of World)
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 
Personal Protected Data

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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 
pretreatment events, 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 [7]. The criteria are provided in the Study 
Manual.
Relationship of the event to study drug administration (ie, its causality) will be determined by the 
investigator responding yes (related) or no (unrelated) to this question: “Is there a reasonable 
possibility that the AE is associated with the study drug?”
10.3
Monitoring of AEs and Period of Observation
AEs, both nonserious and serious, will be monitored throughout the study as follows: 
AEs will be reported from start of study administration through 30 days (+10 days) after 
administration of the last dose of study drug and recorded in the eCRFs. 
SAEs will be reported as follows:

Serious pretreatment events will be reported to the Takeda Global Pharmacovigilance 
department or designee from the time of the signing of the informed consent form (ICF) up to 
the first dose of study drug.

Related and unrelated treatment-emergent SAEs will be reported to the Takeda Global 
Pharmacovigilance department or designee from the first dose of study drug through 30 days 
(+10 days) after administration of the last dose of study drug and recorded in the eCRF. After 
this period, only related SAEs must be reported to the Takeda Global Pharmacovigilance 
department or designee. SAEs should be monitored until they are resolved or are clearly 
determined to be due to a patient’s stable or chronic condition or intercurrent illness(es).
10.4
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events
If a woman becomes pregnant or suspects that she is pregnant while participating in this study, she 
must inform the investigator immediately and permanently discontinue study drug. The sponsor 
must also be contacted immediately by faxing a completed Pregnancy Form to the Takeda Global 
Pharmacovigilance department or designee (see Section 10.2). The pregnancy must be followed 
for the final pregnancy outcome.
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.

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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 or medication errors in and of themselves are not AEs. If a product complaint 
or a medication error results in an SAE, an SAE form should be completed and sent to Cognizant 
(refer to Section 10.2).
10.6
Safety Reporting to Investigators, IRBs, or IECs and Regulatory Authorities
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
and any other applicable SAEs to regulatory authorities, including the European Medicines 
Agency, investigators, and IRBs or IECs as applicable, in accordance with national regulations in 
the countries where the study is conducted. Relative to the first awareness of the event by/or 
further provision to the sponsor or sponsor’s designee, SUSARs (suspected unexpected serious 
adverse reactions) 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. 
Personally Protected Data

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11.0
STUDY-SPECIFIC COMMITTEES
Safety data will be reviewed and assessed periodically by an internal safety working group 
throughout the conduct of the study. These reviews will include a safety physician, a clinical 
physician from the study team, and other representation from the Clinical Research, 
Pharmacovigilance, Biostatistics, Clinical Pharmacology, Regulatory Affairs, Drug Safety 
Evaluation/Toxicology, and Clinical Operations departments at Takeda. Escalation of safety 
issues to a senior management cross-functional safety board will be performed on an ad hoc basis.
11.1
Sponsor Safety Assessments
Safety data will be reviewed and assessed periodically by an internal safety working group 
throughout the conduct of the study. These reviews will include a safety physician, a clinical 
physician from the study team, and other representation from the Clinical Research, 
Pharmacovigilance, Biostatistics, Clinical Pharmacology, Regulatory Affairs, Drug Safety 
Evaluation/Toxicology, and Clinical Operations departments at Millennium. Escalation of safety 
issues to a senior management cross-functional safety board will be performed on an ad hoc basis.
11.2
Independent Data Monitoring Committee 
An IDMC has been formed to periodically monitor the overall conduct of studies within the 
pevonedistat program, including review of accumulating clinical study data and safety data (both 
clinical and nonclinical) and to make recommendations to Takeda to safeguard the interests of 
study participants. Additionally, the IDMC may make recommendations relating to the 
selection/recruitment/retention of study participants, patient management, improving adherence to 
protocol-specified regimens, and the procedures for data management and quality control. Further 
details regarding the IDMC are located in the IDMC charter.

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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, pretreatment events, 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 the 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, Contact Research 
Organization partners, and regulatory authorities. The 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 sites.
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 sites 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 sites and filed with the original in the subject’s chart 

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to ensure long term legibility. Furthermore, ICH E6 Section 4.9.5 requires the investigator to retain 
essential documents specified in ICH E6 (Section 8) until at least 2 years after the last approval of 
a marketing application for a specified drug indication being investigated or, if an application is 
not approved, until at least 2 years after the investigation is discontinued and regulatory authorities 
are notified. In addition, ICH E6 Section 4.9.5 states that the study records should be retained until 
an amount of time specified by applicable regulatory requirements or for a time specified in the 
Clinical Study Site Agreement between the investigator and sponsor.
Refer to the Clinical Study Site Agreement for the sponsor’s requirements on record retention. The 
investigator should contact and receive written approval from the sponsor before disposing of any 
such documents.

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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: patients who receive at least 1 dose of study drug. The safety population 
will be used for all safety analyses.

PK population: patients who a) receive the protocol-specified single [14C]-pevonedistat dose in 
Part A; b) do not receive any excluded concomitant medications through the completion of 
Part A; and c) have sufficient concentration-time data to permit reliable estimation of PK 
parameters and mass balance.
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 chemotherapy will be based on the best overall response as 
determined by the investigator using RECIST Version 1.1 guidelines (Appendix E) [6]. 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 
The PK analysis will be based on concentrations of pevonedistat. All data will be summarized 
using descriptive statistics and will be listed and summarized in tabular and/or graphical form.
The following PK parameters will be calculated by noncompartmental analysis and tabulated for 
each individual:

TRA in plasma and whole blood: Cmax, tmax, AUClast, and as permitted by data, t1/2z and AUC∞.

TRA in urine: amount of [14C]-radioactivity excreted into urine per sampling interval 
(Aeurine,14
C,t1-t2 in ng-eq and percentage of dose) and cumulative amount of [14C]-radioactivity 
excreted in urine up to the last sampling interval (Aeurine,14
C in ng-eq and percentage of dose).

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
TRA in feces: amount of [14C]-radioactivity excreted into feces per sampling interval (daily 
excretion) (Aefeces,
14
C,t1-t2 in ng-eq and percentage of dose) and cumulative amount of 
[14C]-radioactivity excreted in feces up to the last sampling interval (Aefeces,
14
C in ng-eq and 
percentage of dose).

The total cumulative excretion of [14C]-radioactivity per interval and over the total collection 
period will be calculated as the sum of the cumulative excretion in urine and feces: total 
cumulative excretion of [14C]-radioactivity from the body (Aetotal,
14
C=Aeurine,
14
C+Aefeces,
14
C) (in 
ng-eq and percentage of dose).

Pevonedistat in whole blood and plasma: Cmax, tmax, AUClast, and as permitted by data, t1/2z, 
AUC∞, and clearance.

Pevonedistat in urine (per sampling interval and total): cumulative amount excreted in urine 
(Aeurine and percentage of dose) and CLR.
Additionally, one of the objectives of this study is to collect plasma, urine, and feces for metabolite 
profiling and identification. While the results of the PK of pevonedistat and TRA, time course of 
excretion of TRA in urine and feces, and overall mass balance will be included in the clinical study 
report, the metabolite profiling and identification results will be reported separately.
13.1.5 Safety Analysis
A safety analysis will be conducted separately for Part A and Part B to respectively characterize 
the safety profiles of [14C]-pevonedistat and pevonedistat in combination with chemotherapy. 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).

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
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 
scatter plots of baseline versus worst postbaseline values, may be used to understand the 
pevonedistat safety profile.
The number and percentage of patients experiencing abnormal ECG results will be summarized 
over each time point separately for Part A and for Part B.
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 for this study is not based on statistical considerations. 
On the basis of the ALARA principle (As Low [radioactive burden] As Reasonably Achievable) 
set forth in the 96/29/EURATOM directive, a sample size of 4 to 6 PK-evaluable patients is 
considered sufficient to provide adequate characterization of the mass balance, PK, and 
metabolism of pevonedistat in patients with cancer. Patients will be replaced if they are not 
evaluable for PK.

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14.0
QUALITY CONTROL AND QUALITY ASSURANCE
14.1
Study-Site Monitoring Visits
Monitoring visits to the study sites 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, 
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 sites should document all protocol deviations in the subject’s source documents. In the event 
of a significant deviation, the sites 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. A Protocol Deviation Form should be completed by the sites and signed by the 
sponsor or designee for any significant deviation from the protocol.
14.3
Quality Assurance Audits and Regulatory Agency Inspections
The study sites also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the sites 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 study site used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, including 
those of foreign governments (eg, the US FDA and OGYEI [Hungarian Regulatory Authorities]). 
If the study sites are 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 country 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. 
The sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the IB, a copy of the ICF, and, if 
applicable, subject recruitment materials and/or advertisements, and other documents required by 
all applicable laws and regulations, must be submitted to a central or local IRB or IEC for 
approval. The IRB’s or IEC’s written approval of the protocol and subject informed consent must 
be obtained and submitted to the sponsor or designee before commencement of the study (ie, 
before shipment of the sponsor-supplied drug or study specific screening activity). The IRB or IEC 
approval must refer to the study by exact protocol title, number, and version date; identify versions 
of other documents (eg, ICF) reviewed; and state the approval date. The sponsor will notify the 
study 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 notification (Part A) or drug (Part B), no protocol activities, including 
Screening, may occur.
The 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 and subject information sheet (if applicable) describe the 
planned and permitted uses, transfers, and disclosures of the subject’s personal and personal health 
information for purposes of conducting the study. The ICF and the subject information sheet (if 
applicable) further explain the nature of the study, its objectives, and potential risks and benefits, 
and the date informed consent is given. The ICF will detail the requirements of the participant and 
the fact that he or she is free to withdraw at any time without giving a reason and without prejudice 
to his or her further medical care.
The sponsor is responsible for the preparation, content, and IRB or IEC approval of the ICF. The 
ICF and subject information sheet (if applicable) must be approved by both the IRB or IEC and the 
sponsor before use.
The ICF 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 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 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
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 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 and subject information sheet (if 
applicable) shall be given to the subject.
All revised ICFs must be reviewed and signed by relevant subjects or the relevant subject’s legally 
acceptable representative in the same manner as the original informed consent. The date the 
revised consent was obtained should be recorded in the subject’s medical record, and the subject 
should receive a copy of the revised ICF.

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15.3
Subject Confidentiality
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or date 
of birth, and subject initials may be used to verify the subject and accuracy of the subject’s unique 
identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the sponsor 
requires the investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (eg, FDA, Medicines and Healthcare products Regulatory Agency, 
Pharmaceuticals and Medical Devices Agency), the sponsor’s designated auditors, and the 
appropriate IRBs and IECs to review the subject’s original medical records (source data or 
documents), including, but not limited to, laboratory test result reports, ECG reports, admission 
and discharge summaries for hospital admissions occurring during a subject’s study participation, 
and autopsy reports. Access to a subject’s original medical records requires the specific 
authorization of the subject as part of the informed consent process (see Section 15.2).
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s eCRF).
15.4
Publication, Disclosure, and Clinical Trial Registration Policy
15.4.1 Publication 
The investigator is obliged to provide the sponsor with complete test results and all data derived by 
the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the sponsor.
The sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 
this section and the Clinical Study Site Agreement. In the event of any discrepancy between the 
protocol and the Clinical Study Site Agreement, the Clinical Study Site Agreement will prevail.
15.4.2 Clinical Trial Registration
To ensure that information on clinical trials reaches the public in a timely manner and to comply 
with applicable laws, regulations and guidance, Takeda will, at a minimum register interventional 
clinical trials it sponsors anywhere in the world on ClinicalTrials.gov or other publicly accessible 

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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 the 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. 
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. Bauer T, Harvey R, Lee C, Aggarwal C, Cohen R, Sedarati F, et al. Investigational 
NEDD8-activating enzyme inhibitor pevonedistat plus chemotherapy in patients with solid 
tumors (phase 1b study): Activity of pevonedistat plus carboplatin/paclitaxel. Annual Meeting 
of the American Society of Clinical Oncology (ASCO); June 03-07, 2016; Chicago, IL. 2580.
2. Lockhart A, Bauer T, Harvey R, Lee C, Aggarwal C, Cohen R, et al. Phase 1b trial of 
investigational NEDD8-activating enzyme (NAE) inhibitor pevonedistat 
(TAK-924/MLN4924) in combination with docetaxel, paclitaxel/carboplatin, or gemcitabine 
in patients with solid tumors. AACR-NCI-EORTC Molecular Targets and Cancer 
Therapeutics Conference; November 5-9, 2015; Boston, MA.
3. TAXOTERE (docetaxel) 20 mg/0.5 mL concentrate and solvent for solution for infusion 
[Summary of Product Characteristics]. SmPC. Antony Cedex, France: Aventis Pharma S.A., 
November, 2005.
4. Carboplatin 10 mg/mL concentrate for infusion (Summary of Product Characteristics). SmPC. 
East Sussex, United Kingdom: TEVA UK Limited, 26 April, 2016.
5. ABRAXANE (paclitaxel) 5 mg/mL powder for suspension for infusion [Summary of Product 
Characteristics]. SmPC. Uxbridge, United Kingdom: Celgene Europe Ltd, January 2013.
6. 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.
7. Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03. U.S. Department 
of Health and Human Services National Cancer Institute. 14 June 2010.
8. Crawford J, Caserta C, Roila F, Group EGW. Hematopoietic growth factors: ESMO Clinical 
Practice Guidelines for the applications. Ann Oncol 2010;21 Suppl 5:v248-51.
9. Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and 
response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 
1982;5(6):649-55.
10. CARBOPLATIN - carboplatin injection, solution [package insert]. Princeton, NJ: Sandoz Inc, 
2011.
11. 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.
12. Naughton CA. Drug-induced nephrotoxicity. Am Fam Physician 2008;78(6):743-50.

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13. 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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Appendix A
Schedule of Events
Schedule of Events for Part A (ADME Portion of the Study)
ADME Assessment Period
EOS (c)
Screening (a)
Week 1
Confinement
Week 2
Discharge (b)
Day -1 
Predose
Day 1 
Predose
Day 
1
Day 
2
Day 
3
Day 
4
Day 
5
Day 
6
Day 
7
Between Days 
8 and 14
Confinement (d)
X
X
X
X
X
X
X
X
X
Study Drug Administration
Single [14C]-pevonedistat IV 
solution administration (e)
X
Lactulose (f)
X
Study Procedures
Informed consent
X
Inclusion/exclusion criteria
X
Demographics
X
Medical history/prior 
therapy
X
Full physical examination
X
X
X
Symptom-directed physical 
examination
X
X
Height
X
Weight
X
X (g)
X (g)
X
Vital signs (h)
X
X
X
X
X
ECOG performance status
X
X
X
12-lead ECG (i)
X
X (g)
X (g)
X
X
Echocardiogram
X
Monitoring of concomitant 
medications, therapies, and 
Recorded from start of study administration through 30 days (+10 days) after the last dose of study drug 

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ADME Assessment Period
EOS (c)
Screening (a)
Week 1
Confinement
Week 2
Discharge (b)
Day -1 
Predose
Day 1 
Predose
Day 
1
Day 
2
Day 
3
Day 
4
Day 
5
Day 
6
Day 
7
Between Days 
8 and 14
procedures
AE reporting(j)
Recorded from start of study administration through 30 days (+10 days) after the last dose of study drug 
SAEs will be reported from signing of the ICF through 30 days (+10 days) after the last dose of study drug.
Samples/Laboratory Assessments
Pregnancy test
X
X (g)
X
Hematology/
chemistry (k) (l)
X
X (g)
X (g)
X
X
X
Urinalysis (m)
X
X (g)
X (g)
X
X
Blood sample collection
See Table A, Part A for Blood Sampling Collection Schedule
Urine sample collection
See Table B, Part A for Urine Collection Sample Schedule
Fecal sample collection
See Table B, Part A for Fecal Collection Sample Schedule
Vomitus 
Collect vomitus if event occurs during first 24 hours after dosing and collect at any other vomiting events afterward
Buccal swabs for DNA 
analysis (optional)
X2
X2=2 samples will be collected.
(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.
(b) Discharge criteria for Part A can be found in Section 9.5.17. Patients can be discharged any time between Days 8 and 14. The discharge assessments are done only once on the day 
of discharge.
(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) During Part A, patients will be required to stay at the Part A study site for approximately 8 days or until the discharge criteria are met, with a maximum estimated confinement 
period of 9-14 days.
(e) Patients will receive a single dose of pevonedistat 25 mg/m2 (equivalent to approximately 43 mg for a typical individual of 1.73 m2 BSA up to a maximum absolute dose of 50 mg) 
given as a 1-hour IV infusion on Day 1. The clinic will be supplied with vials containing approximately 60-98 µCi (approximately 2.22-3.626 MBq) of [14C]-pevonedistat as the 
radioactive tracer.
(f) To ensure defecation before release from the Part A study site, two 15 mL doses of oral lactulose will be administered, separated by approximately 2 hours, on the evening of Day 
4; the second dose of lactulose will be withheld if the first dose was not tolerated. Lactulose may also be administered as needed.
(g) 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, with the 

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exception of an ECG that must be repeated predose on Day 1. 
(h) 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. All vital signs are measured with the patient in the sitting position. 
When the timing of vital signs assessment coincides with the timing of a blood draw, vital signs will be measured before blood sample collection.
(i) A 12-lead ECG will be performed during Screening and before administration (within 3 hours) of pevonedistat on Day 1 and immediately after the pevonedistat infusion is 
complete (±20 min) on Day 1. When the timing of ECG measurements coincides with the timing of a blood draw, the ECG will be completed before the blood sample collection, with 
the exception of the end-of-infusion PK sample, which should be collected before the ECG is completed.
(j) Including serious pretreatment events; see Section 10.1.1.
(k) Hematology samples will be collected during Screening and before dosing with study drug on Day 1. These 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, samples will be taken on Day 1 predose and postdose, at the time of discharge, 
and at the EOS visit.
(l) Clinical chemistry samples will be collected during Screening, before dosing with study drug, and 3 hours (30 min) after completion of the pevonedistat infusion. Predose samples 
can be drawn within 24 hours predose. If dosing falls on a Monday, the collection window may be extended to collect samples on the previous Friday. In addition, samples will be 
taken on Day 1 predose and postdose, at the time of discharge, and at the EOS visit.
(m) Urinalysis samples (with microscopic analysis) will be analyzed at the Part A study site’s local laboratory.

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Table A
Blood Sampling Schedule (Part A, ADME)
Study Day
Time Point (hour)
Whole Blood Sample 
Collection
Plasma Sample 
Collection
Matrix
Blood 1 (a)
Blood 2 (a)
Plasma 1 (b)
Plasma 2 (b)
Plasma 3 (b)
Day 1
Predose(c)
X2
X3
Day 1
EOI (d) (5 to 1 min)
X2
X3
Day 1
0.5 hour postinfusion (e) (±5 min)
X2
X3
Day 1
1 hour postinfusion (e) (15 min)
X2
X3
Day 1
2 hours postinfusion (e) (15 min)
X2
X3
Day 1
3 hours postinfusion (e) (30 min)
X2
X3
Day 1
4 hours postinfusion (e) (45 min)
X2
X3
Day 1
8 hours postinfusion (e) (1 hour)
X2
X3
Day 1
12 hours postinfusion (e) (1 hour)
X2
X3
Day 2
24 hours postdose (f) (1 hour)
X2
X3
Day 3
48 hours postdose (f) (2 hours)
X2
X3
Day 4
72 hours postdose (f) (3 hours)
X2
X3
Day 5
96 hours postdose (f) (4 hours)
X2
X3
Day 6
120 hours postdose (f) (4 hours)
X2
X3
Day 7
144 hours postdose (f) (4 hours)
X2
X3
Day 8
168 hours postdose (f) (4 hours)
X2
X3
EOI=end of infusion, X2=2 samples will be collected, X3=3 samples will be collected.
(a) For determination of TRA (Blood 1) and pevonedistat (Blood 2).
(b) For determination of TRA (Plasma 1), pevonedistat (Plasma 2), and metabolite profiling (Plasma 3).
(c) The sample is to be collected within 1 hour before the start of pevonedistat infusion on Day 1.
(d) 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.
(e) Samples are to be collected after completion of pevonedistat IV infusion on Day 1.
(f) Samples are to be collected after initiation of the pevonedistat IV infusion on Day 1. 

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Table B
Urine and Fecal Sample Schedule (Part A, ADME)
Study Day
Time Interval (hour) (a)
Urine Sample 
Collection
Feces Sample Collection
Matrix
Urine 1, Urine 2 (b)
Fecal (c)
Day -1
0 (predose)
X2
X
Day 1
0-6 hours
X2
X (0-24 hours)
Day 1
6-12 hours
X2
Day 2
12-24 hours
X2
Day 3
24-48 hours
X2
X
Day 4
48-72 hours
X2
X
Day 5
72-96 hours
X2
X
Day 6
96-120 hours
X2
X
Day 7
120-144 hours
X2
X
Day 8
144-168 hours (d)
X2
X
X=1 sample collected, X2=2 samples will be collected.
(a) Sampling times are relative to the initiation of the IV infusion on Day 1.
(b) For determination of TRA and metabolite profiling (Urine 1); pevonedistat (Urine 2).
(c) For determination of TRA and metabolite profiling (Feces).
(d) Samples will continue to be collected at 24-hour intervals until radioactivity in urine and feces combined is ≤1% 
per day of the total administered radioactivity per day for at least 2 consecutive days or the excretion of radioactivity is 
≥80% of the administered radioactive dose. When radioactivity levels have fallen below these thresholds, patients can 
be discharged from the Part A study site.

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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).
Schedule of Events for Optional Continued Treatment With Pevonedistat+Chemotherapy (Part B) (All Cycles)
Pevonedistat+Chemotherapy Treatment
21-Day Cycle
EOS/
Early Termination (b)
Day 1 
Predose (a)
Day 1
Day 3
Day 5
Day 8
Study Drug Administration
Chemotherapy administration (c)
X
Pevonedistat administration (c)
X
X
X
Study Procedures
Inclusion/exclusion criteria
X
Full physical examination 
X
X
Symptom-directed physical 
examination
X
X
X
X
ECOG performance status
X (d)
X (d)
X
X
Weight
X
X
Vital signs (e)
X
X
X
X
X
12-Lead ECG (f)
X
X
Tumor assessments (g)
To be completed before dosing in Part B, end of Cycle 2, and every 3 cycles 
thereafter 
X
Monitoring of concomitant 
medications, therapies, and 
procedures
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 reporting (h)
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 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

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Pevonedistat+Chemotherapy Treatment
21-Day Cycle
EOS/
Early Termination (b)
Day 1 
Predose (a)
Day 1
Day 3
Day 5
Day 8
Samples/Laboratory Assessments
Pregnancy test (i)
X
X
Hematology/chemistry (j) (k) 
X
X (k)
X
X
X
X
Urinalysis (l)
X
X
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 9.5.18). 
(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) If ECOG performance status is measured at Screening, it does not need to be repeated on Day 1 predose and Day 1. Only 1 ECOG measurement is needed on Day 1 predose and 
Day 1.
(e) 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. All vital signs are measured with the patient in the sitting position. When the timing of vital signs assessment coincides with the timing of a blood draw, vital signs will be 
measured before blood sample collection. 
(f) A 12-lead ECG will be performed on Day 1 before administration (within 3 hours) of the chemotherapy regimen and immediately after the infusion of pevonedistat is complete 
(±10 min). When the timing of ECG measurements coincides with the timing of a blood draw, the ECG will be completed before the collection of the blood sample, with the exception 
of the end of infusion PK sample, which should be taken before the ECG is completed.
(g) Radiological evaluations (CT scan or MRI) of the chest, abdomen, and pelvis 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. 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.
(h) Including serious pretreatment events in Part A; see Section 10.1.1.
(i) A pregnancy test must also be performed for women of childbearing potential at every cycle (typically performed on Day 1 of the cycle; however, if a serum pregnancy test is used, 
this may be performed up to 3 days before Day 1) with negative results available before the first dose is administered in that cycle. A pregnancy test will also be performed for women 
of childbearing potential at the EOS/Early Termination visit. Pregnancy tests may also be repeated during the study if requested by an IEC/IRB or if required by local regulations.
(j) 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. On dosing days, samples can 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, samples will be taken on Day 8 and at 
the EOS visit. 

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(k) 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. If dosing falls on a Monday, the collection window may be extended to collect samples on the previous Friday. On Cycle 1 Day 1, an additional 
sample will be taken 3 hours (±30mins) after the completion of the pevonedistat infusion. In addition, samples will be taken on Day 8 and at the EOS visit. 
(l) Urinalysis samples (with microscopic analysis) will be analyzed at the Part A study site’s local laboratory.

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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:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff who will assist in the protocol.
3. Ensure that study related procedures, including study specific (nonroutine/nonstandard panel) 
screening assessments are NOT performed on potential subjects, before the receipt of written 
approval from relevant governing bodies/authorities.
4. Ensure that all colleagues and employees assisting in the conduct of the study are informed of 
these obligations.
5. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform to 
ICH, and local regulatory requirements.
6. 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.
7. Ensure that requirements for informed consent, as outlined in ICH and local regulations, are 
met.
8. 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.
9. 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.
10. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.

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11. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor.
12. 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 [9]. 

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Appendix E
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 one or more nontarget lesion(s) or/and maintenance of tumor marker level above the 
normal limits.
PD
Appearance of one or more new lesions and/or unequivocal progression of existing nontarget lesions.
Source: Eisenhauer, et al, 2009 [6]. 
SD=stable disease.
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 [6]. 
SD=stable disease.

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Appendix F
Excluded CYP3A Inhibitors and Inducers
Note that HIV medications that are strong or moderate CYP3A inhibitors or inducers are not 
included in this list because HIV-positive patients are excluded from study participation.
Classification of CYP3A Inhibitors 
Use of moderate and strong CYP3A inhibitors listed in the table below should be avoided during 
pevonedistat therapy. The moderate CYP3A inhibitor amiodarone has a long t1/2 (mean of 
58 days); consequently, amiodarone must be discontinued 6 months before the first dose of 
pevonedistat. 
In Vivo Inhibitors of CYP3A
Strong (a)
Moderate (a)
5-fold increase in AUC
2-fold, but <5-fold Increase in AUC
Clarithromycin
Amiodarone
Itraconazole
Aprepitant
Ketoconazole
Diltiazem
Nefazodone
Erythromycin
Voriconazole
Ciprofloxacin
Posaconazole
Cimetidine
Telithromycin
Fluconazole
Conivaptan
Verapamil
Tofisopam
Dronedarone
Isavuconazole
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.
(a) Azole antifungal agents are CYP3A inhibitors and are excluded during Part A of the study. During Part B of the 
study, if the patient’s clinical condition requires the use of an azole antifungal agent, the patient may receive 
voriconazole and fluconazole 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), Friday (Day 5) 
schedule, an azole may be administered (if clinically necessary and no suitable alternative) from the Saturday after the 
Day 5 dose (Day 6) up to the Friday (Day 19) before the Monday dose of the next cycle.

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Classification of CYP3A Inducers
Use of the CYP3A inducers listed in the table below should be avoided during pevonedistat 
therapy.
In Vivo Inducers of CYP3A
Strong Inducers
≥80% Decrease in AUC
Moderate Inducers
50%-80% Decrease in AUC
Carbamazepine
Bosentan
Phenytoin
Efavirenz
Phenobarbital
Modafinil
Primidone
Nafcillin
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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Appendix G
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 [10]. 
NCIC CTG=National Cancer Institute of Canada Clinical Trials Group, SWOG=Southwest Oncology Group. 
In a randomized clinical trial, 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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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
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 [11]. 
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.
The symbol “--” denotes “not defined”.
(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; 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.

Pevonedistat (MLN4924; TAK-924)
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Protocol 
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CONFIDENTIAL
Appendix H
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 aristocholic 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 [12].

Pevonedistat (MLN4924; TAK-924)
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Protocol 
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CONFIDENTIAL
Appendix I
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 [13]. 

Pevonedistat (MLN4924; TAK-924)
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Appendix J
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. Please refer to 
the following source for additional information: European Heads of Medicines Agencies Clinical 
Trial Facilitation Group; see 
hma.eu/fileadmin/dateien/Human_Medicines/01-About_HMA/Working_Groups/CTFG/2014_09
_HMA_ CTFG_Contraception.pdf

Pevonedistat (MLN4924; TAK-924)
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Page 103 of 103
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Appendix K
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:

Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulationa:
–
Oral.
–
Intravaginal.
–
Transdermal.

Progestogen-only hormonal contraception associated with inhibition of ovulationa:
–
Oral.
–
Injectable.
–
Implantable.b

Intrauterine device.b

Intrauterine hormone-releasing system.b

Bilateral tubal occlusion.b

Vasectomised 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:

Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mode of action.

Male or female condom with or without spermicide.e

Cap, diaphragm, or sponge with spermicide.e
a Hormonal contraception may be susceptible to interaction with the investigational medicinal product, which may 
reduce the efficacy of the contraception method.
b Contraception methods that in the context of this guidance are considered to have low user dependency.
c Vasectomised partner is a highly effective birth control method provided that partner is the sole sexual partner of the 
woman of childbearing potential participant of the study and that the vasectomised partner has received medical 
assessment of the surgical success.
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 trial 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) are 
also considered acceptable, but not highly effective, birth control methods.

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