Clinical trial NCT02699749
Conditions: Nonhematologic Neoplasms, Advanced
Keywords: Drug Therapy
Sponsor: Millennium Pharmaceuticals, Inc.
Start date: 2016-03-24; Completion date: 2019-12-21
Enrollment: 80 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics (PK), and maximum tolerated dose (MTD) of TAK-931 in participants with advanced nonhematologic tumors.

Detailed description:
The drug being under investigation in this study is called TAK-931. The effect of TAK-931 is being evaluated in up to 100 participants who have nonhematologic (solid) neoplasms. This study will look at the safety, tolerability, and PK to determine the maximum tolerated dose (MTD) of TAK-931.

This multi-center trial will be conducted in Japan. The overall study duration is approximately 42 months for total of dose escalation cohorts and the safety expansion cohort. Participants will make multiple visits to the clinic with final visit approximately 30-40 days after last dose of study drug for a follow-up assessment.

Arms: arm 1: TAK-931 30 mg, capsules, orally, QD or BID on Days 1-14 of each 21-day treatment cycle in dosing schedule A followed by dosing schedule B, C, D, E and F. In dosing schedules B through F, starting doses and dosing escalations will vary depending on the dosing data obtained from dosing in the previous schedule.

Dose escalation of TAK-931 will be based on evaluation of clinical safety and tolerability and guided by accumulating PK data. 3-4 dose cohorts are expected for each dosing schedule.

If the PK from the early cohorts support BID dosing, then study drug administration in subsequent cohorts may transition to a BID dosing schedule.
Interventions: intervention 1: TAK-931
Intervention descriptions: intervention 1: TAK-931 oral capsules.

Protocol documents:
Prot_001.pdf: 
Title: An Open-Label, Phase 1, Dose-Escalation Study to Evaluate the Safety, Tolerability, 
and Pharmacokinetics of TAK-931, a Cell Division Cycle 7 (CDC7) Inhibitor, in Adult 
Patients With Advanced Nonhematologic Tumors 
NCT Number: NCT02699749 
Protocol Approve Date: 23-FEB-2018 
Certain information within this protocol has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable 
information or company confidential information. 
This may include, but is not limited to, redaction of the following: 

Named persons or organizations associated with the study.

Patient identifiers within the text, tables, or figures or in by-patient data listings.

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.
If needed, certain appendices that contain a large volume of personally identifiable 
information or company confidential information may be removed in their entirety if it 
is considered that they do not add substantially to the interpretation of the data (eg, 
appendix of investigator’s curriculum vitae). 


 
 
CONFIDENTIAL
PROTOCOL AMENDMENT
An Open-Label, Phase 1, Dose-Escalation Study to Evaluate the Safety, Tolerability, and 
Pharmacokinetics of TAK-931, a Cell Division Cycle 7 (CDC7) Inhibitor, in Adult Patients With 
Advanced Nonhematologic Tumors
Sponsor:
Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda 
Pharmaceutical Company Limited
40 Landsdowne 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:
TAK-931-1002
IND Number:
127,126
EudraCT Number:
Not Applicable
Compound:
TAK-931
Date:
23 February 2018
Amendment Number:
04
Date
Amendment Number
Amendment Type
Region
02 November 2015
Initial Protocol
Not applicable
Global
26 January 2016
01
Substantial
Global
30 June 2016
02
Substantial
Global
12 December 2016
03
Substantial
Global
23 February 2018
04
Substantial
Global
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement by 
the recipient that no information contained herein will be published or disclosed without written authorization from 
Takeda except to the extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. Furthermore, the information is only meant for review and compliance by the recipient, his or her staff, 
and applicable institutional review committee and regulatory agencies to enable conduct of the study.
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1.0
ADMINISTRATIVE 
1.1
Contacts 
A separate contact information list will be provided to each site.
Serious adverse event and pregnancy reporting information is presented in Section 11.0, as is 
information on reporting product complaints. 
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site. Information on service providers is given in Section 3.1 and relevant guidelines 
provided to the site.
Contact Type/Role
Contact
Serious adverse event and pregnancy reporting
See Section 11.0
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1.2
Approval 
REPRESENTATIVES OF TAKEDA 
This study will be conducted with the highest respect for the individual participants in accordance 
with the requirements of this clinical study protocol and also in accordance with the following:
!
The ethical principles that have their origin in the Declaration of Helsinki.
!
International 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.
Property of Takeda: For non-c
and subject to the applicable Terms of Use
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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 11.0 of this 
protocol.

Terms outlined in the Clinical Study Site Agreement.

Appendix B, Responsibilities of the investigator.
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix C of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Province)
Location of Facility (Country)
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!
Minor grammatical, editorial, formatting, and administrative changes not affecting the conduct 
of the study are included for clarification and administrative purposes only. For specific 
descriptions of text changes and where the changes are located, see Appendix H. 
Changes in Amendment 04
1. Added Dosing Schedules E and F. 
2. Modified schedule for skin punch 
 biopsies.
3. Clarified method of calculation for the TAK-931 accumulation ratio.
4. Updated nonclinical data. 
5. Added appendix of clinically significant strong metabolic enzyme inducers. 
6. Revised criteria for beginning or delaying a subsequent treatment cycle. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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TABLE OF CONTENTS
1.0
ADMINISTRATIVE.......................................................................................................2
1.1
Contacts.................................................................................................................... 2
1.2
Approval............................................................................................................... ....3
1.3
Rationale for Amendment 04 ..................................................................... . . ..........5
2.0
STUDY SUMMARY ................................................................................... .. ............12
3.0
STUDY REFERENCE INFORMATION ................................................ .. ..................17
3.1
Study-Related Responsibilities......................................................... .......................17
3.2
Principal Investigator/Coordinating Investigator .................... .. ..............................17
3.3
List of Abbreviations ......................................................... .. ..................................18
3.4
Corporate Identification............................................... ... .......................................20
4.0
INTRODUCTION........................................................ . ..............................................21
4.1
Background ...................................................... ... ..................................................21
4.1.1
Nonclinical Experience ............................ . .......................................................21
4.1.2
Risks and Benefits............................... ..............................................................24
4.2
Rationale for the Proposed Study............ ................................................................25
5.0
STUDY OBJECTIVES ..................... ..........................................................................26
5.1
Primary Objectives .................. ...............................................................................26
5.2
Secondary Objectives...............................................................................................26
6.0
STUDY ENDPOINTS... ...............................................................................................27
6.1
Primary Endpoints ...................................................................................................27
6.2
Secondary Endpoints ...............................................................................................27
6.3
Additional Endpoints............................................................................27
7.0
STUDY DESIGN..........................................................................................................28
7.1
Overview of Study Design.......................................................................................28
7.2
Number of Patients ..................................................................................................34
7.3
Duration of Study ....................................................................................................34
8.0
STUDY POPULATION................................................................................................35
8.1
Inclusion Criteria .....................................................................................................35
8.2
Exclusion Criteria ....................................................................................................36
9.0
STUDY DRUG .............................................................................................................39
9.1
Study Drug Administration......................................................................................39
9.2
Definitions of Dose-Limiting Toxicity.....................................................................39
Property of Takeda: For 
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9.3
Dose Escalation Rules..............................................................................................40
9.4
Dose Modification Guidelines..................................................................................43
9.4.1
Intrapatient Dose Escalation...............................................................................43
9.4.2
Criteria for Beginning or Delaying a Subsequent Treatment Cycle................ .. 43
9.4.3
Criteria for Treatment Interruption and Dose Reduction............................ . ......43
9.4.4
Criteria for Discontinuation of TAK-931.............................................. .. .........45
9.5
Management of Specific Adverse Events.............................................. . ................46
9.5.1
Hematologic Toxicities .............................................................. .......................46
9.5.2
Gastrointestinal Adverse Events........................................... . ...........................47
9.5.3
Hepatobiliary Disorders .....................................................................................48
9.5.4
Cardiac Toxicities ................................................... .... ....................................48
9.5.5
Hypotension........................................................ . ............................................48
9.6
Excluded Concomitant Medications and Procedures ...............................................50
9.7
Permitted Concomitant Medications and Procedures................................................51
9.8
Precautions and Restrictions ....................... ............................................................51
9.8.1
Pregnancy and Contraception........ . ................................................................51
9.8.2
Females Who are Lactating or Breastfeeding......................................................52
9.8.3
Patients with Prior Exposure to Hepatitis B or Hepatitis C .................................52
9.8.4
Photosensitivity............. ... ...............................................................................52
9.9
Blinding and Unblinding... ......................................................................................53
9.10
Description of Investigational Agents ......................................................................53
9.11
Preparation, Reconstitution, and Dispensation..........................................................53
9.12
Packaging and Labeling...........................................................................................53
9.13
Storage, Handling, and Accountability.....................................................................53
9.14
Other Protocol-Specified Materials ..........................................................................54
10.0
STUDY CONDUCT......................................................................................................55
10.1
Study Personnel and Organizations..........................................................................55
10.2
Arrangements for Recruitment of Patients................................................................55
10 3
Treatment Group Assignments.................................................................................55
10.4
Study Procedures.....................................................................................................55
10.4.1 Informed Consent...............................................................................................55
10.4.2 Patient Demographics ........................................................................................55
10.4.3 Medical History .................................................................................................56
10.4.4 Physical Examination.........................................................................................56
10.4.5 Patient Height and Weight .................................................................................56
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10.4.6 Vital Signs .........................................................................................................56
10.4.7 Pregnancy Test...................................................................................................56
10.4.8 Concomitant Medications and Procedures..........................................................56
10.4.9 Adverse Events ............................................................................................. .. 57
10.4.10
Enrollment........................................................................................... . ......57
10.4.11
Electrocardiogram........................................................................... .. .........57
10.4.12
Eastern Cooperative Oncology Group Performance Status......... . ................57
10.4.13
Echocardiogram or Multiple Gated Acquisition Scan............ .......................57
10.4.14
Clinical Laboratory Evaluations...................................... . ...........................57
10.4.15
Skin Punch Biopsies .....................................................................................59
10.4.18
Disease Assessment ................................... ..................................................60
10.4.19
Pharmacokinetic Measurements.............. ....................................................60
10.4.21
Sample Retention..................... . ................................................................61
10.5
Completion of Treatment .................. . ....................................................................61
10.6
Completion of Study................. .. ..........................................................................61
10.7
Discontinuation of Treatment With Study Drug and Patient Replacement................61
10.8
Withdrawal of Patients From Study .........................................................................62
10.9
Study Compliance...... . ..........................................................................................62
10.10 Post-treatment Follow-up Assessments (Progression-Free Survival) ........................63
11.0
ADVERSE EVENTS ....................................................................................................64
11.1
Definitions. .. ..........................................................................................................64
11.1.1 Pretreatment Event Definition............................................................................64
11.1.2 Adverse Event Definition...................................................................................64
11.1.3 Serious Adverse Event Definition ......................................................................64
11.2
Procedures for Recording and Reporting Adverse Events and Serious 
Adverse Events........................................................................................................65
11.3
Monitoring of Adverse Events and Period of Observation........................................66
11.4
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities...........66
11.5
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events.........67
11.6
Procedures for Reporting Product Complaints..........................................................67
12.0
STUDY-SPECIFIC COMMITTEES .............................................................................68
13.0
DATA HANDLING AND RECORDKEEPING............................................................69
Property of Takeda: For non-commercial use only
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13.1
Electronic Case Report Forms..................................................................................69
13.2
Record Retention .....................................................................................................69
14.0
STATISTICAL METHODS..........................................................................................71
14.1
Statistical and Analytical Plans ........................................................................... .. 71
14.1.1 Populations for Analysis ........................................................................... . ......71
14.1.2 Procedures for Handling Missing, Unused, and Spurious Data ............. .. .........71
14.1.3 Analysis of Demographics and Other Baseline Characteristics........ . ................72
14.1.4 Pharmacokinetic Analysis .......................................................... .......................72
14.1.5 Safety Analysis .................................................................... . ...........................72
14.1.6 Efficacy Analysis...............................................................................................73
14.1.7 Pharmacodynamic Analysis ......................................... ....................................74
14.2
Interim Analysis and Criteria for Early Termination ...............................................74
14.3
Determination of Sample Size........................ ... ....................................................74
15.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................80
15.1
Study-Site Monitoring Visits .............. . ................................................................80
15.2
Protocol Deviations........................... . ....................................................................80
15.3
Quality Assurance Audits and Regulatory Agency Inspections ................................81
16.0
ETHICAL ASPECTS OF THE STUDY........................................................................82
16.1
IRB and/or IEC Approval . ......................................................................................82
16.2
Subject Information, Informed Consent, and Subject Authorization .........................83
16.3
Subject Confidentiality ............................................................................................84
16.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................84
16.4.1 Publication and Disclosure.................................................................................84
16.4.2 Clinical Trial Registration..................................................................................85
16.4.3 Clinical Trial Results Disclosure ........................................................................85
16.5
Insurance and Compensation for Injury....................................................................85
17.0
REFERENCES..............................................................................................................86
LIST OF IN-TEXT TABLES
Table 9.a
Dose Modification Recommendations for TAK-931 Toxicities ..........................45
Table 9.b
TAK-931 Dose Adjustments for Hematologic Toxicities....................................47
Table 9.c
Contraceptive Methods ......................................................................................52
Table 10.a
Clinical Chemistry and Hematology Tests..........................................................58
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to the applicable Terms of Use
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Table 10.b
Clinical Urinalysis Tests ....................................................................................58
Table 14.a
An Example of Possible Dose Escalation With Accelerated and Modified 
Fibonacci Escalation ..........................................................................................76
Table 14.b
Dose Escalation Simulation Study of the Probability of Dose-Limiting Toxicity
..........................................................................................................................77
Table 14.c
Operating Characteristics for Bayesian Logistic Regression Modeling Dose 
Escalation Rule ................................................................................. .. ............78
Table 14.d
Hypothetical Dose Escalation Step............................................... .. ..................78
LIST OF IN-TEXT FIGURES
Figure 4.a
Proof-of-Concept Studies Showing Antitumor Activity of TAK-931..................23
Figure 7.a 
Overview of Study Design (Cycle 1)................... . ...........................................32
LIST OF APPENDICES
Appendix A
Schedule of Events.............................................................................................88
Appendix B
Responsibilities of the Investigator...................................................................127
Appendix C
Investigator Consent to Use of Personal Information........................................129
Appendix D
Eastern Cooperative Oncology Group (ECOG) Scale for Performance Status...130
Appendix E
Cockcroft-Gault Equation ................................................................................131
Appendix F
New York Heart Association Classification of Cardiac Disease........................132
Appendix G
Clinically Significant Strong Metabolic Enzyme Inducers................................133
Appendix H
Detailed Description of Amendments to Text...................................................134
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2.0
STUDY SUMMARY
Name of Sponsor:
Millennium Pharmaceuticals, Inc
Compound:
TAK-931
Title of Protocol: 
An Open-Label, Phase 1, Dose-Escalation Study to 
Evaluate the Safety, Tolerability, and Pharmacokinetics of 
TAK-931, a Cell Division Cycle 7 (CDC7) Inhibitor, in 
Adult Patients With Advanced Nonhematologic Tumors
IND No.: 
127,126
EudraCT No.: 
Not Applicable
Study Number: TAK-931-1002 
Phase: 1
Study Design:
This is a phase 1, open-label, dose-escalation study designed to evaluate the safety, tolerability, and pharmacokinetics 
(PK), and to determine the maximum tolerated dose (MTD) or a maximum tested dose of TAK-931, a CDC7 inhibitor, 
in adult patients with histologically confirmed, nonhematologic (solid) tumors. 
Eligibility will be determined during the screening period, which may last for up to 28 days before the Cycle 1, Day 1 
(C1D1) visit. Patients who meet all eligibility criteria and provide written informed consent will be enrolled in this 
study. 
Up to 4 schedules of TAK-931 will be tested in this study:
1.
Dosing Schedule A: TAK-931 administered once daily (QD) (or twice daily [BID]) for 14 consecutive days 
followed by 7 days of rest in a 21-day cycle.
2.
Dosing Schedule B: TAK-931 administered QD (or BID) for 7 consecutive days followed by another 7 days of 
rest and repeated for a 28-day cycle. 
3.
Dosing Schedule C: TAK-931 administered QD (or BID) for 7 consecutive days followed by 14 days of rest for a 
21-day cycle.
4.
Dosing Schedule D: TAK-931 will be administered QD (or BID) continuously in a 21-day cycle.
5.
Dosing Schedule E: TAK-931 will be administered QD (or BID) for 2 consecutive days followed by 5 days of rest 
and repeated weekly for a 21-day cycle.
6.
Dosing Schedule F: TAK-931 will be administered QD (or BID) for 1 day followed by 6 days of rest and repeated 
weekly for a 21-day cycle.
Subsequent cohorts may transition to a BID dosing schedule (by dividing the daily dose in 2) if Cmax-related AEs are 
observed, or if it is recommended by the potential pharmacodynamic effect. 
Patient assignment to a specific schedule will be decided jointly by the investigator and sponsor with the aim of 
maximizing enrollment efficiency in the study. 
Approximately 100 patients will be enrolled into this study. A minimum of 3 patients will be enrolled in each cohort to 
support safety and PK-guided dose escalation. Once the MTD is determined, a safety expansion cohort of up to 16 
patients may be initiated, including patients treated at the same dose during doses escalation, for all or some of the 
schedules, to better define the safety and tolerability of TAK-931 and to help in the selection of the schedule(s) for 
further development. The decision of whether to expand a specific schedule will be jointly considered by the 
investigators and the sponsor and based on the feasibility of the schedule to be further developed.
Study drug may be discontinued early if a patient experiences study drug-related toxicities, if a patient requires 
prolonged treatment interruption to recover from toxicity, or if the toxicity recurs upon retreatment. Patients will 
attend the End-of-Treatment (EOT) visit 30 to 40 days after receiving their last dose of study drug or before initiating 
new anticancer therapy (whichever comes first). Patients who discontinue study drug treatment for reasons other than 
progressive disease (PD) will undergo computed tomography/magnetic resonance imaging (CT/MRI) scans every 
12 weeks from EOT until the occurrence of PD, the start of subsequent antineoplastic therapy, or until 6 months after 
the discontinuation of study treatment, whichever occurs first.
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 are collected between 4 to 9 hours after study drug administration (simultaneously if possible).
If skin biopsy 
 is taken on a non-PK sampling day, sparse PK plasma samples should be collected at 
predose, 1 to 3 hours postdose, and 4 to 9 hours postdose on the day of biopsy. The exact dosing, biopsy, and PK 
sampling date and times will be recorded.
Toxicity will be evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI CTCAE), Version 4.03, effective date 14 June 2010. 
Primary Objectives:
!
To evaluate the safety and tolerability of TAK-931. 
!
To identify the MTD or maximum tested dose of TAK-931 in adult patients with nonhematologic tumors.
Secondary Objectives:
!
To characterize the PK of TAK-931 in adult patients with nonhematologic tumors.
!
To assess the pharmacodynamic effect of TAK-931 by measuring basal and postdose levels of phosphorylated 
MCM2 (Ser40), a CDC7 substrate, in skin.
!
To assess preliminary clinical activity of TAK-931.
Subject Population: Adult patients (≥20 years old) with advanced nonhematologic tumors.
Number of Subjects: 
Approximately 100 patients
Number of Sites: 
Approximately 2 to 4 sites in Japan
Dose Levels:
TAK-931:
Schedule A: Starting at 30 mg QD (or BID) for 14 
consecutive days followed by 7 days of rest in a 21-day
cycle.
Schedule B: Starting at 60 mg QD (or BID) for 7 
consecutive days followed by 7 days of rest and repeated in 
a 28-day cycle.
Schedule C: Maximum administered dose in Schedule B 
administered QD (or BID) for 7 consecutive days and 
followed by 14 days of rest in a 21-day cycle.
Schedule D: Starting at 20 mg QD (or BID) continuously in
a 21-day cycle.
Schedule E: Starting at 100 mg QD (or BID), on Day 1 and 
Day 2 every week in a 21-day cycle.
Schedule F: Dose will be determined based on outcome of 
Schedule E. QD (or BID) on Day 1 every week and repeated 
in a 21-day cycle. 
Route of Administration:
TAK-931: oral
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Duration of Treatment:
Patients will receive study drug until disease progression, 
unacceptable toxicity, withdrawal of consent, death, or 
termination of the study by the sponsor.
Period of Evaluation:
Patients will be followed for safety for approximately 
30 days after their last dose of study drug. Patients will 
be followed for PFS for 6 months after the 
discontinuation of study treatment at maximum
It is anticipated that this study will last for 
approximately 3.5 years.
Main Criteria for Inclusion:
Adult male or female patients who are ≥20 years old with histologically confirmed, advanced nonhematologic tumors 
for which no effective standard treatment is available. Eligible patients must have adequate bone marrow reserve and 
renal and hepatic function based on minimum laboratory criteria, adequate cardiac function, Eastern Cooperative 
Oncology Group (ECOG) performance of 0 or 1, and a life expectancy of ≥3 months. In addition, patients must have 
recovered from all toxic effects of previous therapy, have suitable venous access for the collection of blood samples, 
and be willing to undergo serial skin punch biopsies.
Main Criteria for Exclusion:
Patients who have seizures requiring antiepileptic treatment, symptomatic and/or progressive central nervous system 
(CNS) metastases, ongoing medical conditions (such as acute exacerbations of chronic illnesses, serious infections, or 
major surgery within 4 weeks before receiving the first dose of study drug), uncontrolled comorbidities such as cardiac 
or blood pressure conditions that might compromise the patient’s participation in the study will be excluded. In 
addition, patients who are treated with proton pump inhibitors (PPIs) or clinically significant enzyme inducers, and 
women who are either breastfeeding or pregnant will be excluded.
Main Criteria for Evaluation and Analyses:
The primary endpoints of the study are the number and percentage of patients with treatment-emergent adverse events 
(TEAEs) and first-cycle DLTs. The secondary endpoints are: PK parameters after the first dose of TAK-931 on C1D1, 
PK parameters after administration of multiple doses of TAK-931 on C1D7, C1D8 or C1D9, the change from baseline 
of pMCM2 (Ser40) levels in skin after administration of multiple doses of TAK-931, overall response rate (ORR), 
progression-free survival (PFS), and duration of response (DOR).
Statistical Considerations:
The primary endpoints of the study are the number and percentage of patients with TEAEs and first-cycle DLTs. An 
adaptive BLRM that implements escalation with overdose control will be used in this study for purposes of dose 
escalation recommendations and estimation of the MTD from the second dose cohort for Dosing Schedule A, B, C, E, 
and F. The 2-parameter model will be used and updated after each group of patients enrolled in the current dose level 
cohort. For each dose level, the posterior probability of having DLT rates that fall into the following intervals will be 
estimated:

[0, 0.16): under-dosing.

[0.16, 0 33): target toxicity.

[0.33, 1.00]: excessive toxicity.
The selection of the next recommended dose will be determined from BLRM along with PK guidance and safety data 
evaluation.
The secondary endpoints include PK parameters after the first dose of TAK-931 on C1D1 and after multiple doses of 
TAK-931 on C1D7, C1D8 or C1D9, including Cmax, time to first occurrence of maximum (peak) concentration (tmax), 
and the area under the plasma concentration-time curve (AUC) from time 0 to 24 hours (AUC24) for QD dosing (or 
AUC12 for BID dosing), and AUC from time 0 to the time of the last quantifiable concentration (AUClast). TAK-931 
accumulation ratio (Rac(AUC)) on C1D7, C1D8 or C1D9, apparent oral clearance (CL/F), and renal clearance (CLr) will 
be estimated for TAK-931. The change from baseline of phosphorylated MCM2 (Ser40) levels in skin will be 
summarized by dose levels. The efficacy parameters ORR, PFS, and DOR will also be summarized by dose levels.
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Sample Size Justification: 
It is anticipated that approximately 100 patients will be enrolled in this study including up to 6 dosing schedules and 
expansion cohort. For Dosing Schedules A, B, C, E, and F, a group of 3 patients will be enrolled in a TAK-931 dose 
cohort each time based on an adaptive design using BLRM with safety data evaluation and PK guidance. Each subject 
will participate in only 1 dose cohort. The total number of subjects to be enrolled is dependent upon the observed 
safety profile and PK guidance, which will determine the number of subjects per dose cohort, as well as the number of 
dose escalations required to achieve the MTD. From the simulation provided in Section 14.3, approximately 
33 patients will be enrolled for up to 9 dose escalation cohorts in Dosing Schedule A. Based on the clinical safety, PK 
and pharmacodynamic information available as of 13 November 2016, the sample size for Dosing Schedule A is 
estimated to be approximately 25 patients including the 4 dose escalation cohorts and safety expansion cohort. During 
dose escalation phase, approximately 18 patients will be enrolled in up to 4 dose cohorts for Dosing Schedule B, 
approximately 15 patients will be enrolled in up to 3 dose cohorts for Dosing Schedule C, approximately 16 patients 
will be enrolled in up to 4 dose cohorts for Dosing Schedule E, and approximately 12 patients will be enrolled in up to 
3 dose cohorts for Dosing Schedule F. The assumption may change based on the observed clinical safety profile. Once 
the MTD is determined, a safety expansion cohort of up to 16 patients (including patients treated at the same doses 
during dose escalation) may be initiated for all or some of the schedules. Additionally, approximately 25 patients will 
be enrolled in up to 3 dose cohorts for Dosing Schedule D. Dosing Schedule D is not guided by BLRM for dose 
escalation. It is anticipated that approximately 100 patients will be enrolled in this study. 
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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 or equivalent. 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/Coordinating Investigator 
Takeda will select a signatory coordinating investigator from the investigators who participate in 
the study. Selection criteria for this investigator will include significant knowledge of the study 
protocol, the study medication, their expertise in the therapeutic area and the conduct of clinical 
research as well as study participation. The signatory coordinating investigator will be required to 
review and sign the clinical study report and by doing so agrees that it accurately describes the 
results of the study.
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3.3
List of Abbreviations
5-HT3
5-hydroxytryptamine (serotonin) type 3
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
ATP
adenosine triphosphate
AUC
area under the plasma concentration-time curve
AUC12
area under the plasma concentration-time curve from the time 0 to 12 hours
AUC24
area under the plasma concentration-time curve from the time 0 to 24 hours
AUClast
area under the plasma concentration-time curve from time 0 to the time of the last 
quantifiable concentration
BCRP
breast cancer resistance protein
BID
twice daily
BLRM
Bayesian Logistic Regression Modeling
BNP
B-type natriuretic peptide
BUN
blood urea nitrogen
CDC7
cell division cycle 7
CIN
chromosome-instability
CL/F
apparent oral clearance
CLr
renal clearance
Cmax
maximum observed plasma concentration
CNS
central nervous system
CR
complete response
eCRF
case report form (electronic or paper)
CRO
contract research organization
CSR
clinical study report
CT
computed tomography
CXDX
Cycle X, Day X
CYP
cytochrome P-450
DDI
drug-drug interaction
DDR
DNA damage response
DI
dose intensity
DLBCL
diffuse large B cell lymphoma
DLT
dose-limiting toxicity
DNA
deoxyribonucleic acid
DOR
duration of response
ECHO
echocardiogram
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EF
ejection fraction
Property of Takeda: For n
-commercial use only and subject to the applicable Terms of Use
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0 to 12 h
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d plasm
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system
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clinical stu
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compu
LBCL
LBCL
DLT
DLT
DN
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EOT
end of treatment
EWOC
escalation with overdose control
FDA
Food and Drug Administration
FFPE
formalin-fixed, paraffin-embedded
GCP
Good Clinical Practice
GGT
∀-glutamyl transferase
GI
gastrointestinal
GLP
Good Laboratory Practice
H2
histamine-2 (receptor)
Hb
hemoglobin
HBV
hepatitis B virus
HBcAb
hepatitis B core antibody
HCV
hepatitis C virus
HCVAb
anti-hepatitis C antibody
HDPE
high-density polyethylene
HIV
human immunodeficiency virus
IB
investigator’s brochure
IC50
the concentration producing 50% inhibition
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IHC
immunohistochemistry
IP
intraperitoneal
IRB
institutional review board
JSH
Japan Society of Hepatology
LDH
lactate dehydrogenase
LVEF
left ventricular ejection fraction
MCM2
minichromosome maintenance complex-2
MedDRA
Medical Dictionary for Regulatory Activities
MIN
microsatellite-instability
MRI
magnetic resonance imaging
MSI
microsatellite instability
MSS
microsatellite stability
MTD
maximum tolerated dose
MUGA
NA
multiple gated acquisition scan
nucleoside antagonist
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NSAIDs
nonsteroidal anti-inflammatory drugs 
NT-proBNP
N-terminal pro-brain natriuretic peptide
ORR
overall response rate
PD
progressive disease (disease progression)
pMCM2
phosphorylation of minichromosome maintenance complex-2
Property of Takeda: For non-com
ial use only and subject to the applicable Terms of Use
hibition
bition
armonisa
rmon
ttee
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ew bo
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Hep
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GA
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NA
NA
NCI C
NCI
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PFS
progression-free survival
P-gp
P-glycoprotein
PK
pharmacokinetics
PO
per os (orally)
POTS
postural orthostatic tachycardia syndrome
PPI
proton pump inhibitor
PR
partial response
PTE
pretreatment event
QD
once daily
Rac(AUC)
accumulation ratio based on AUC
RECIST
Response Evaluation Criteria in Solid Tumors
RP2D
recommended Phase 2 dose(s) 
SAE
serious adverse event
SAP
statistical analysis plan
SOP
standard operating procedures
STD10
severely toxic dose in 10% of animals administered test article
SUSAR
suspected unexpected serious adverse reactions
TEAE
treatment-emergent adverse event
TK
toxicokinetic
tmax
time to first occurrence of maximum (peak) concentration
ULN
upper limit of normal
UDPGA
uridine-5’-diphosphateglucuronic acid
Vss
volume of distribution at steady state
WHO
World Health Organization
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
TAK-931 is a highly potent and selective inhibitor of the cell division cycle 7 (CDC7) kinase. 
CDC7 is a serine/threonine kinase that contributes to initiation of deoxyribonucleic acid (DNA) 
replication by phosphorylating the minichromosome maintenance 2 (MCM2) complex [1,2]. 
Kinase activity of CDC7 is controlled by its binding protein DBF4 in a cell-cycle dependent 
manner [3]. Recent studies revealed that CDC7 is also involved in DNA damage response (DDR) 
as well as DNA replication, suggesting that CDC7 plays important roles in both cell proliferation 
during the S phase and genomic stability in DDR [4-7].
Furthermore, elevated CDC7 expression has been reported in various cancers and correlates with 
poor prognosis, such as in diffuse large B-cell lymphoma (DLBCL), oral squamous carcinoma, 
and breast, colon, colorectal, ovarian, and lung tumors [8-12]. However, it is not clear to what 
extent this increased expression reflects proliferative potential [13].
In vitro inhibition of the CDC7/DBF4 kinase complex arrests cell proliferation and induces 
apoptosis in cancer cell lines [14]. The major reason why the inhibition of the CDC7/DBF4 kinase 
complex is highly relevant for cancer is that activation of diverse oncogenes and loss of some 
tumor suppressors evoke replication stress and consequent DNA damage that triggers the 
checkpoint responses of specific signaling cascades, as demonstrated in cell culture experiments 
and in analyses of clinical specimens from a range of human malignancies [15,16]. Taken together, 
these data suggest that development of CDC7 kinase inhibitors present a novel class of molecular 
targets for cancer therapy [17].
Given that CDC7 is responsible for 2 key functions of DNA replication and DDR, CDC7 appears 
to be a critical gene for proliferation and survival of cancer cells, and inhibition of CDC7 is 
expected to be antiproliferative and induce apoptosis in a broad range of cancers. Based on its dual 
mechanism of action, CDC7 inhibitors may also produce clinically meaningful efficacy both as 
single agents and in combination with other DNA damaging agents. 
4.1.1
Nonclinical Experience
In vitro and in vivo pharmacology studies indicate that TAK-931 is a highly potent and selective 
inhibitor of CDC7 kinase with a concentration producing 50% inhibition (IC50) of less than 
0.3 nM. Time-dependent inhibition assays in the presence of high and low adenosine
5’-triphosphate (ATP) concentrations revealed that TAK-931 is an ATP-competitive inhibitor 
with slow-binding kinetics to CDC7 kinase. The specificity of TAK-931 was evaluated at 1 M 
against a panel of 308 kinases. Of the 308 kinases, TAK-931 at 1 M inhibited 10 kinases by 80% 
or more. The IC50 values for the 10 kinases: DAPK3, DAPK1, CDK9/Cyclin T1, DMPK, 
CDK8/Cyclin C, MAPK12, STK17A, CLK4, DYRK1A, and GSK3B ranged from 36.9 to 
338 nM. TAK-931 exhibited >120-fold selectivity for CDC7 kinase inhibition compared with the 
other kinases in this panel study demonstrating that TAK-931 is a highly potent and selective 
inhibitor of CDC7 kinase.
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Figure 4.a
Proof-of-Concept Studies Showing Antitumor Activity of TAK-931
Abbreviations: T/C=treatment-to-control; PDX=patient-derived xenograft.
The pharmacokinetic (PK) and pharmacodynamic response of TAK-931 was evaluated after a 
single PO administration of 10, 20, 40, 60, and 80 mg/kg to female BALB/c nude mice bearing 
COLO205 human colorectal adenocarcinoma xenografts. Plasma and tumor samples were 
obtained and analyzed for TAK-931 concentrations and derived PK parameters. Phosphorylated 
MCM2 at Ser40, which CDC7 kinase phosphorylates directly, was used as a target-engagement 
pharmacodynamic marker. Pharmacodynamic analysis was performed using Western blot and 
immunohistochemistry (IHC). The plasma and tumor exposures of TAK-931 are increased in an 
approximately dose-proportional manner in female BALB/c nude mice bearing COLO205 
xenografts. Both Western blot and IHC analysis detected modulations of the pharmacodynamic 
biomarker pMCM2 in a dose- and time-dependent manner in this xenograft model. Furthermore, 
antitumor activity and duration of saturated pMCM2 suppression in tumor was well-correlated in 
nude mouse bearing COLO205 xenografts. These results indicate the potential utility of pMCM2 
as clinical pharmacodynamic biomarkers to evaluate the pharmacodynamic response of TAK-931.
TAK-931 exposure after a single PO administration demonstrated the compound is rapidly 
absorbed in vivo, with 35.1% and 21.6% oral bioavailability in Sprague-Dawley rats and beagle 
dogs, respectively. After a single intravenous dose, TAK-931 demonstrated high plasma clearance 
in rats (3260 mL) and dogs (2630 mL/hr/kg), and high volume of distribution at steady state (Vss) 
in both species (rats: 2460 mL/kg; dogs: 3060 mL/kg). Both rats and dogs exhibited nonlinear oral 
PK.
Additionally, there were no pronounced sex-related differences in plasma concentrations or 
derived toxicokinetic (TK) parameters of TAK-931 (anhydrous) in Good Laboratory Practice 
(GLP)-compliant toxicity studies in Sprague-Dawley rats and beagle dogs; all GLP-compliant TK 
data were obtained with validated assays. TAK-931 exhibited nonlinear oral TK in rats and dogs 
Property of Takeda: For non-commercial use only and 
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with single-dose maximum (peak) concentration (Cmax) and area under the plasma 
concentration-time curve (AUC) from time 0 to 24 hours (AUC24) increasing in a greater than 
dose-proportional manner with a higher dose. No accumulation of TAK-931 was observed in 
either species.
TAK-931 has high permeability and is a substrate for breast cancer resistance protein (BCRP), but 
is not likely a substrate for P-glycoprotein (P-gp) based on transcellular transport investigations 
across Caco-2 cell monolayers. Additionally, TAK-931 may have a weak inhibitory effect on 
P-gpmediated efflux activity (IC50>100 M). The drug-drug interaction (DDI) potential of 
TAK-931 with P-gp substrates and inhibitors is low.
In an in vitro study, the plasma protein binding was 59% to 62% in mice, 73% to 74% in rats, 57% 
to 58% in dogs, and 73% to 74% in humans, with no concentration dependency observed from 
0.01 to 1 g/mL.
The in vitro oxidative metabolism of TAK-931 was evaluated using liver microsomes from CD-1 
mice, Sprague-Dawley rats, beagle dogs, cynomolgus monkeys, and humans. TAK-931 was 
metabolized primarily to the unidentified metabolite UK-1 and, to a lesser extent, UK-2. There 
was no metabolite unique to human liver microsomes through oxidative metabolism.
Evaluation of the in vitro metabolism of TAK-931 in the presence of uridine-5’-
diphosphateglucuronic acid (UDPGA) showed the compound is metabolized through 
glucuronidation by liver microsomes from all species except dogs.
Investigations into cytochrome P450 enzyme (CYP)-mediated metabolism showed that CYP2D6 
and CYP3A are the main CYPs involved in the metabolism of TAK-931. There is a DDI potential 
with UDP-glucuronosyltransferase inducers; however, the DDI potential with CYP inhibitors, 
while involved in metabolism, is unlikely. TAK-931 is unlikely to cause DDIs as a perpetrator 
with concomitant medications metabolized via CYP isozymes at Cmax values <800 ng/mL. 
Details on these studies are provided in the TAK-931 investigator’s brochure (IB).
4.1.2
Risks and Benefits
The TK profile and systemic toxic potential of TAK-931 have been well-defined in 
Sprague-Dawley rats and beagle dogs.
The primary dose-limiting toxicities (DLTs), particularly in the dog, appear to be associated with 
Cmax and are closely associated with the cardiovascular changes observed. The effects on blood 
pressure and heart rate were dose-dependent and clearly related to compound concentration in 
plasma. The mechanism is likely related to the off-target pharmacological effects of TAK-931. 
The effects of TAK-931 on heart rate and blood pressure have been confirmed to be monitorable 
and reversible upon clearance of TAK-931. In addition, renal injury (obstructive nephropathy) was 
confirmed to be a DLT in rats, although similar changes were not observed in dogs. Renal effects 
of TAK-931 were monitored with clinical and urine chemistry, and renal tubular damage is 
considered reversible.
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The target organ toxicities after the repeated dosing of TAK-931 were largely similar in rats and 
dogs and generally consistent with inhibition of CDC7 activity, with test article-related findings in 
the hematopoietic and lymphoid systems, gastrointestinal mucosa, and reproductive organs. 
Decreased white blood cells or single cell necrosis in the gastrointestinal mucosa appeared from 
lower dose with minimal degree and its severity increased with increment of dose level. All target 
organ toxicities observed in the repeated-dose studies were generally monitorable and reversible, 
except for the effect on the germ cells.
On the basis of these results, the toxicology studies conducted with TAK-931 support the proposed 
clinical program in adult patients with advanced malignancies. The nonclinical toxicology profile 
demonstrated target organ toxicity that was generally reversible and monitorable. The primary 
toxicity (Cmax-related) was cardiovascular effects (decreased blood pressure with reflex 
tachycardia). The DLTs with total exposure were effects on the gastrointestinal mucosa and 
lymphoid systems consistent with pharmacology-mediated CDC7 inhibition. The severely toxic 
dose in 10% of animals administered test article (STD10) in rats was 180 mg/m2 (15 mg/kg twice 
daily [BID]) and the highest nonseverely toxic dose (HNSTD) in dogs was 80 mg/m2 (2 mg/kg 
BID). Dogs tolerated one-tenth of the rat STD10. Therefore, the safe starting dose for the proposed 
open-label, dose escalation, in this study is 18 mg/m2 daily, which is one-tenth of the STD10 in 
rodents. The proposed starting dose of TAK-931 is 30 mg daily, assuming a human body weight of 
60 kg.
During this study, risk mitigation strategies include, but are not limited to, strict application of the 
study inclusion and exclusion criteria, frequent monitoring of clinical and laboratory results, 
guidelines for management and prophylaxis of potential toxicities, criteria for dose modification, 
and regular monitoring of treatment-emergent adverse events (TEAEs) and serious adverse events 
(SAEs) by the sponsor.
Further details are presented in the TAK-931 IB.
4.2
Rationale for the Proposed Study
This is a first-in-human study designed to determine a safe and tolerated dose and schedule for 
TAK-931 in patients with nonhematologic tumors that can effectively inhibit the activity of CDC7 
in tissue, as measured by inhibition of the phosphorylation of MCM2 (which is a target substrate of 
the CDC7/DBF4 complex) in skin biopsies [6].
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5.0
STUDY OBJECTIVES
5.1
Primary Objectives
The primary objectives are:
!
To evaluate the safety and tolerability of TAK-931. 
!
To identify the MTD or maximum tested dose of TAK-931 in adult patients with 
nonhematologic tumors.
5.2
Secondary Objectives
The secondary objectives are:
!
To characterize the PK of TAK-931 in adult patients with nonhematologic tumors.
!
To assess the pharmacodynamic effect of TAK-931 by measuring basal and postdose levels of 
phosphorylated MCM2 (Ser40), a CDC7 substrate, in skin.
!
To assess preliminary clinical activity of TAK-931.
Property of Takeda: For non
 and subject to the applicable Terms of Use
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6.0
STUDY ENDPOINTS
6.1
Primary Endpoints
The primary endpoints are:
!
The number and percentage of patients with first cycle DLTs.
!
The number and percentage of patients with TEAEs.
6.2
Secondary Endpoints
The secondary endpoints are:
!
PK parameters after the first dose of TAK-931 on Cycle 1, Day 1(C1D1): Cmax, time to first 
occurrence of maximum (peak) concentration (tmax), AUC24 (or AUC from time 0 to 12 hours 
[AUC12] for BID dosing on C1D1), and AUC from time 0 to the time of the last quantifiable 
concentration (AUClast).
!
PK parameters after administration of multiple doses of TAK-931 (C1D7, C1D8, or C1D9): 
Cmax, tmax, AUC24 (or AUC12 for BID dosing), and AUClast.
!
The change from baseline of phosphorylated MCM2 (Ser40) levels in skin after administration 
of multiple doses of TAK-931.
!
Overall response rate (ORR) (complete response [CR] + partial response [PR]) as measured by 
Response Evaluation Criteria in Solid Tumors (RECIST) guidelines (version 1.1).
!
Progression-free survival (PFS).
!
Duration of response (DOR)
6.3
Additional Endpoints 
The additional endpoint is:
!
TAK-931 accumulation ratio (Rac(AUC)) on C1D7, C1D8 or C1D9, apparent oral clearance 
(CL/F) and renal clearance (CLr) of TAK-931. 
Property 
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ommercial use only and subject to the applicable Terms of Use
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7.0
STUDY DESIGN
7.1
Overview of Study Design
This is a phase 1, open-label, dose-escalation study designed to evaluate the safety, tolerability, 
and PK and to determine the MTD or a maximum tested dose of TAK-931, a CDC7 inhibitor, in 
adult patients with histologically confirmed, nonhematologic (solid) tumors. Dose escalation of 
TAK-931 will be cohort based with an adaptive design using Bayesian Logistic Regression 
Modeling (BLRM) with PK guidance (except for Dosing Schedule D). 
Eligibility will be determined during the screening period, which may last for up to 28 days before 
the C1D1 visit. Patients who meet all eligibility criteria and provide written informed consent will 
be enrolled in this study. 
TAK-931 initially will be administered once daily (QD) for 14 days of each 21-day treatment cycle 
(Dosing Schedule A). The starting dose will be 30 mg. Subsequent cohorts may transition to a BID 
dosing schedule (by dividing the daily dose in 2) if Cmax-related AEs are observed, or if it is 
recommended by potential pharmacodynamic effect in a cohort during escalation.
Up to 3 additional schedules will be tested after implementation of Amendment 03:

Dosing Schedule B: TAK-931 will be administered QD or BID for 7 consecutive days 
followed by another 7 days of rest and repeated (ie, 7 days on and 7 days off treatment), for a 
cycle duration of 28 days. The starting dose of 60 mg QD was the maximum administered dose 
in Schedule A (2 out of 3 patients presented a DLT). Schedule B is less dose-intense than 
Schedule A: 14-day dosing over 28-day cycles versus 14-day dosing over 21-day cycles. Dose 
escalation will be governed using the same BLRM method with PK guidance as described in 
Section 9.3.

Dosing Schedule C: Dosing Schedule C derives from Dosing Schedule B. TAK-931 will be 
administered QD or BID for 7 consecutive days followed by 14-day rest period in 21-day 
cycles. If, during the dose escalation of Schedule B, it is not possible to dose patients in the 
second half of Cycle 1 (Day 15 onwards) due to AEs not meeting DLT category, it may be 
decided to continue the escalation using Dosing Schedule C. The starting dose for this schedule 
will be the maximum administered dose in Schedule B. Dose escalation will be governed using 
the same BLRM method with PK guidance as described in Section 9.3.

Dosing Schedule D: Schedule D will be implemented in parallel with Schedules A and B. 
Initially, TAK-931 will be administered at 20 mg QD continuously in cycles of 21 days. 
Further adjustment of the continuous TAK-931 dose may be possible in this schedule 
depending on the observed safety, PK, antitumor activity and pMCM2 inhibition.
Up to 2 additional schedules will be tested after implementation of Amendment 04:

Dosing Schedule E: TAK-931 will be administered QD for 2 consecutive days followed by 
another 5 days of rest and repeated weekly (2 days on and 5 days off), for a cycle duration of 
21 days. The starting dose will be 100 mg QD, the current maximum administered dose in 
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Schedule B. Schedule E is less dose-intense than Schedule B. Change from QD to BID (ie,
splitting total daily dose) will be decided primarily if there are Cmax-related TEAEs with QD 
administration during dose escalation. Changing from QD to BID is allowed for any given
patient during treatment if clinically indicated. This decision can be extended to current or 
future patients receiving QD dosing. Dose escalation from dose level 2 onwards will be 
governed using the same BLRM method with PK guidance as described in Section 9.3.

Dosing Schedule F: The decision to implement Schedule F will be determined based on the 
safety, tolerability, PK, and pharmacodynamics of Schedule E. TAK-931 will be administered 
QD or BID on Day 1 every week (1 day “on” and 6 days “off” treatment) in a 21-day treatment 
cycle. The starting dose will be determined based on data of Schedule E. The dose intensity 
(DI) of starting dose in Schedule F will not exceed that of the maximum administered dose in 
Schedule E. Dose escalation will be governed using the same BLRM method with PK 
guidance as described in Section 9.3. If Schedule E safety data suggest a once-weekly dosing 
schedule may allow higher dose escalation it may be decided to continue the escalation using 
Dosing Schedule F. 
Patient assignment to a specific schedule will be decided jointly by the investigator and sponsor 
with the aim of maximizing enrollment efficiency in the study.
Approximately 100 patients will be enrolled into this study in up to 6 dosing schedules. A 
minimum of 3 patients will be enrolled in each cohort to support safety and PK-guided dose 
escalation. Once the MTD is determined, a safety expansion cohort of up to 16 patients may be 
initiated, including patients treated at the same doses during dose escalation, for all or some of the 
schedules, to better define the safety and tolerability of TAK-931 and to help in the selection of the 
schedule(s) for further development. The decision of whether to expand a specific schedule will be 
jointly considered by the investigators and the sponsor and based on the feasibility of the schedule 
to be further developed. Once MTD is determined, inpatient monitoring is not necessary and 
patients enrolled in the safety expansion cohort will be managed with modified Schedule of Events
in Cycle 1 as specified in Appendix A.
Study drug may be discontinued early if a patient experiences study drug-related toxicities, if a 
patient requires prolonged treatment interruption to recover from toxicity, or if the toxicity recurs 
upon retreatment. Patients will attend the End-of-Treatment (EOT) visit 30 to 40 days after 
receiving their last dose of study drug or before initiating new anticancer therapy (whichever 
comes first). Patients who discontinue study drug treatment for reasons other than PD will undergo 
computed tomography (CT)/magnetic resonance imaging (MRI) scans every 12 weeks from EOT 
until the occurrence of PD, the start of subsequent antineoplastic therapy, or until 6 months after 
the discontinuation of study treatment, whichever occurs first.
To ensure patient safety and to minimize the number of patients exposed to nonefficacious doses, 
the dose escalation in Schedule A will consist of an initial accelerated escalation phase in which 
dose levels are increased by 100%. The accelerated escalation phase will transition to modified 
Fibonacci escalation steps after 1 patient experiences a DLT in Cycle 1 or when 2 patients 
experience Grade ≥2 hematologic or nonhematologic, related or possibly related, drug toxicity 
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(see Section 9.2) or when geometric mean plasma Cmax for the cohort reaches or exceeds 
800 ng/mL. For Schedules B, C, D, E, and F, accelerated escalation is not applicable. The dose 
escalation steps will be modified, as needed, based on clinical safety and PK results. The 
escalation steps for Schedules A, B, C, E, and F may also be modified based on accumulating PK 
data and BLRM that would provide narrower escalation steps and potentially decrease the number 
of patients exposed to doses above the MTD. In Schedule D, BLRM will not be applied  Clinical 
safety, PK, and pharmacodynamic information will be used to make escalation (or de-escalation) 
decisions.
There will be a minimum 1-week interval between C1D1 of the first patient dosed and C1D1 of the 
second patient dosed for each dose escalation cohort for Schedules A, B, and C. Subsequent 
patient dosing (third patient per cohort and beyond) may occur at a shorter interval (eg, <7 days 
from previous patient’s C1D1 dosing) but no more than 1 patient will undergo C1D1 dosing within 
a 1-day period. These intervals are not applicable to patients enrolled in Schedule D, to cases of 
dose de-escalation and to patients enrolled in the safety expansion cohorts. For Schedules E and F,
it is necessary to wait at least 24 hours from the last dose administered in the first week of 
treatment of the first patient to C1D1 of the second and third patients dosed in each escalation 
cohort.
Vital signs, physical examinations, adverse event (AE) assessments, laboratory values (chemistry, 
hematology, and urinalysis as specified in Section 10.4), and 12-lead electrocardiograms (ECGs) 
will be obtained to evaluate the safety and tolerability of TAK-931. There are specific Schedules
of Events for each dosing schedule to be tested in this study. Patients will have their blood pressure 
and heart rhythm monitored starting on their first day of dosing (C1D1) and during dosing days in 
Cycle 1 inpatient observation (see Section 10.4.6 and Schedule of Events). Patients enrolled in
Schedule D will not have intensive heart rate and blood pressure monitoring during Cycle 1 
although they will be hospitalized for the duration of Cycle 1. Baseline blood pressure will be 
determined for each individual patient during the screening period, calculated as the median value 
of at least 3 separate measurements. Each patient’s cardiac function will be assessed by either 
echocardiogram (ECHO) or multiple gated acquisition scan (MUGA) at the screening visit and on 
the first day of Cycle 2 (C2D1). Additional assessments during the study will include measurement 
of cardiac enzymes in serum that are predictive of acute injury (eg, troponin I or T) and chronic or 
progressive failure (eg, B-type natriuretic peptide [BNP] or N-terminal pro-brain natriuretic 
peptide [NT proBNP]). 
Serial blood samples for determination of the plasma concentration of TAK-931 
 
will be obtained during Cycle 1 at prespecified time points as described in the 
respective Schedule of Events. 
pMCM2 (Ser40) will be detected semiquantitatively by immunohistochemistry of histologic 
sections of formalin-fixed, paraffin-embedded (FFPE) skin 
 biopsies. The finding of 
inhibition of pMCM2 (Ser40) in the on-treatment specimen compared with the pretreatment 
specimen will demonstrate that TAK-931 is reaching and affecting the target in surrogate tissue 
 at the tested dose. This information may be used to refine the dose escalation steps 
and to define a future recommended Phase 2 dose(s) (RP2D). 
 
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Dosing Schedule F (once weekly; 21-day cycle)
Other time points for biopsy collection (for example in Cycle 1 
Week 3 or outside Cycle 1) can be agreed with the sponsor.
Abbreviation: PD, pharmacodynamic.
(a) A bar shows the predose sampling point for biopsies. A dotted box shows the postdose sampling point for biopsies 
with sampling window (after completion of 3 consecutive dosing days)
(b) A bar shows the series PK sampling (see Table Ga to Table Ge,f). If skin
biopsy is taken on a non-series 
PK sampling day, sparse PK plasma sample should be collected at predose, at 1 to 3 hours postdose, and at 4 to 
9 hours postdose on the day of biopsy (dotted box).
Toxicity will be evaluated according to National Cancer Institute Common Terminology Criteria 
for Adverse Events (NCI CTCAE), Version 4 03, effective date 14 June 2010 [20]. DLTs are 
defined in Section 9.2.
7.2
Number of Patients
Approximately 100 patients will be enrolled in this study from approximately 2 to 4 study centers 
in Japan. Enrollment is defined as when the written informed consent has been obtained and the 
subject’s eligibility has been confirmed per the inclusion and exclusion criteria. 
7.3
Duration of Study
Patients will receive TAK-931 until they experience disease progression, unacceptable toxicity, 
withdrawal of consent, death, or termination of the study by the sponsor (Section 10.7). Patients 
will be followed for 30 days after the last dose of study drug or until the start of subsequent 
alternative anticancer therapy to permit the detection of any delayed AEs. Patients who 
discontinue study treatment for reasons other than PD will continue PFS follow-up every 12 weeks 
from EOT until the occurrence of PD, the start of subsequent antineoplastic therapy, or until 
6 months after the discontinuation of study treatment, whichever occurs first. 
It is anticipated that this study will last for approximately 3.5 months per cohort and 3.5 months for 
the safety expansion cohort or 42 months for dose escalation and the safety expansion cohorts 
(approximately 3.5 years).
21-Day Cycle
Study Drug Administration
1
8
15
21
PD Biopsies (a)
PK Sampling (b)
Day
Dose
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ows the po
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8.0
STUDY POPULATION
8.1
Inclusion Criteria
Each patient must meet all of the following inclusion criteria to be enrolled in the study:
1. Male or female patients 20 years or older.
2. Histologically confirmed diagnosis of an advanced, nonhematologic/solid tumor (with the 
exception of primary brain tumor).
3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (refer to 
Appendix D).
4. Patients for whom no effective standard therapy is available. 
5. Life expectancy of 3 months.
6. Female patients who:

Are postmenopausal (natural amenorrhea and not due to other medical reasons) for at least 
1 year before the screening visit, OR

Are surgically sterile, OR

If they are of childbearing potential, agree to practice 2 effective methods of contraception, 
at the same time, from the time of signing the informed consent through 30 days 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] and withdrawal are not acceptable methods of contraception.)
Male patients, even if surgically sterilized (eg, status postvasectomy), who:

Agree to practice effective barrier contraception during the entire study treatment period 
and through 120 days 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] and withdrawal are not acceptable methods of 
contraception.)

Agree not to donate sperm during this study and for 120 days after receiving their last dose 
of study drug.
7. 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.
8. Ability to swallow oral medications, willingness to undergo serial skin punch biopsies, and 
suitable venous access for the study-required PK and pharmacodynamic sampling.
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9. Clinical laboratory values as specified below within 28 days before the first dose of study drug:

Bone marrow reserve consistent with absolute neutrophil count (ANC) ≥1500/mm3, 
platelet count ≥100,000/mm3, and hemoglobin ≥9 g/dL.

Total bilirubin must be 1.5 times the upper limit of normal (ULN).

Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) must be 3ULN. 
AST and ALT may be elevated up to 5 times the ULN if their elevation can be reasonably 
ascribed to the presence of hepatocellular carcinoma, biliary tract cancer, or metastatic 
disease in liver.

Serum albumin 3.0 g/dL.

Serum creatinine 1.5 times the institutional ULN or creatinine clearance based on the 
Cockcroft-Gault estimate 50 mL/minute for patients with serum creatinine 
concentrations above institutional limits (refer to Appendix E). 
10. Left ventricular ejection fraction (LVEF) >50% as measured by ECHO or MUGA within 
4 weeks before receiving the first dose of study drug.
11. Recovered (Grade 1 toxicity) from the reversible effects of prior anticancer therapy. Patients 
with ongoing toxicities at baseline may be eligible; however, any Grade 2 baseline toxicity 
(except for alopecia) should be discussed with the medical monitor.
8.2
Exclusion Criteria
Patients meeting any of the following exclusion criteria are not to be enrolled in the study.
1. Patients who require continuous use of proton pump inhibitors (PPIs) or histamine-2 (H2)
receptor antagonists and patients who are taking PPIs within 5 days before the first dose of 
study drug.
2. Treatment with clinically significant enzyme inducers (see Appendix G) within 14 days before 
the first dose of study drug.
3. Treatment with any investigational products within 30 days before the first dose of study drug.
4. Female patients who are lactating and breastfeeding or have a positive serum pregnancy test 
during the screening period or a positive urine pregnancy test on Day 1 before the first dose of 
study drug.
5. Any serious medical or psychiatric illness that could, in the investigator’s opinion, potentially 
interfere with the completion of treatment according to this protocol.
6. History of any of the following within the last 3 months before administration of the first dose 
of study drug:

Ischemic myocardial event including angina requiring therapy and artery revascularization 
procedures, myocardial infarction, and unstable symptomatic ischemic heart disease. 
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
Ischemic cerebrovascular event, including transient ischemic attack and artery 
revascularization procedures.

Thromboembolic events (eg, deep vein thrombosis, pulmonary embolism, or symptomatic 
cerebrovascular events).

Significant, uncontrolled cardiac arrhythmia (including atrial flutter/fibrillation, 
ventricular fibrillation, or ventricular tachycardia). 

Use of rate control drugs for arrhythmias (including beta blockers [such as metoprolol], 
acetylcholine, digoxin, and non-dihydropyridine calcium channel blockers diltiazem and 
verapamil).

Placement of a pacemaker for control of cardiac rhythm. 

Requirement for inotropic support (including digoxin).

New York Heart Association Class II to IV heart failure (Appendix F).

Any other cardiac condition that in the opinion of the investigator could pose an additional 
risk for the participation in the study (eg, pericardial effusion or restrictive 
cardiomyopathy).

Baseline prolongation of the rate-corrected QT interval (QTc; eg, repeated demonstration 
of QTc interval >480 msec, or history of congenital, long QT syndrome, or torsades de 
pointes). 
7. Patients with any of the following blood pressure conditions:

History of orthostatic hypotension or syncope that required medical intervention. 
Orthostatic hypotension is defined as a 20 mmHg fall in systolic blood pressure and/or a 
10 mmHg fall in diastolic blood pressure within 2 to 5 minutes of quiet standing 
immediately after a 5-minute period of supine rest.

Postural orthostatic tachycardia syndrome (POTS) or postural tachycardia syndrome 
(defined as an increase in heart rate of >30 beats per minute over baseline after 10 minutes 
of quiet standing). 

Hypertension that is unstable or not controlled by medication.
8. Seizures requiring antiepileptic treatment. 
9. History of uncontrolled brain metastasis unless: 

Previously treated with surgery, whole-brain radiation, or stereotactic radiosurgery.

Stable disease for ≥60 days, without steroid use (or stable steroid dose established for 
≥28 days before the first dose of TAK-931).
10. Symptomatic and/or progressive central nervous system (CNS) metastases.
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11. Ongoing medical conditions, such as acute exacerbations of chronic illnesses, serious 
infections, or major surgery within 4 weeks before receiving the first dose of study drug.
12. Known history of human immunodeficiency virus (HIV) infection.
13. Known hepatitis B (HBV) surface antigen seropositive or detectable hepatitis C (HCV) 
infection viral load. Note: Patients who have positive hepatitis B core antibody or hepatitis B 
surface antibody can be enrolled but must have an undetectable hepatitis B viral load. Patients 
who have positive hepatitis C antibody must have an undetectable hepatitis C viral load.
14. Known gastrointestinal (GI) disease or GI procedure that could interfere with the GI 
absorption of study drug, such as total gastrectomy or GI conditions that could substantially 
modify gastric pH.
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9.0
STUDY DRUG
9.1
Study Drug Administration
All protocol-specific criteria for administration of study drug must be met and documented prior to 
drug administration. Study drug will be administered only to eligible patients under the 
supervision of the investigator or identified subinvestigator(s).
TAK-931 will be administered according to the assigned dosing schedule (Figure 7.a)  TAK-931 
will be administered to patients on an empty stomach. Patients should not eat for 2 hours before 
taking the capsules with 8 ounces of water. Patients should be instructed to eat a meal or snack 
>1 hour after taking study drug. In case of postdose biopsy, patients may drink water only after 
taking the study drug as indicated by the local surgical procedures.
Patients should be instructed to take their study medication at approximately the same time each 
day and not to take more than the prescribed dose at any time. Patients should swallow the study 
medication whole and not chew it, open it, or manipulate it in any way before swallowing. If a 
patient fails to take the TAK-931 dose within the time frame specified (±12 hours for QD, ±6 hours 
for BID), that dose should be skipped. Patients should record any skipped doses in their dosing 
diary (see Study Manual) and resume dosing at the next scheduled time with the prescribed 
dosage.
If severe emesis or mucositis prevents the patient from taking a TAK-931 dose, that dose will be 
skipped. If emesis occurs after study medication ingestion and if whole capsule(s) are visible in the 
vomitus, replacement capsule(s) should be taken; otherwise the dose will not be re-administered, 
and patients should simply adhere to the dosing schedule and resume dosing at the next scheduled 
time with the prescribed dosage. Patients should record the time of the emesis in their dosing diary 
(see Study Manual). Except for the case of emesis with visible capsules in the vomitus as described 
above, a patient should never repeat a dose or double-up on doses.
TAK-931 will be administered only during the stipulated days for each schedule. TAK-931 doses 
missed due to any reason, including treatment interruption due to toxicity, will not be made up by 
extending the cycle length (either 21 or 28 days).
9.2
Definitions of Dose-Limiting Toxicity
Toxicity will be evaluated according to the NCI CTCAE, version 4.03, effective 14 June 2010 
[20]. These criteria are provided in the Study Manual. A DLT will be defined as any of the 
following events occurring during Cycle 1 that are considered by the investigator to be at least 
possibly related to therapy with TAK-931:

Nonfebrile Grade 4 neutropenia (ANC <500 cells/mm3) lasting more than 7 consecutive days.
If myeloid growth factors are used, the event will be considered as DLT irrespective of the 
duration.
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
Febrile neutropenia: Grade ≥3 neutropenia (ANC <1000 cells/mm3) with fever and/or 
infection, where fever is defined as a single temperature >38.3°C or sustained temperature of 
≥38°C for more than 1 hour.

Grade 4 thrombocytopenia lasting more than 7 consecutive days. A platelet count 
<10,000/mm3 at any time is a DLT.

Grade ≥3 thrombocytopenia of any duration accompanied by Grade 2 bleeding or requiring 
transfusion.

Delay in the initiation of Cycle 2 by more than 14 days (7 days for Schedules D, E, and F) due 
to a lack of adequate recovery of treatment-related hematological or nonhematologic toxicities.

Grade 2 ejection fraction (EF) decreased by ECHO or MUGA.

Other Grade 2 nonhematologic toxicities that are considered by the investigator to be related to 
study drug and dose-limiting. 

Patients who receive <50% of doses of the planned TAK 931 dosing in Cycle 1 for related 
AEs: <7 QD doses or <14 BID doses for Schedules A and B; <4 QD doses or <7 BID doses for 
Schedule C and; <11 QD doses or <21 BID doses for Schedule D, <3 QD doses or <6 BID 
doses for Schedule E, <2 QD doses or <3 BID doses for Schedule F. 

Grade 3 or greater nonhematologic toxicity with the following exceptions:
–
Grade 3 arthralgia/myalgia that responds to nonsteroidal anti-inflammatory drugs 
(NSAIDs).
–
Grade 3 fatigue that lasts less than 1 week.
–
Isolated Grade ≥3 laboratory abnormalities if it is asymptomatic and resolves to Grade ≤1 
or baseline levels in ≤7 days.
–
Grade 3 nausea and/or emesis that can be controlled to Grade <3 in ≤3 days with the use of 
optimal antiemetics (defined as an antiemetic regimen that employs both a 
5-hydroxytryptamine (serotonin) type 3 [5-HT3] receptor antagonist and a corticosteroid 
given in standard doses and according to standard schedules).
–
Grade 3 diarrhea that can be controlled to Grade <3 in ≤3 days with appropriate treatment. 
9.3
Dose Escalation Rules 
The safe starting dose of TAK-931 in humans is 30 mg/day based on one-tenth of the STD10 in 
rodents. Possible toxicities in clinical studies are hematologic and gastrointestinal effects based on 
the mechanism of action. Transient hypotension with reflex tachycardia was seen in dogs with 
approximately Cmax>1000 ng/mL due to vasodilatation and decreased peripheral resistance. This 
would translate to Cmax of 1584 ng/mL in humans by correcting the difference in TAK-931 plasma 
protein binding for humans and dogs.
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To ensure patient safety and minimize the number of patients exposed to nonefficacious doses, 
dose escalation in Schedule A will consist of an initial accelerated escalation phase in which dose 
levels are increased by 100%. This accelerated escalation is not applicable to Schedules B, C, D, E,
and F. The accelerated escalation phase will transition to modified Fibonacci escalation steps after 
1 patient experiences a DLT in Cycle 1 or when 2 patients experience Grade ≥2 hematologic or 
nonhematologic related or possibly related drug toxicity or when geometric mean plasma Cmax for 
the cohort reaches or exceeds 800 ng/mL. Hematologic, cardiovascular, gastrointestinal, and other 
nonhematologic AEs that will be considered DLTs are summarized in Section 9.2  An expansion 
cohort of up to 15 patients (including patients treated at the same dose during doses escalation) 
may be treated with all or some schedules to better define the safety and tolerability of TAK-931.
For Schedules A, B, C, E, and F, the dose escalation steps will be modified as needed, based on 
accumulating PK data and clinical safety (utilizing BLRM) that would provide narrower 
escalation steps and potentially decrease the number of patients exposed to doses above the MTD 
(see details in Section 14.3). In addition, there will be a minimum of a 1-week interval between 
C1D1 of the first patient dosed and C1D1 of the second patient dosed for each dose escalation 
cohort for Schedules A, B, and C. Subsequent patient dosing (third patient per cohort and beyond) 
may occur at a shorter interval (eg, <7 days from previous patient’s C1D1 dosing), but no more 
than 1 patient will undergo C1D1 dosing within a 1-day period. These intervals are not applicable 
to patients enrolled in Schedule D, to cases of dose de-escalation and to patients enrolled in the 
safety expansion cohorts. For Schedules E and F, it is necessary to wait at least 24 hours from the 
last dose administered in the first week of treatment of the first patient to C1D1 of the second and 
third patients dosed in each escalation cohort.
The Schedule D starting dose level is 20 mg QD, to be administered continuously in 21-day cycles. 
As with the other schedules, the DLT-observation period will be in Cycle 1. However, with this 
schedule, there is a higher risk of delayed or cumulative toxicity after Cycle 1. For this reason, 
patients in this schedule will be evaluated every week at least during Cycles 2 and 3. After Cycle 1, 
AEs meeting DLT definitions will be managed according to Section 9.4.3 guidelines. In case of 
non-dose-limiting drug-related AEs that preclude a safe TAK-931 administration, the preference 
will be to interrupt treatment for 1 week to allow for recovery and then re-start treatment at the 
same dose (See Section 9.4.3). This strategy will help define the period during which TAK-931 
can be dosed continuously at low doses and to determine, if necessary, standardized dosing breaks. 
For Schedule D, BLRM will not be used to guide escalation decisions. Other dose levels (including 
de-escalation to 10 mg, escalation to 30 mg QD or BID administration) may be possible depending 
on the observed safety, treatment interruptions, PK, antitumor activity, and pMCM2 
pharmacodynamics. 
Dose Escalation With PK Guidance
The 2-parameter BLRM implementing the escalation with overdose control (EWOC) principle 
[21,22] will be used to inform dose escalation decisions and MTD estimation from the second dose 
cohort in Dosing Schedule A, B, C, E, and F. The starting dose level is 30 mg QD for Schedule A, 
60 mg QD for Schedule B, the maximum administered dose in Schedule B will be used for 
Schedule C, 20 mg QD for Schedule D, 100 mg QD for Schedule E. The starting dosing for 
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Schedule F will be determined based on clinical data of Schedule E. The DI of the starting dose in 
Schedule F will not exceed that of the maximum administered dose in Schedule E. If transition to 
BID administration is decided during dose escalation, the next dose level will have the same total 
daily dose used in the previous level divided in 2 equal doses administered every 12 hours. An 
individual patient can be changed from QD to BID based on clinical safety only if allowed by the 
sponsor. Initially, 3 patients will be enrolled at starting dose level. The following rules will be used 
only for this initial dose level for Schedules A, B, and C:

If no DLTs are observed in Cycle 1, 3 patients will be enrolled at the next dose level. 

If 2 or more of the first 3 patients experience a DLT in Cycle 1, then the starting dose level will 
be considered not tolerated.

If 1 patient experiences a DLT in Cycle 1, 3 more patients will be enrolled at the starting dose. 
–
If no more than 1 patient out of the 6 total patients has a Cycle 1 DLT, 3 patients will be 
enrolled at the next dose level. 
–
If 3 or more of the 6 patients experience a Cycle 1 DLT, the starting dose level will be 
considered not tolerated. 
–
If 2 of the 6 patients have a Cycle 1 DLT, 3 additional patients will be enrolled. If any of 
those 3 additional patients have a Cycle 1 DLT, the starting dose will be considered not 
tolerated. If none of the 3 additional patients have a Cycle 1 DLT, the starting dose will be 
considered the MTD.
Once the dose is escalated above the starting dose level, the BLRM (with PK guidance) will be 
used for all subsequent dose recommendations. The recommended dose will be that which has the 
highest posterior probability of having a DLT rate that falls into the interval [0.16, 0.33). 
Following the EWOC principle, the posterior probability of the recommended dose having a DLT 
rate above 0.33 must not exceed 35%. In addition, the PK profile will also be evaluated to support 
the dose escalation. Escalation will continue until one of the following stopping rules is met:

At least 6 patients are enrolled at the current dose and the current dose is the recommended 
dose for the next group of patients, or

At least 9 patients are enrolled at the next recommended dose and the posterior probability of 
the next recommended dose having a DLT rate that falls into the interval [0.16, 0.33) exceeds 
50%.
Once either of the above rules has been met, MTD may be declared. Alternative stopping rules 
may also be considered following discussions between the sponsor and the investigators.
For Schedule D, initially 3 patients will be dosed with 20 mg QD, if 0 or 1 DLT is observed in 
Cycle 1, 3 more patients will be enrolled in this cohort. If 0 or 1 DLT is observed out of 6 patients 
in total, the 20-mg dose level will be considered tolerated and escalation up to 30 mg will be 
considered. If 3 or more out of these 6 patients has a DLT (or ≥2 patients out the first 3), the 20-mg 
dose level will be considered not tolerated, and de-escalation to 10 mg QD or stopping Schedule D 
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will be considered. If 2 of the 6 patients have a DLT, 3 additional patients will be enrolled. If any 
of those 3 additional patients have a DLT, the 20-mg dose level will be considered not tolerated. If 
none of the 3 additional patients have a DLT, the 20-mg dose level will be considered the MTD. 
For Schedule D escalation decisions, all the available safety and dose modification information 
after Cycle 1 will be considered.
More conservative dose escalation, evaluation of intermediate doses, and expansion of an existing 
dose level are all permissible following discussions between the sponsor and the investigators, if 
such measures are needed for patient safety or for a better understanding of the dose-related 
toxicity, exposure, or pharmacodynamics of TAK-931.
9.4
Dose Modification Guidelines
Dose modification guidelines for toxicities are described below for TAK-931 based on the type 
and severity of AEs and causality determination by investigators. Further clarification can be 
obtained in consultation with the sponsor clinician (or designee). 
9.4.1
Intrapatient Dose Escalation
Intrapatient dose escalation is not allowed; however, it would be possible to change from QD to 
BID administration based on individual patient clinical safety if allowed by the sponsor (eg, if 
Cmax-related toxicity is observed).
9.4.2
Criteria for Beginning or Delaying a Subsequent Treatment Cycle
Before starting a new treatment cycle, TAK-931–related AEs or laboratory abnormalities that 
require dose modification must have returned to Grade ≤1 or baseline levels. For Schedule B these 
criteria also apply to Day 15 dosing For Schedules E and F, in general these criteria also apply to 
Day 8 and Day 15 dosing; however, for patients with Grade 2 neutropenia on Day 8 or Day 15, 
treatment can be administered at the investigator’s discretion. For Schedule D, this requirement is 
applicable also for restarting treatment after an interruption due to toxicity.
If there is a delay of a subsequent cycle longer than 2 weeks because of an AE, the patient may be 
withdrawn from treatment unless there is clinical benefit as assessed by the investigator, with 
agreement by the sponsor’s medical monitor. TAK-931 dosing may be continued at the previously 
established safe dose level or below. 
9.4.3
Criteria for Treatment Interruption and Dose Reduction
All toxicities that occur during the study will be actively managed following the standard of care 
unless otherwise specified in the protocol. Patients experiencing AEs attributed to TAK-931 may 
continue study treatment with the same dose, may have TAK-931 treatment held, may have their 
dose reduced, or may be permanently discontinued from the study. Patients who have study drug 
held because of treatment-related or possibly related AEs may resume study drug treatment after 
resolution of the AE at the same dose level or at a reduced dose depending on the nature and 
severity of the AE and whether it is the first occurrence or it is recurrent. 
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Refer to Table 9.a for general dose modification recommendations. When the dose of TAK-931 is 
withheld based on these criteria, clinical and laboratory reevaluation should be repeated at least 
weekly or more frequently, depending on the nature of the toxicity observed until the toxicity 
resolves to Grade ≤1 or baseline. In events where there are transient laboratory abnormalities that, 
based on investigator assessment, are not clinically significant or drug-related, continuation of 
therapy without dose modification is permissible upon discussion with the sponsor. See details for 
the management of specific TEAEs in Section 9.5.
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Table 9.a
Dose Modification Recommendations for TAK-931 Toxicities
Criteria
Action
Grade 1 AEs
No dose reductions or interruptions 
Grade 2 AEs
Treat according to local practice. Whether to hold treatment or to continue it at the 
same or at a reduced dose is at the discretion of the investigator.
Patients experiencing Grade 2 AEs considered related to study treatment that are not 
easily managed or corrected and are not tolerable to the patient, or AEs that are not 
acceptable in the investigator’s judgment, should have study treatment interrupted 
until the AE resolves to Grade ≤1 or baseline and then restarted at the same dose or, 
depending on the toxicity, at the previous safe dose level or below.
Grade 3 AEs
Hold TAK-931 until resolution to Grade ≤1 or baseline, and then resume treatment 
at either the same dose or a reduced dose level at the discretion of the investigator.
Grade 4 (life-threatening) AEs
Consider permanently withdrawing the patient from the study, except when the 
investigator determines that the patient is receiving clinical benefit and has 
discussed this with the sponsor, then treatment may be restarted at a reduced dose 
level or below when toxicity recovers to Grade ≤1 or baseline.
AEs of all grades
If treatment has been held for >14 consecutive days without resolution of the 
toxicity (to baseline or Grade ≤1), consider permanently discontinuing study 
treatment unless there is clinical benefit for the patient as assessed by the 
investigator and with sponsor’s approval. Treatment can be resumed at a reduced 
dose level after resolution of AEs to Grade ≤1 or baseline.
Abbreviations: AE, adverse event. 
When a dose reduction occurs, the TAK-931 dose will be reduced to the next lower dose that has 
been established as a safe dose during dose escalation. If initial dose adjustment does not provide 
sufficient relief, the dose of TAK-931 can be further reduced if the treating physician considers 
that the patient is receiving benefit  In general, after a dose is reduced it should not be re-escalated 
even if there is minimal or no toxicity with the reduced dose. However, if further evaluation 
reveals that the AE that led to the dose reduction was not study drug-related, the dose may be 
re-escalated to the original dose level. Dose reductions due to AEs of 1 or 2 dose levels are 
generally recommended. 
The dose of TAK-931 will not be reduced for an individual patient during Cycle 1 unless a DLT 
has been declared and it is still possible for the patient to receive treatment within the remaining 
dosing period scheduled. In this case, the patient can complete Cycle 1 at a reduced dose level.
9.4.4
Criteria for Discontinuation of TAK-931
TAK-931 should be discontinued in patients experiencing an AE in Cycle 1 meeting criteria for a 
DLT for which the investigator considers that retreatment of the patient could be dangerous. For 
Grade 4 life-threatening TEAEs consider permanently withdrawing the patient from the study, 
except when the investigator determines that the patient is receiving clinical benefit and has 
discussed this with the sponsor, then treatment may be restarted at the previously safe dose level or 
below when toxicity recovers to Grade ≤1 or baseline.
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If more than 2 dose reductions are required, or if the next cycle of TAK-931 is delayed for 
>14 days because of TAK-931–related toxicities, then the patient should have study treatment 
discontinued unless the investigator considers that the patient will receive benefit continuing in the 
study. If treatment discontinuation is determined, the EOT visit should be completed within 30 to 
40 days of the last administration of TAK-931.
9.5
Management of Specific Adverse Events
Therapies that are required to manage AEs and control cancer symptoms are allowed based on 
standard clinical practice, unless specifically excluded. Supportive care agents, such as 
erythropoietin, G-CSF, blood products (RBC and platelet transfusions), and pain medications are 
permitted as needed per American Society of Hematology (ASH)/ASCO guidelines or local 
institutional practice. However, these agents (excluding NSAIDs) should be avoided at baseline to 
meet inclusion criteria or to mitigate toxicity during Cycle 1 before DLT declaration. Each 
treatment intervention should be clearly documented.
9.5.1
Hematologic Toxicities
Please refer to Table 9.b for dose delay and reduction recommendations for hematologic toxicities. 
TAK-931 should be held if a significant treatment-emergent cytopenia or bleeding is suspected to 
be related to, or can be worsened by, study treatment  Precautionary measures should be taken to 
prevent bleeding and overwhelming infections. Blood transfusions (red blood cell [RBC] or 
platelet) and hematopoietic or thrombopoietic stimulating factors may be used to treat 
cytopenia/thrombocytopenia at the discretion of the investigator per standard clinical practice. It 
should be noted that use of myeloid growth factors (eg, G-CSF, GM- CSF) are not allowed in 
Cycle 1 before confirmation of DLT. In case of a first event, a dose reduction is preferred over the 
usage of myeloid growth factors
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Table 9.b
TAK-931 Dose Adjustments for Hematologic Toxicities
Criteria
Action
Neutropenia (ANC)
Grade 1 (ANC <LLN-1500 cells/mm3)
Continue TAK-931 at the same dose level.
Grade 2 (ANC 1000-1499 cells/mm3)
Continue TAK-931 at the same dose level.
Grade 3 (ANC 500-999 cells/mm3)
without fever
Withhold dose until resolved to Grade ≤1 or baseline, then:
If resolved in ≤7 days, resume treatment at the same dose level;
If resolved in >7 days, resume treatment at a reduced dose level;
If it is a repeat occurrence, resume treatment at a reduced level.
Grade 4 (ANC <500 cells/mm3)
without fever
Withhold dose until resolved to Grade ≤1 or baseline, then resume 
treatment at a reduced dose level.
Febrile neutropenia (ANC <1000 cells/mm3, with a 
single temperature of >38.3°C or sustained 
temperature of ≥38°C for more than 1 hour)
Withhold dose until fever/infection have recovered, then resume 
treatment at a reduced dose level.
Thrombocytopenia (PLT)
Grade 1 (PLT < LLN-75,000 cells/mm3)
Continue TAK-931 at the same dose level.
Grade 2 (PLT 50,000-74,999 cells/mm3)
Continue TAK-931 at the same dose level.
Grade 3 (PLT 25,000-49,999 cells/mm3)
without bleeding
Withhold dose until resolved to Grade ≤1 or baseline, then:
If resolved in ≤7 days, resume treatment at the same dose level;
If resolved in >7 days, resume treatment at a reduced dose level.
Grade 4 (PLT <25,000 cells/mm3)
without bleeding
Withhold dose until resolved to Grade ≤1 or baseline, resume treatment at 
a reduced dose level.
Platelets <10,000 cells/mm3, thrombocytopenia 
Grade ≥3 associated clinically significant bleeding
Consider permanently withdrawing the patient from the study, except 
when the investigator determines that the patient is obtaining clinical 
benefit and has discussed this with the sponsor.
Abbreviations: ANC=absolute neutrophil count  LLN=lower limit of normal, PLT=platelets.
9.5.2
Gastrointestinal Adverse Events
Nausea and/or Vomiting
This study will not initially use prophylactic antiemetics. However, a patient who develops nausea 
and/or vomiting will be actively managed by using optimal antiemetic treatment based on local 
standard practice. Additionally, antiemetics could be used prophylactically as clinically indicated 
following the occurrence of first event of TAK-931–related or possibly related nausea and/or 
vomiting. An optimal antiemetic regimen is defined as one that uses both a 5-HT3 antagonist and a 
corticosteroid given in standard doses and according to standard schedules. PPIs and anti-H2
receptor antagonists are not allowed during treatment.
Diarrhea
Prophylactic antidiarrheals will not be used in this study. However, diarrhea should be managed 
according to clinical practice, including the administration of antidiarrheals once infectious causes 
are excluded. Fluid intake should be maintained to avoid dehydration. Fluid deficit should be 
corrected before initiation of treatment and during treatment.
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9.5.3
Hepatobiliary Disorders
Liver function tests should be monitored throughout participation in the study (AST, ALT, ALP, 
and bilirubin). If abnormalities are observed, the subject should be assessed for causes other than 
the TAK-931. Transaminase elevations should be managed according to locally accepted clinical 
practice including frequent monitoring of appropriate laboratory functions (2 to 3 times per week). 
If possible, hepatotoxic concomitant medications should be discontinued in subjects who develop 
elevated transaminases.
Dose interruption should be considered in any subject who develops Grade 2 elevated 
transaminases lasting longer than 2 weeks or at any time if subject develops a Grade ≥3 elevation. 
If transaminase levels resolve to Grade ≤1 or baseline within 14 days of dose interruption, 
treatment should be restarted at a reduced dose level.
Subjects who develop elevation of transaminase AST or ALT >3 times upper limit of normal 
(ULN) in conjunction with bilirubin >1.5×ULN must be permanently discontinued from study 
treatment, unless a correctable non–drug-related cause of hepatic injury is identified. Strict 
monitoring (daily or every other day) of liver function tests should be established.
9.5.4
Cardiac Toxicities
A MUGA scan or echocardiogram (ECHO) will be performed at screening, predose on C2D1, and 
at end-of-treatment follow-up. ECHO or MUGA will also be performed if symptoms of heart 
failure are noted. Patients with significant abnormalities should be treated as per standard of care at 
their institution documenting the treatment in the electronic case report forms (eCRFs). In case of 
Grade ≥2 decrease in cardiac ejection fraction, treatment should be discontinued until resolution to 
Grade ≤1, then the study drug will be resumed at a reduced dose level.
The routine 12-lead ECG will be performed predose in Cycle 1 at the specified time points 
including 2, 4, and 8 hours postdose as described in Schedule of Events. Single safety ECGs will 
be collected before administration of TAK-931 on Day 1 of Cycle 2 and at the EOT visit. In case of 
Grade 3 QTc prolongation or arrhythmia, treatment should be discontinued until resolution to 
Grade ≤1. An evaluation by a cardiologist must be performed and adequate patient management 
and follow-up (including hospitalization if deemed necessary) should be put in place immediately 
after observation of the QTc prolongation or arrhythmia. Review of concomitant medications for 
QT effects is also required. Upon resolution of the event to Grade ≤1, the study drug will be 
resumed at a reduced dose level. For Grade 4 QTc prolongation or arrhythmia, treatment should be 
permanently discontinued. If the patient shows a clinically significant benefit and is willing to 
resume treatment, treatment can be resumed at a reduced dose level after consultation with a 
cardiologist and the approval from the sponsor (see Section 9.4.4).
9.5.5
Hypotension
Transient hypotension with reflex tachycardia was observed in toxicology studies with dogs at 
Cmax. For this reason, close blood pressure (BP) and heart rhythm monitoring is indicated during 
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Cycle 1, and after Cycle 1 if clinically indicated. This monitoring takes advantage of the 
hospitalization requirement for the first cycle in phase 1 studies performed in Japan. 
In Cycle 1, heart rhythm will be continuously monitored with electronic equipment at a minimum 
on Days 1 through 3 in all patients except those enrolled in Schedule D and in the safety expansion 
cohorts. For Schedules E and F, continuous heart rhythm monitoring will be performed on all 
dosing days in Cycle 1, starting before dosing and up to 12 hours after the intake of the dose. 
Continuous monitoring should not interfere with in-hospital normal patient activities including 
eating, sleeping, walking, or personal care. Blood pressure will also be measured (as described in 
Section 10.4.6) before dosing and 2, 4, and 8 hours after dosing on Days 1 through 3 in Cycle 1 and 
if the patient presents with symptoms. For Schedules E and F, blood pressure will be measured 
before dosing and 2, 4, and 8 hours after dosing on all dosing days in Cycle 1. Outside this window 
in Cycle 1 and for patients enrolled in Schedule D and the safety expansion cohorts, resting heart 
rate and BP will be assessed and recorded once at the estimated Cmax time (approximately 2 hours 
after dosing) together with orthostatic changes in both. Orthostatic heart rate and BP are required 
for patients enrolled in Schedules E and F but not for those enrolled in Schedule D.

Grade 1 hypotension: hypotension (at least 20 mmHg systolic BP drop and/or at least 
10 mmHg diastolic BP drop versus individual patient’s baseline BP) without symptoms and no 
reflex tachycardia at rest. Individual patient’s baseline normal BP is defined as the median of at 
least 3 BP measurements taken during the screening period (the median value of systolic BP 
and diastolic BP will be evaluated separately). No treatment modification or monitoring is 
indicated. 

Grade 2 hypotension: hypotension with compatible symptoms and reflex tachycardia (or 
Grade 2 presyncope). BP, heart rate, and ECG will be performed on the spot. Repeated 
assessments should be performed as clinically indicated. Treat according to local practice. 
After recovery and normalization to baseline, the patient can continue receiving treatment with 
the same dose if it is the first occurrence or with a reduced dose if it is a reoccurrence. 

Grade ≥3 hypotension: Stop treatment. Treat the event according local practice. Consider 
continuous electronic monitoring of heart rhythm, BP, and ECG until complete normalization 
of vital signs. Depending on the seriousness of the event, associated pathologies, and recovery 
consider either discontinuing the patient’s treatment or continue treatment at a reduced dose 
level. 
For patients experiencing Grade ≥2 hypotension at any time during Cycle 1, careful BP monitoring 
as described for Cycle 1 Days 1 through 3 should be performed in the following 3 administration 
days of TAK-931.
For any patient experiencing Grade ≥2 hypotension on non-PK sampling days during Cycle 1, an 
additional PK plasma specimen should be collected (if feasible) at the time of the event.
The patient should be advised of the possibility of orthostatic hypotension and recommended to lie 
down and seek assistance if symptoms occur, and, if possible, to measure heart rate and BP. The 
patient also should be advised not to perform dangerous activities or to drive during the Cmax time. 
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If the hypotensive event recurs, the patient should be advised to contact the site for instructions. BP 
and heart rate monitoring should be instituted at home and values recorded in the patient’s diary.
9.6
Excluded Concomitant Medications and Procedures
All prescription and over-the-counter medications, including influenza vaccines, taken by a patient 
as of the first study drug administration through 30 days from the last dose or before initiation of 
new anticancer therapy (whichever comes first) will be recorded on the designated electronic case 
report form (eCRF). Subjects must be instructed not to take any medications, including 
over-the-counter medications and herbal supplements, without first consulting with the 
investigator.
The following medications and procedures are prohibited during the study:

Use of myeloid growth factors (eg, G-CSF, GM-CSF) are not allowed in the first cycle before 
confirmation of DLT, but may be administered to manage patients who experience severe 
and/or febrile neutropenia if clinically indicated in accordance with American Society of 
Clinical Oncology (ASCO) guidelines and/or institutional practices. For the first episode of 
neutropenia, dose reduction is preferred. Use of myeloid growth factors with Grade 4 
neutropenia in Cycle 1 is considered a DLT.

Any investigational agent other than TAK-931.

Medications used for rate control of arrhythmias and cardiac frequency (including beta 
blockers [such as metoprolol], acetylcholine, digoxin, and non-dihydropyridine calcium 
channel blockers diltiazem and verapamil).

Clinically significant cytochrome P450 enzyme inducers (see Appendix G) within 14 days 
prior to the first dose of TAK-931 and during the study.

Chronic concomitant administration of any PPI is not allowed during the study. Patients 
receiving PPI therapy before enrollment must stop using the PPI for 5 days before their first 
dose of TAK-931. Examples of PPIs include omeprazole, esomeprazole, pantoprazole, 
lansoprazole, vonoprazan, and rabeprazole. During study participation, patients who develop 
new clinical symptoms that may require treatment with PPIs should be discussed with the 
sponsor to determine dose and schedule and suitability of the patient for continued study 
participation. 

H2-receptor antagonists (eg, cimetidine, nizatidine, and ranitidine) are not permitted from the 
day before (Day -1) through the last day of active TAK-931 dosing in the treatment cycle. 
Intermittent use may be considered especially during the resting period if needed. Patients who 
require additional therapy with H2-receptor antagonists during the active treatment period with 
TAK-931 should be discussed with the sponsor to determine dose and schedule and suitability 
of the patient for continued study participation. 

Over-the-counter (OTC) antacid preparations such as calcium carbonate are allowed, but 
should not be taken from 2 hours before and until 2 hours after administration of TAK-931.
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Patients currently on chronic erythropoietin support for anemia may continue to receive 
erythropoietin; however, initiation of new erythropoietin therapy is not allowed during the first 
cycle. Initiation of prophylactic growth factors will be allowed after the first cycle. Note: 
Erythropoietin has not been approved for the treatment of anemia associated with cancer 
chemotherapy in Japan. 
9.7
Permitted Concomitant Medications and Procedures 
Other medications considered necessary for the safety and wellbeing of the patient may be 
administered at the discretion of the investigator. Any concomitant medications added or 
discontinued during the study should be recorded on the eCRF.
9.8
Precautions and Restrictions
9.8.1
Pregnancy and Contraception
It is not known what effects TAK-931 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 effective methods of contraception through 
defined periods during and after study treatment as specified below.
Female patients must meet 1 of the following:

Postmenopausal for at least 1 year before the screening visit, OR

Surgically sterile, OR

If they are of childbearing potential, agree to practice 2 effective methods of contraception 
from the time of signing of the informed consent form through 30 days 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] and withdrawal are not acceptable methods of contraception.)
Male patients, even if surgically sterilized (ie, status postvasectomy) must agree to the following:

Practice effective barrier contraception during the entire study treatment period and through 
120 days 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] and withdrawal are not acceptable methods of contraception.)
AND

Agree not to donate sperm during this study and for 120 days after receiving their last dose of 
study drug.
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Contraception methods meeting criteria defined above are provided below. If male condoms were 
used as a barrier method by male subjects, his partner must use intrauterine devices (Copper T, or 
Progesteron T) or hormonal contraceptives (combined pills) instead of spermicide.
Table 9.c
Contraceptive Methods
Barrier Methods (Each Time the 
Subject has Intercourse): 
Intrauterine Devices: 
Hormonal Contraceptives
• Male condom PLUS spermicide*
• Cap* (plus spermicidal cream* or 
jelly*) PLUS male condom and 
spermicide*
• Diaphragm (plus spermicidal cream* 
or jelly*) PLUS male condom and 
spermicide*
• Copper T PLUS condom or 
spermicide*
• Progesterone T PLUS condom or 
spermicide*
• Implants*
• Hormone injections*
• Combined pills
• Minipills*
• Patches*
• Vaginal ring* PLUS male condom 
and spermicide*
* Spermicide, cap, spermicidal cream, jelly, implant, hormone injections, minipills, patches, and vaginal ring are not 
used in Japan.
9.8.2
Females Who are Lactating or Breastfeeding
Female patients who are lactating must refrain from breastfeeding from the start of study 
participation (Section 8.2, exclusion criterion #4) through 30 days after the last dose of study drug.
9.8.3
Patients with Prior Exposure to Hepatitis B or Hepatitis C
Patients who have detectable hepatitis B or C viral loads are excluded from study participation (see 
Section 8.2, exclusion criterion #13). Patients with prior exposure to HBV or HCV who have 
subsequently cleared the infection (based on a negative viral load) are allowed on study, but should 
be monitored for re-activation every 2 months. Patients who develop detectable HBV or HCV in 
their blood will have TAK-931 treatment held with administration of a nucleoside antagonist (NA) 
per institutional guidelines and a consultation with a hepatologist should be considered. 
Restarting TAK-931 after HBV or HCV is no longer detected may be considered in the setting of 
continued NA prophylaxis and after a discussion with the Takeda medical monitor to review the 
potential benefit versus risk to the patient in the setting of a controlled HBV or HCV infection. 
Refer to the Japan Society of Hepatology (JSH) Guidelines for the management of Hepatitis B 
Virus infection [23].
9.8.4
Photosensitivity
In the photoabsorption spectrum, TAK-931 exhibits a peak at 294 nm, which is within the zone of 
concern for potential phototoxicity and/or photoallergy. Photosafety assessment of TAK-931 has 
not yet been performed; therefore, patients should be cautioned to take protective measures (eg, 
avoidance of exposure to direct sunlight, use of sunglasses and long sleeves).
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Because TAK-931 is an investigational agent, it should be handled with due care. In case of 
contact with broken capsules, raising dust should be avoided during the clean-up operation. The 
product may be harmful if inhaled, ingested, or absorbed through the skin. Gloves and protective 
clothing should be worn during the clean-up operation. The area should be ventilated and the spill 
site washed after material pick-up is complete. The spilled material should be disposed of as 
hazardous medical waste in compliance with federal, state, and local regulations. In case of contact 
with the powder (eg, from a broken capsule), skin should be washed immediately with soap and 
copious amounts of water for at least 15 minutes. In case of contact with the eyes, copious amounts 
of water should be used to flush the eyes for at least 15 minutes. Medical personnel should be 
notified.
Patients will receive instructions for home storage and administration of TAK-931. 
Patients will be instructed to return any unused study drug in the original packaging along with 
their completed diary cards at the appropriate visits.
Please refer to the Study Manual for additional instructions. 
9.14
Other Protocol-Specified Materials
Not applicable.
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10.0
STUDY CONDUCT
This trial will be conducted in compliance with the protocol, Good Clinical Practice (GCP), 
applicable regulatory requirements, and International Conference on Harmonisation (ICH) 
guidelines.
10.1
Study Personnel and Organizations
The contact information for the Takeda project clinician for this study, the central laboratory and 
any additional clinical laboratories, the coordinating investigator for each member state/country 
(where applicable), and the contract research organization (CRO) team may be found in the Study 
Manual. A full list of investigators is available in the sponsor’s investigator database.
10.2
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). 
10.3
Treatment Group Assignments
Patient assignment to a specific schedule will be decided jointly by the investigator and sponsor 
with the aim of maximizing enrollment efficiency in the study. The dose escalation scheme is 
outlined in Section 9.3.
10.4
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. Evaluations during the screening period are to be 
conducted within 28 days before administration of the first dose of study drug. Unless otherwise 
noted, evaluations during the Treatment period must occur before study drug administration. Tests 
and procedure should be performed on schedule for all visits. The timing of PK assessments is 
specified in Table Ga through Table Ge,f (Appendix A). All EOT evaluations should occur 30 to 
40 days after the last dose of study drug. Patients enrolled in the safety expansion cohorts will be 
managed with modified Schedule of Events in Cycle 1 as specified in Appendix A; hospitalization 
is not required for these cohorts.
10.4.1 Informed Consent
Each patient must provide written informed consent before any study-required procedures are 
conducted, unless those procedures are performed as part of the patient’s standard care.
10.4.2 Patient Demographics
The date of birth, race, and sex of the patient are to be recorded during screening.
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10.4.3 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 10.4.8.
10.4.4 Physical Examination
A physical examination will be completed per standard of care at the times specified in the 
Schedule of Events.
10.4.5 Patient Height and Weight
Height will be measured only during screening (within 28 days before the first dose of TAK-931). 
Body weight will be measured at the visits specified in the Schedule of Events.
10.4.6 Vital Signs
Standard vital signs should be obtained at least once during a visit specified in the Schedule of 
Events and will include temperature (may be oral or body temperature), blood pressure, and heart 
rate/pulse. Orthostatic vital sign measurements will include blood pressure and heart rate/pulse 
while supine (after 5 minutes in this position) and standing (after 2 minutes in this position) 
measurements at the visits specified in the Schedule of Events.
10.4.7 Pregnancy Test
A serum pregnancy test will be performed for women of childbearing potential at screening and 
within 4 days prior to the first dose of study drug. 
Women of childbearing potential will be defined as sexually mature females who meet the 
following criteria:

Those who have not undergone hysterectomy or bilateral oophorectomy, and

Those who have not had natural menopause for 12 consecutive months or longer (eg, FSH 
>40 IU/L and no menopausal period for at least 12 consecutive months). Note that a loss of 
menopausal periods following chemotherapy may not rule out childbearing potential.
The results from these tests must be available and negative before the first dose of study drug is 
administered. If C1D1 serum pregnancy results will not be available before dosing, a urine 
pregnancy test may be performed.
10.4.8 Concomitant Medications and Procedures
Medications used by the patient and therapeutic procedures completed by the patient will be 
recorded in the eCRF from the first dose of study drug through 30 days after the last dose of study 
drug or before initiation of new anticancer therapy (whichever comes first). See Section 9.6 and 
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Section 9.7 for a list of medications and therapies that are prohibited and/or allowed during the 
study.
10.4.9 Adverse Events
Monitoring of TEAEs, serious and nonserious, will be conducted throughout the study as specified 
in the Schedule of Events. Refer to Section 11.0 for details regarding definitions, documentation, 
and reporting of pretreatment events (PTEs), TEAEs, and SAEs.
10.4.10 Enrollment
Enrollment is defined as when the written informed consent has been obtained and the subject’s 
eligibility has been confirmed per the inclusion and exclusion criteria. Procedures for completion 
of the enrollment information are described in the Study Manual.
10.4.11 Electrocardiogram
Continuous cardiac rhythm monitoring and standard 12-lead ECGs will be administered at the 
time points specified in the Schedule of Events. Patients will be in the supine position for at least 
5 minutes before the ECG is to be performed. Additional ECGs may be obtained as clinically 
indicated.
10.4.12 Eastern Cooperative Oncology Group Performance Status
The ECOG performance status (refer to Appendix D) will be assessed at the times specified in the 
Schedule of Events.
10.4.13 Echocardiogram or Multiple Gated Acquisition Scan
A MUGA scan or ECHO will be administered at the time points specified in the Schedule of 
Events.
10.4.14 Clinical Laboratory Evaluations
Clinical laboratory evaluations will be performed locally. Handling of clinical laboratory samples
will be outlined in the Study Manual. Clinical laboratory evaluations will be performed as outlined 
below.
Blood samples for analysis of the clinical chemistry and hematological parameters shown in 
Table 10.a and urine samples for analysis of the parameters shown in Table 10.b will be obtained 
as specified in the Schedule of Events.
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Table 10.a
Clinical Chemistry and Hematology Tests
Hematology
Serum Chemistry
Hematocrit
Hemoglobin
Leukocytes with differential
Absolute neutrophil count
Platelet (count)
Albumin
Alkaline phosphatase
Alanine aminotransferase
Aspartate aminotransferase
Bilirubin (total)
Blood urea nitrogen
Calcium
Bicarbonate (HCO3
-)
Creatinine
Chloride
γ-Glutamyl transferase
Glucose
Lactate dehydrogenase
Magnesium
Phosphate
Potassium
Sodium
Urate
Table 10.b
Clinical Urinalysis Tests
Urinalysis
Bilirubin
Glucose
Ketones
Leukocytes
Nitrite
Occult blood
pH
Protein
Specific gravity
Turbidity and color
Urobilinogen
Fecal immunochemical testing for detecting blood in the stool will be obtained at screening and 
prior to C2D1 and C3D1. If a patient has a positive FIT test at screening, further collection is not 
required. If a patient has a negative FIT test at screening but a positive FIT test during study 
treatment, a consultation is recommended with a gastroenterologist to evaluate the patient for 
subacute gastro-intestinal injury as the source of the detected occult blood.
Blood samples for analysis of cardiac enzymes (ie, troponin I or T, BNP, or NT-proBNP) will be 
obtained as specified in the Schedule of Events.
HBV and HCV screening should be conducted during the screening period if valid results from 
prior testing that have been confirmed by the investigator are not available. HBV screening will 
include testing for hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (HBsAb) and 
hepatitis B core antibody (HBcAb). For patients who test positive for HBsAg, HBsAb or HBcAb, 
HBV DNA will also be assessed at screening. HCV screening will include testing for the 
anti-HCV antibody (HCVAb). Patients who test positive for HCVAb will also be tested for HCV 
RNA at screening. 
Note that patients who have positive HBcAb or HBsAb can be enrolled but must have undetectable 
hepatitis B viral load. Patients who have a positive HCVAb can be enrolled but must have 
undetectable hepatitis C viral load. 
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Patients who are HBcAb positive or HCVAb positive with a negative viral load at screening who 
are enrolled in this study will be monitored by assessment of viral load (DNA titers for HBV, RNA 
titers for HCV) every 2 months.
HIV screening should be conducted during the screening period if valid results from prior testing 
that have been confirmed by the investigator are not available.
10.4.15 Skin Punch Biopsies
pMCM2 will be detected semiquantitatively by IHC of histologic sections of formalin-fixed, 
paraffin-embedded skin biopsies. Skin punch biopsies (2-4 mm) will be obtained for all patients 
either during screening or predose on C1D1, and for patients in Schedule A to D postdose on any 
drug dosing day after 3 consecutive dosing days (eg, Day 4 or after) in Cycle 1. A postdose skin 
biopsy will be obtained on Day 9 in Schedule E and on Day 8 in Schedule F. Other time points for 
biopsy collection outside Cycle 1 can be performed if explicitly approved by the sponsor. It is 
strongly recommended that postdose skin biopsies are collected 4-9 hours after study drug 
administration 
Refer to Section 10.4.21 for 
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10.4.18 Disease Assessment
Patients will undergo a CT scan (with contrast) or MRI, as appropriate, to monitor and assess 
disease status. Investigators will assess patients’ disease status using RECIST guidelines 
(version 1.1), where measurable disease is defined as ≥1 extraosseous lesion that can be accurately 
measured in at least 1 dimension [24]. Specific disease sites that cannot be adequately imaged by 
CT may be documented by MRI. Anatomical measurements will be collected at baseline and at 
each subsequent evaluation for each target lesion using an imaging modality consistent with that 
used at screening. The same method (CT with contrast, MRI, or bone scan) must be consistently 
used on a patient throughout the study. Bone scans may be performed on patients with bone 
metastases rather than CT or MRI. 
Objective assessments will be performed at each time point as described in the Schedule of Events.
When possible, the same qualified physician will interpret results to reduce variability.
Radiographic images will be maintained at the site, and test results and physicians’ findings will be 
filed in patient source documents. The sponsor may request electronic images for those patients 
who demonstrate a response. 
10.4.19 Pharmacokinetic Measurements
Serial blood and urine specimens for PK analysis of TAK-931 will be collected at the time points 
specified in Table Ga through Table Ge,f (Appendix A). The dates and exact times of 
administration of TAK-931 before collection of the blood or urine sample for PK analysis and the 
dates and exact times of the postdose PK sample collection will be recorded on the eCRF. 
If a skin biopsy 
 is taken on a non-PK sampling day, sparse PK plasma samples 
should be collected at predose, at 1 to 3 hours postdose, and at 4 to 9 hours postdose on the day of 
biopsy. The exact dosing, biopsy, and PK sampling date and time will be recorded. It is preferable 
but not necessary to synchronize 
, skin biopsy, and PK sampling. 
For the timed 12-hour urine collection on C1D1, patients should be asked to void completely in a 
container approximately 30 minutes before administration of the first dose of study drug. An 
aliquot of this spot urine specimen will be a predose sample. After the administration of the first 
dose of TAK-931, all subsequent voided urine through the point of collection of the 12-hour PK 
sample on Day 1 will be collected and will constitute the 0- to 12-hour postdose urine specimen 
collection  At the end of the 12-hour period, when the 12-hour PK plasma specimen is obtained, 
the patient must void completely so that all the urine during the timed period is collected. The 
volume of the urine collected during the 12-hour period on C1D1 will be recorded, and a 50-mL 
aliquot of collected urine will be shipped for bioanalysis. Detailed instructions on the procedure 
for collection, processing, storage, and shipment of the urine samples will be provided in the Study 
Manual. Plasma and urine samples may be stored for possible future analysis of metabolites.
 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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Once study drug has been discontinued, all study procedures outlined for the EOT visit will be 
completed as specified in the Schedule of Events. The primary reason for study drug 
discontinuation will be recorded on the eCRF.
Patients who receive <75% of their assigned TAK-931 doses (ie, <11 QD doses or <21 BID doses 
for Schedules A and B; <6 QD doses or <11 BID doses for Schedule C; and <16 QD doses or <32 
BID doses for Schedule D; <5 QD doses or <9 BID doses for Schedule E; <2 QD doses or <5 BID 
doses for Schedule F) in Cycle 1 for reasons other than study drug-related AEs will be replaced.
10.8
Withdrawal of Patients From Study
A patient may be withdrawn from the study for any of the following reasons:

Lost to follow-up.

Complete response. 

Progressive disease. 

Withdrawal by subject.

Death. 

Initiation of another systemic anticancer treatment. 

Study terminated by sponsor.

Other.
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.
10.9
Study Compliance
Study drug will be administered or dispensed only to eligible patients under the supervision of the 
investigator or identified subinvestigator(s). The appropriate study personnel will maintain records 
of study drug receipt and dispensing.
During the Cycle 1 inpatient dosing period, study drug will be administered under supervision of 
site personnel. From Cycle 2 onwards, patients will receive a sufficient quantity of study drug. 
Patients will be given a diary to record study drug dosing. The study center staff will check the 
patient’s drug diary versus the patient’s supply of TAK-931 capsules to assess compliance.
Tests and procedures should be performed on schedule; however, unless otherwise specified, 
occasional changes are allowable within a 3-day window for holidays, vacations, and other 
administrative reasons. If extenuating circumstances prevent a patient from beginning treatment or 
completing a planned procedure or assessment within 3 days of the scheduled time, the patient 
may continue the study only with the written permission of the medical monitor.
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10.10 Post-treatment Follow-up Assessments (Progression-Free Survival)
Patients who stop treatment for any reason other than PD will continue to have PFS follow-up 
visits. The PFS follow-up visit should be conducted at the site every 12 weeks from the EOT visit 
until the occurrence of PD, the start of subsequent antineoplastic therapy, or until 6 months after 
the patient discontinued treatment, whichever occurs first.
NOTE: During PFS follow-up, study drug-related SAEs must be reported to the sponsor’s 
Department of Pharmacovigilance or designee. This includes deaths that the investigator considers 
related to study drug and that occur during the post-treatment follow-up period. Refer to 
Section 11.0 for details regarding definitions, documentation, and reporting of SAEs.
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11.0
ADVERSE EVENTS
11.1
Definitions
11.1.1 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.
11.1.2 Adverse Event 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.
11.1.3 Serious Adverse Event 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 11.2 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 [20]. Clarification should be made 
between an SAE and an AE that is considered severe in intensity (Grade 3 or 4), because the terms 
serious and severe are not synonymous. The general term severe is often used to describe the 
intensity (severity) of a specific event; the event itself, however, may be of relatively minor 
medical significance (such as a Grade 3 headache). This is not the same as serious, which is based 
on patient/event outcome or action criteria described above, and is usually associated with events 
that pose a threat to a patient’s life or ability to function. A severe AE (Grade 3 or 4) does not 
necessarily need to be considered serious. For example, a white blood cell count of 1000/mm3 to 
less than 2000/mm3 is considered Grade 3 (severe) but may not be considered serious. Seriousness 
(not intensity) serves as a guide for defining regulatory reporting obligations.
11.2
Procedures for Recording and Reporting Adverse Events and Serious 
Adverse Events
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 11.3 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 11.1) must be 
reported (see Section 11.3 for the period of observation) by the investigator to the Takeda Global 
Pharmacovigilance department or designee (contact information provided below). This should be 
done by faxing the SAE Form within 24 hours after becoming aware of the event. The SAE Form, 
created specifically by Takeda, will be provided to each clinical study site. A sample of the SAE 
Form may be found in the Study Manual. Follow-up information on the SAE or serious 
pretreatment event may be requested by Takeda. SAE report information must be consistent with 
the data provided on the eCRF.
SAE Reporting Contact Information
Bell Medical Solutions, Inc
Planned hospital admissions or surgical procedures for an illness or disease that existed before the 
patient was enrolled in the trial are not to be considered AEs unless the condition deteriorated in an 
unexpected manner during the trial (eg, surgery was performed earlier or later than planned). 
Prolongation of hospitalization as a matter of practical convenience is not to be considered an AE 
unless the patient’s condition deteriorated.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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For both serious and nonserious AEs, the investigator must determine both the intensity of the 
event and the relationship of the event to study drug administration. For serious pretreatment 
events, the investigator must determine both the intensity of the event and the relationship of the 
event to study procedures.
Intensity for each AE, including any lab abnormality, will be determined using the NCI CTCAE, 
Version 4.03, effective date 14 June 2010 [20]. The criteria are provided in the Study Manual.
Relationship to study drug administration will be determined by the investigator responding “yes” 
or “no” to this question: Is there a reasonable possibility that the AE is associated with the study 
drug? 
11.3
Monitoring of Adverse Events and Period of Observation
AEs, both nonserious and serious, will be monitored throughout the study as follows: 

AEs will be reported from the first dose of study drug through 30 days after administration of 
the last dose of study drug or before initiation of new anticancer therapy (whichever comes 
first) and recorded in the eCRF. 

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 
first dose of study drug, but will not be recorded in the eCRF.

Related and unrelated SAEs will be reported to the Takeda Global Pharmacovigilance 
department or designee from the first dose of study drug through 30 days after administration 
of the last dose of study drug or before initiation of new anticancer therapy (whichever comes 
first) 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)
11.4
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, including the European 
Medicines Agency (EMA), investigators and IRBs or the head of the study site, as applicable. 
Relative to the first awareness of the event by/or further provision to the sponsor or sponsor’s 
designee, SUSARs will be submitted to the regulatory authorities as expedited 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 
products administration or in the overall conduct of the trial. 
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11.5
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 11.2). 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 11.2). Every effort 
should be made to follow the pregnancy for the final pregnancy outcome.
11.6
Procedures for Reporting Product Complaints
A product complaint is a verbal, written, or electronic expression that implies dissatisfaction 
regarding the identity, strength, purity, quality, or stability of a drug product. Individuals who 
identify a potential product complaint situation should immediately report this via the phone 
numbers or email addresses below:
Call Center
Phone Number
E-mail
Fax
Hours
Dohmen Life 
Science Services
Mon-Fri
9 AM to 7 PM ET
Abbreviation: ET, Eastern standard time. 
Product complaints in and of themselves are not AEs. If a product complaint results in an SAE, an 
SAE form should be completed and sent to Bell Medical Solutions, Inc (refer to Section 11.2).
Property of Takeda: For non-commercial use 
 and subject to the applicable Terms of Use
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12.0
STUDY-SPECIFIC COMMITTEES
No steering committee, data safety monitoring committee, or clinical endpoint committee will be 
used in this study.
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13.0
DATA HANDLING AND RECORDKEEPING 
The full details of procedures for data handling will be documented in the Data Management Plan. 
If selected for coding, AEs, PTEs, medical history, and concurrent conditions will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA). Drugs will be coded using the 
World Health Organization (WHO) Drug Dictionary.
13.1
Electronic Case Report Forms 
Completed eCRFs are required for each subject who was administered study drug.
The sponsor or its designee will supply investigative sites with access to eCRFs and will make 
arrangements to train appropriate site staff in the use of the eCRF. These forms are used to transmit 
the information collected in the performance of this study to the sponsor, CRO partners, and 
regulatory authorities. Investigative sites must complete eCRFs in English.
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site. 
Any change of, modification of, or addition to the data on the eCRFs should be made by the 
investigator or appropriate site personnel. Corrections to eCRFs are recorded in an audit trail that 
captures the old information, the new information, identification of the person making the 
correction, the date the correction was made, and the reason for change.
The principal investigator must review the eCRFs for completeness and accuracy and must sign 
and date the appropriate eCRFs as indicated. Furthermore, the principal investigator must retain 
full responsibility for the accuracy and authenticity of all data entered on the eCRFs.
eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The sponsor or its designee will be permitted to review the subject’s medical 
and hospital records pertinent to the study to ensure accuracy of the eCRFs. The completed eCRFs 
are the sole property of the sponsor and should not be made available in any form to third parties, 
except for authorized representatives of appropriate governmental health or regulatory authorities, 
without written permission of the sponsor.
13.2
Record Retention
The investigator and the head of the institution agree to keep the records stipulated in Section 13.1
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 informed consent forms, subject 
authorization forms regarding the use of personal health information (if separate from the 
informed consent forms), electronic copy of eCRFs, including the audit trail, and detailed records 
of drug disposition to enable evaluations or audits from regulatory authorities, the sponsor or its 
designees. Any source documentation printed on degradable thermal sensitive paper should be 
photocopied by the site and filed with the original in the subject’s chart to ensure long term 
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legibility. Furthermore, International Conference on Harmonisation (ICH) E6 Section 4.9.5 
requires the investigator and the head of the institution to retain essential documents specified in 
ICH E6 (Section 8) until at least 3 years after the last approval of a marketing application for a 
specified drug indication being investigated or, if an application is not approved, until at least 
2 years after the investigation is discontinued and regulatory authorities are notified. In addition, 
ICH E6 Section 4.9.5 states that the study records should be retained until an amount of time 
specified by applicable regulatory requirements or for a time specified in the Clinical Study Site 
Agreement between the investigator and/or the head of the institution and sponsor.
Refer to the Clinical Study Site Agreement for the sponsor’s requirements on record retention. The 
investigator and the head of the institution should contact and receive written approval from the 
sponsor before disposing of any such documents.
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14.0
STATISTICAL METHODS
14.1
Statistical and Analytical Plans
A statistical analysis plan (SAP) will be prepared and finalized prior to database lock. This 
document will provide further details regarding the definition of analysis variables and analysis 
methodology to address all study objectives.
14.1.1 Populations for Analysis
The populations used for analysis will include the following:
!
Safety population: The safety population is defined as all patients who receive any amount of 
study drug.
!
Pharmacokinetic population: The pharmacokinetic population is defined as all patients for 
whom there are sufficient dosing and TAK-931 concentration-time data to reliably estimate 
the PK parameter(s). This population will be used for analyses of PK parameters. 
!
Pharmacodynamics population: The pharmacodynamics population is defined as all patients 
who receive at least the first dose of TAK-931, have a baseline skin punch 
 biopsy 
sample, and have at least 1 additional postbaseline skin punch 
 biopsy sample. The 
skin 
 biopsies must contain detectable basal pMCM2 signals to permit an estimate of 
pMCM2 (Ser40) levels.
!
DLT-evaluable population: The DLT-evaluable population is defined as all patients who 
receive at least 75% of their planned TAK-931 doses for their first cycle of treatment (unless 
interrupted by study drug-related AEs) and who have sufficient follow-up data to allow the 
investigators and sponsor to determine whether DLT occurred. Patients who receive <75% of 
doses of TAK-931 in Cycle 1 for reasons other than study drug-related AEs are not evaluable 
for DLT and will be replaced. Patients will be analyzed by the dose level to which they were 
originally assigned, including those who receive subsequent treatment at a lower or higher 
dose level.
!
Response-evaluable population: The response-evaluable population is defined as patients who 
receive at least 1 dose of study drug, have measurable disease at baseline, and at least 
1 post-baseline response assessment. The response-evaluable population will be used for the 
analysis of ORR and DOR.
14.1.2 Procedures for Handling Missing, Unused, and Spurious Data
All available safety, tolerability, efficacy, PK, and pharmacodynamic data will be included in data 
listings and tabulations. No imputation of values for missing data will be performed. The relevance 
of missing sample data will be assessed. 
Data that are potentially spurious or erroneous will be examined according to standard data 
management operating procedures.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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14.1.3 Analysis of Demographics and Other Baseline Characteristics
Demographic (age, sex, and other parameters as appropriate) and baseline disease characteristics 
(weight, height, and other parameters as appropriate) will be summarized by dose cohort.
14.1.4 Pharmacokinetic Analysis 
PK parameters will be estimated using non-compartmental methods with WinNonlin® Phoenix™
Version 6.2 or higher (Pharsight Corp., Mountain View, CA). The plasma PK parameters will be 
estimated from the concentration-time profiles for all PK population patients.
The plasma and urine PK of TAK-931 after the first dose on C1D1 and after multiple doses on 
C1D7 (Schedules B and C), C1D8 (Schedules A and D), or C1D7, C1D8 or C1D9 (Schedules E 
and F) will be determined based on the PK parameters below, as permitted by data.

Cmax.

tmax.

AUC24 (or AUC12 for BID dosing) and AUClast after the first dose on C1D1 and after 
administration of multiple doses on C1D7, C1D8, or C1D9.

CL/F, Rac(AUC) (for C1D7, C1D8 or C1D9 only).

Amount of TAK-931 excreted over 12 hours Ae12 (C1D1 only), CLr (C1D1 only).
PK parameters will be summarized using descriptive statistics. Individual TAK-931 
concentration-versus-time data and individual PK parameters will be presented in listings and also 
tabulated using summary statistics by dose cohort. Individual and mean plasma concentration-time 
profiles will be plotted by dose cohort.
14.1.5 Safety Analysis
The incidence of DLT will be tabulated for each dose cohort. In addition, to assess the relationship 
between toxicities and TAK-931 dose, the preferred term of individual toxicities will be 
summarized by their frequency and intensity for each dose cohort. The DLT-evaluable population 
will be used for the analysis of DLT. 
Safety will be evaluated by the incidence of TEAEs, defined as any AEs that occur after 
administration of the first dose of study drug and up through approximately 30 days after the last 
dose of study drug, and severity, as well as by changes from baseline in the patient’s vital signs, 
weight, ECG, and clinical laboratory results using the Safety population. Exposure to study drug 
will be summarized and reasons for discontinuation will be tabulated. ECHO, MUGA, and 
additional assessments such as measurement of cardiac enzymes in serum that are predictive of 
acute injury (eg, troponin I or T) and chronic or progressive failure (eg, B-type natriuretic peptide 
[BNP] or N-terminal pro-brain natriuretic peptide [NT-proBNP]) may also be summarized. Safety 
will be summarized by dose level within each dose cohort. 
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TEAEs will be tabulated according to the MedDRA by system organ class, high level terms, and 
preferred terms and will include the following categories:

TEAEs.

Drug-related TEAEs.

Grade ≥3 TEAEs.

Grade ≥3 drug-related TEAEs.

The most commonly reported TEAEs (≥10% of all patients).

SAEs.
A listing of TEAEs resulting in study drug discontinuation will be provided.
Descriptive statistics for the actual values of clinical laboratory parameters (and/or change from 
baseline in clinical laboratory parameters) and other safety parameters as deemed appropriate 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 and other safety parameters as deemed appropriate will be 
generated based on changes in NCI CTCAE grade from baseline to the worst post-baseline value. 
Graphical displays of key safety parameters, such as scatter plots of baseline versus worst 
post-baseline values, may be used to understand the TAK-931 safety profile.
Concomitant medications collected from the first dose of study drug through the study period will 
be coded using the WHO Drug Dictionary. The number and percentage of patients taking 
concomitant medications will be tabulated by WHO drug generic term using the safety population.
Additional safety analyses may be performed to more clearly enumerate rates of toxicities and to 
further define the safety profile of TAK-931.
Electrocardiogram Analysis
ECG intervals (QT and QTc with Fridericia correction, and PR), QRS duration, and ventricular 
rate will be summarized at each scheduled time point, along with mean change from baseline to 
each posttreatment time point. The number and percentage of patients with ECG abnormalities 
will be summarized at each time point.
14.1.6 Efficacy Analysis
The secondary efficacy parameters include ORR (CR+PR), PFS, and DOR.
The estimate of the ORR will be presented with 2-sided 95% exact binomial confidence intervals 
for each dose cohort. ORR will be analyzed using the response-evaluable population.
PFS is defined as the time from the date of first dose to the date of first documentation of 
progressive disease or death due to any cause, whichever occurs first. The Kaplan-Meier survival 
curves, 25th, 50th (median), and 75th percentiles (if estimable), along with their 2-sided 95% 
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where πi is the DLT rate for dosei and doseref is a reference dose. A quantile-based, 
non-informative, bivariate normal prior will be used for ln(α) and ln(β). This prior will be assigned 
based on prestudy estimates of the DLT rate at each dose level, as described in Neuenschwander, 
et al [21].
The model will be updated after each group of 3 patients enrolled in the current dose level. For 
each dose level, the posterior probability of having DLT rates that fall into the following intervals 
will be estimated:

[0, 0.16): under-dosing.

[0.16, 0.33): target toxicity.

[0.33, 1.00]: excessive toxicity.
The next recommended dose will be selected as described in Section 9.3.
Dosing Schedule A:
A group of 3 patients will be enrolled in a TAK-931 dose cohort each time based on BLRM, with 
safety data evaluation and PK guidance. Each subject will participate in only 1 dose cohort. An 
example of possible dose escalation with accelerated escalation and modified Fibonacci escalation 
steps is shown in Table 14.a. The actual dose levels may be adjusted based on the observed safety 
profile. The simulation to evaluate the sample size is performed based on possible dose level range 
(30, 50, 60, 80, 100, 120, 150, 200, 240, 300, 400, 480, 500, 600, 800, 1000, 1200, 1600, and 
2000 mg) from Table 14.a. The simulation considers the escalation transition to modified 
Fibonacci escalation steps. The simulation is performed based on 6 scenarios of the assumed true 
DLT rates at dose levels (30, 50, 60, 80, 100, 120, 150, 200, 240, 300, 400, 480, 500, 600, 800, 
1000, 1200, 1600, and 2000 mg), representing various distributions of toxicity across dose levels, 
detailed as shown in Table 14.b  The curve of the dose-DLT relationship becomes steeper and 
MTD is reached earlier from Scenario 1 to Scenario 6. It is assumed that the probability of having 
accelerated escalation phase transition to modified Fibonacci escalation steps is 20% more than the 
probability of having 1 DLT event. The quantile-based, noninformative, bivariate normal prior of 
ln(α) and ln(β) is determined based on prestudy estimates of DLT rate (0.01, 0.02, 0.03, 0.04, 0.05, 
0.08, 0.11, 0.14, 0 19, 0.21, 0.25, 0.29, 0.33, 0.40, 0.50, 0.60, 0.70, 0.80, and 0.90) at various dose 
levels (30, 50, 60, 80, 100, 120, 150, 200, 240, 300, 400, 480, 500, 600, 800, 1000, 1200, 1600, and 
2000 mg). Table 14.c shows the operating characteristic results. 
In Scenario 1, the probability of recommending a target dose is above 70% when the true DLT rate 
increases slowly with dose, and the target true DLT occurs at the highest dose level (2000 mg). In 
Scenario 1, the average number of patients required is approximately 30 with fewer than 2 DLTs 
expected on average. The true DLT rates in Scenarios 2 and 3 increase faster than Scenario 1, and 
both have less chance of successfully recommending target dose levels, since the dose level just 
below the lowest target dose level (1200 and 300 mg, respectively) has a DLT rate very close to 
16%. The chance of recommending a toxic dose is very low in both scenarios (2.7% and 0.9%, 
respectively). The average number of patients required is approximately 28 and 22, respectively, 
with fewer than 3 DLTs expected on average. In Scenario 4, with further faster increase of DLT 
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rate over doses, there is a 79% probability of recommending target dose levels, whereas the 
probability of recommending toxic doses is low (4.7%). The average number of patients required 
is approximately 20 with fewer than 4 DLTs expected on average. In Scenario 5, when the starting 
dose is the only target dose, and the second dose level has a DLT rate close to 33%, there is 29% 
chance of claiming the starting dose is MTD, and approximately 45% chance of claiming all doses 
are toxic. Most of the patients (around 70%) do not receive doses above the MTD dose. The 
average number of patients required is approximately 11 with fewer than 4 DLTs expected on 
average. In Scenario 6 when all doses are toxic, there is a 96.5% chance of successfully claiming 
all doses are toxic. The average number of patients required is approximately 5 and fewer than 
3 DLTs are expected on average. 
The accuracy of the BLRM recommendation relies on the true DLT rate, thus the clinical PK 
guidance and safety evaluation are combined to support the dose escalation. 
From a simulation analysis, approximately 33 patients may be needed for up to 9 dose escalation 
cohorts in Dosing Schedule A. The candidate dose levels may be adjusted according to 
accumulating knowledge of observed safety profile in the study. The simulation provides the 
maximum sample size evaluated using different dosing scenarios. As an example, a hypothetical 
dose escalation step based on Scenario 4 of true DLT rate is shown in Table 14.d to illustrate how 
BLRM guides dose escalation.
Table 14.a
An Example of Possible Dose Escalation With Accelerated and Modified 
Fibonacci Escalation 
Dose 
Level
Daily Dose
(BID Dose), mg
Alternative Modified Fibonacci Escalation a
Accelerated 
Escalation
1
30
50
80 (40) c
100 (50)
120 (60)
2
60
100 (50) b
150 (75)
200 (100)
240 (120)
3
120 (60) b
200 (100)
300 (150)
400 (200)
500 (250)
4
240 (120)
400 (200)
600 (300)
800 (400)
1000 (500)
5
480 (240)
—
—
—
—
Modified 
Fibonacci 
Escalation
6
800 (400)
—
—
—
—
7
1200 (600)
—
—
—
—
8
1600 (800)
—
—
—
—
9
2000 (1000) c
—
—
—
—
Abbreviation: BID, twice daily. 
Assumes an initial Cmax of 40 ng/mL after a single 30 mg dose and linear increase in Cmax with rising doses. 
Accelerated escalation: 100%, Modified Fibonacci escalation: ~67%, ~50%, ~33%, and ~20% to 25%.
Italics indicates that the predicted Cmax for a single dose at the dose level will likely be >IC90 for pMCM2 inhibition.
a Alternative standard escalation is the transition to standard escalation during the accelerated escalation phase before 
Cohort 5 has been enrolled.
b A BID schedule will be instituted in Cohort 3 if the pharmacokinetic profile supports this schedule.
c Not applicable if the mean Cmax in the prior dose cohort is >800 ng/mL. 
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Table 14.b
Dose Escalation Simulation Study of the Probability of Dose-Limiting 
Toxicity 
Dose Level
True P(DLT) at each scenario
1
2
3
4
5
6
30 mg a
0.000
0.001
0.029
0.046
0.275
0.586
50 mg
0.000
0.001
0.048
0.086
0.363
0 621
60 mg
0.000
0.003
0.058
0.106
0.407
0.638
80 mg
0.000
0.004
0.071
0.134
0.448
0.656
100 mg
0.001
0.006
0.083
0.162
0.490
0.674
120 mg
0.001
0.007
0.096
0.189
0.532
0.692
150 mg
0.001
0.010
0.108
0.215
0.562
0.707
200 mg
0.002
0.014
0.129
0.259
0.613
0.731
240 mg
0.003
0.017
0.145
0.294
0.653
0.750
300 mg
0.004
0.021
0.159
0.322
0.679
0.764
400 mg
0.005
0.029
0.184
0.349
0.723
0.788
480 mg
0.007
0.034
0.203
0.404
0.759
0.807
500 mg
0.008
0.036
0.207
0.411
0.764
0.810
600 mg
0.011
0.045
0.228
0.443
0.792
0.826
800 mg
0.017
0.064
0.270
0.507
0.846
0.860
1000 mg
0.028
0.093
0.314
0.556
0.885
0.887
1200 mg
0.039
0.123
0.359
0.605
0.924
0.915
1600 mg
0.092
0.251
0.478
0.671
0.979
0.967
2000 mg
0.219
0.651
0.638
0.690
1.000
1.000
Abbreviation: P(DLT), probability of a DLT at each dose level.
a Starting dose.
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Table 14.c
Operating Characteristics for Bayesian Logistic Regression Modeling Dose 
Escalation Rule
Scenario
Probability of recommending a:
Average proportion of patients 
receiving a:
Average number of patients
Low Dose Target Dose High Dose Low Dose
Target 
Dose
High Dose Per Study
Experiencing 
DLT per Study
1
29.3%
70.7%
NA
84.6%
15.4%
NA
30.3
1.64
2
63.5%
33.7%
2.72%
86.0%
10.2%
3.80%
27.8
2.55
3 a
65.7%
33.2%
0.90%
85.0%
14.5%
0.51%
21.7
2.42
4 b
15.2%
79.0%
4.74%
45.2%
52.0%
2.83%
19.5
3.27
5 c
NA
29.2%
26.1%
NA
69.5%
30.5%
10.9
3.66
6 d
NA
NA
3.52%
NA
NA
100%
4.95
2.92
Abbreviations: DLT, dose-limiting toxicity; NA, not available.
Low Dose, true DLT rate is [0, 0.16); Target Dose, true DLT rate is [0.16, 0.33); High Dose, true DLT rate is [0.33, 
1.00].
a Probability of 0.24% to claim all doses are toxic. 
b Probability of 1.00% to claim all doses are toxic.
c Probability of 44.6% to claim all doses are toxic.
d Probability of 96.5% to claim all doses are toxic.
Table 14.d
Hypothetical Dose Escalation Step
Step
Dose (mg)
No. of Patients
No. of DLTs
Next Recommended Dose (mg)
1
30
3
0
60 
2
30
3
0
60
3
1
100
3
30
3
0
60
3
1
100
3
0
150
4
30
3
0
60
3
1
100
3
0
150
3
2
100
5
30
3
0
60
3
1
100
6
2
150
3
2
60
6
30
3
0
60
6
1
60 mg is claimed as the MTD
100
6
2
150
3
2
Abbreviation: MTD, maximum tolerated dose. 
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Based on the clinical safety, PK and pharmacodynamic information available as of 13 November 
2016, the sample size for Dosing Schedule A is estimated to be approximately 25 patients 
including the 4 dose escalation cohorts and safety expansion cohort.
Dosing Schedules B and C:
Similarly, in Dosing Schedules B and C, the sample size is evaluated in the simulation using 
BLRM for up to 4 dose cohorts in Schedule B (60, 80, 100, and 120 mg) and up to 3 dose cohorts 
in Schedule C (100, 120, and 150 mg). The candidate dose levels may be adjusted according to 
accumulating knowledge of observed safety profile in the study. It is anticipated that 
approximately 18 patients will be enrolled in Dosing Schedule B and approximately 15 patients 
will be enrolled in Dosing Schedule C for dose escalation cohorts. 
Dosing Schedule D:
Approximately 25 patients will be enrolled for Dosing Schedule D to test lower TAK-931 doses. 
The starting dose is 20 mg. Depending on clinical, PK, and pharmacodynamic information, it may 
be possible to explore a 10-mg dose even if the 20-mg dose is found to be safe. Also, if the 20-mg 
initial dose level is tolerable, it may be possible to escalate to 30 mg.
Dosing Schedules E and F:
In Dosing Schedules E and F, the sample size is evaluated in the simulation using BLRM for up to 
4 dose cohorts in Schedule E (100, 120, 150, and 200 mg) and up to 3 dose cohorts in Schedule F 
(200, 240, and 300 mg). The candidate dose levels may be adjusted according to accumulating 
knowledge of the observed safety profile in the study. It is anticipated that approximately 
16 patients will be enrolled in Dosing Schedule E and approximately 12 patients will be enrolled in 
Dosing Schedule F for dose escalation cohorts.
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15.0
QUALITY CONTROL AND QUALITY ASSURANCE
15.1
Study-Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and institution guarantee access to source documents by the sponsor or its 
designee (CRO) and by the IRB or IEC.
All aspects of the study and its documentation will be subject to review by the sponsor or designee 
(if blinding is not jeopardized), including but not limited to the investigator’s binder, study 
medication, subject medical records, informed consent documentation, documentation of subject 
authorization to use personal health information (if separate from the informed consent forms), 
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.
15.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will require 
deviation from protocol-specified procedures, the investigator should consult with the sponsor or 
designee (and IRB or IEC, as required) to determine the appropriate course of action. There will be 
no exemptions (a prospectively approved deviation) from the inclusion or exclusion criteria.
The site should document all protocol deviations in the subject’s source documents. In the event of 
a significant deviation, the site should notify the sponsor or its designee (and IRB or EC, as 
required). Significant deviations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the subject, or confound interpretation of primary study 
assessment. A protocol deviation form should be completed by the site and signed by the sponsor 
or designee for any significant deviation from the protocol.
The investigator can deviate and change from the protocol for any medically unavoidable reason, 
for example, to eliminate an immediate hazard to study subjects, without a prior written agreement 
with the sponsor or a prior approval from IRB. In the event of a deviation or change, the principal 
investigator should notify the sponsor and the head of the site (when appropriate) of the deviation 
or change as well as its reason in a written form, and then retain a copy of the written form. When 
necessary, the principal investigator may consult and agree with the sponsor on a protocol 
amendment. If the protocol amendment is appropriate, the amendment proposal should be 
submitted to the head of the site as soon as possible and an approval from IRB should be obtained.
The investigator should document all protocol deviations.
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15.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, including 
those of foreign governments (eg, the United States Food and Drug Administration [FDA], the 
United Kingdom [UK] Medicines and Healthcare Products Regulatory Agency, the 
Pharmaceuticals and Medical Devices Agency of Japan). If the study site is contacted for an 
inspection by a regulatory body, the sponsor should be notified immediately. The investigator and 
institution guarantee access for quality assurance auditors to all study documents as described in 
Section 15.1.
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16.0
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.
16.1
IRB and/or IEC Approval
IRBs and IECs must be constituted according to the applicable requirements of each participating 
region. The sponsor or designee will require documentation noting all names and titles of members 
who make up the respective IRB or IEC. If any member of the IRB or IEC has direct participation 
in this study, written notification regarding his or her abstinence from voting must also be 
obtained. Those American sites unwilling to provide names and titles of all members due to 
privacy and conflict of interest concerns should instead provide a Federal Wide Assurance 
Number or comparable number assigned by the Department of Health and Human Services.
The sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the Investigator’s Brochure, a copy of 
the informed consent form, 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, informed consent form) 
reviewed; and state the approval date. The sponsor will notify the 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 
no protocol activities, including screening may occur.
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the informed consent 
form, 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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16.2
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 informed consent form, subject authorization form (if 
applicable), and subject information sheet (if applicable) describe the planned and permitted uses, 
transfers, and disclosures of the subject’s personal and personal health information for purposes of 
conducting the study. The informed consent form and the subject information sheet (if applicable) 
further explain the nature of the study, its objectives, and potential risks and benefits, as well as the 
date informed consent is given. The informed consent form will detail the requirements of the 
participant and the fact that he or she is free to withdraw at any time without giving a reason and 
without prejudice to his or her further medical care.
The investigator is responsible for the preparation, content, and IRB or IEC approval of the 
informed consent form and if applicable, the subject authorization form. The informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) must 
be approved by both the IRB or IEC and the sponsor prior to use.
The informed consent form, subject authorization form (if applicable), and subject information 
sheet (if applicable) must be written in a language fully comprehensible to the prospective subject. 
It is the responsibility of the investigator to explain the detailed elements of the informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) to the 
subject. Information should be given in both oral and written form whenever possible and in the 
manner deemed appropriate by the IRB or IEC. In the event the subject is not capable of rendering 
adequate written informed consent, then the subject’s legally acceptable representative may 
provide such consent for the subject in accordance with applicable laws and regulations.
The subject, or the subject’s legally acceptable representative, must be given ample opportunity to: 
(1) inquire about details of the study and (2) decide whether or not to participate in the study. If the 
subject, or the subject’s legally acceptable representative, determines he or she will participate in 
the study, then the informed consent form and subject authorization form (if applicable) must be
signed and dated by the subject, or the subject’s legally acceptable representative, at the time of 
consent and prior to 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 informed consent 
form and subject authorization (if applicable) at the time of consent and prior to 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 informed consent form, subject authorization form (if applicable), and 
subject information sheet (if applicable) will be stored in the investigator’s site file. The 
investigator must document the date the subject signs the informed consent in the subject’s 
medical record. Copies of the signed informed consent form, the signed subject authorization form 
(if applicable), and subject information sheet (if applicable) shall be given to the subject.
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All revised informed consent forms 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 informed consent form.
16.3
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 16.2).
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (eg, subject name, address, and other identifier fields 
not collected on the subject’s eCRF).
16.4
Publication, Disclosure, and Clinical Trial Registration Policy
16.4.1 Publication and Disclosure
The investigator is obliged to provide the sponsor with complete test results and all data derived by 
the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the sponsor.
The sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 
this section and the Clinical Study Site Agreement. In the event of any discrepancy between the 
protocol and the Clinical Study Site Agreement, the Clinical Study Site Agreement will prevail.
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16.4.2 Clinical Trial Registration
To ensure that information on clinical trials reaches the public in a timely manner and to comply 
with applicable laws, regulations and guidance, Takeda will, at a minimum register interventional 
clinical trials it sponsors anywhere in the world on ClinicalTrials.gov or other publicly accessible 
websites before start of study, as defined in Takeda Policy/Standard. Takeda contact information, 
along with investigator’s city, state (as applicable), country, and recruiting status will be registered 
and available for public viewing. 
For some registries, Takeda will assist callers in locating trial sites closest to their homes by 
providing the investigator name, address, and phone number to the 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. 
16.4.3 Clinical Trial Results Disclosure
Takeda will post the results of clinical trials on ClinicalTrials.gov or other publicly accessible 
websites, as required by Takeda Policy/Standard, applicable laws and/or regulations.
16.5
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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17.0
REFERENCES
1. Labib K. How do Cdc7 and cyclin-dependent kinases trigger the initiation of chromosome 
replication in eukaryotic cells? Genes & Development 2010;24(12):1208-19.
2. Masai H, Matsui E, You Z, Ishimi Y, Tamai K, Arai K. Human Cdc7-related kinase complex. 
In vitro phosphorylation of MCM by concerted actions of Cdks and Cdc7 and that of a criticial 
threonine residue of Cdc7 bY Cdks. Journal of Biological Chemistry 2000;275(37):29042-52.
3. Bousset K, Diffley JF. The Cdc7 protein kinase is required for origin firing during S phase. 
Genes Dev 1998;12(4):480-90.
4. Furuya K, Miyabe I, Tsutsui Y, Paderi F, Kakusho N, Masai H, et al. DDK phosphorylates 
checkpoint clamp component Rad9 and promotes its release from damaged chromatin. 
Molecular Cell 2010;40(4):606-18.
5. Swords R, Mahalingam D, O'Dwyer M, Santocanale C, Kelly K, Carew J, et al. Cdc7 kinase -
a new target for drug development. European Journal of Cancer 2010;46(1):33-40.
6. Montagnoli A, Moll J, Colotta F. Targeting cell division cycle 7 kinase: a new approach for 
cancer therapy. Clinical Cancer Research 2010;16(18):4503-8.
7. Yamada M, Watanabe K, Mistrik M, Vesela E, Protivankova I, Mailand N, et al. 
ATR-Chk1-APC/CCdh1-dependent stabilization of Cdc7-ASK (Dbf4) kinase is required for 
DNA lesion bypass under replication stress. Genes & Development 2013;27(22):2459-72.
8. Hou Y, Wang HQ, Ba Y. Effects of CDC7 gene silencing and Rituximab on apoptosis in 
diffuse large B cell lymphoma cells. Journal of Cancer Research & Clinical Oncology 
2012;138(12):2027-34.
9. Cheng AN, Jiang SS, Fan CC, Lo YK, Kuo CY, Chen CH, et al. Increased Cdc7 expression is 
a marker of oral squamous cell carcinoma and overexpression of Cdc7 contributes to the 
resistance to DNA-damaging agents. Cancer Letters 2013;337(2):218-25.
10. Bonte D, Lindvall C, Liu H, Dykema K, Furge K, Weinreich M. Cdc7-Dbf4 kinase 
overexpression in multiple cancers and tumor cell lines is correlated with p53 inactivation. 
Neoplasia (New York) 2008;10(9):920-31.
11. Kulkarni AA, Kingsbury SR, Tudzarova S, Hong HK, Loddo M, Rashid M, et al. Cdc7 kinase 
is a predictor of survival and a novel therapeutic target in epithelial ovarian carcinoma. Clinical 
Cancer Research 2009;15(7):2417-25.
12. Chen HJ, Zhu Z, Wang XL, Feng QL, Wu Q, Xu ZP, et al. Expression of huCdc7 in colorectal 
cancer. World Journal of Gastroenterology 2013;19(20):3130-3.
13. Malumbres M. Physiological relevance of cell cycle kinases. Physiological Reviews 
2011;91(3):973-1007.
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14. Sasi NK, Tiwari K, Soon FF, Bonte D, Wang T, Melcher K, et al. The potent Cdc7-Dbf4 
(DDK) kinase inhibitor XL413 has limited activity in many cancer cell lines and discovery of 
potential new DDK inhibitor scaffolds. PLoS One 2014;9(11):e113300.
15. Yamada M, Masai H, Bartek J. Regulation and roles of Cdc7 kinase under replication stress. 
Cell Cycle 2014;13(12):1859-66.
16. Kastan MB, Bartek J. Cell-cycle checkpoints and cancer. Nature 2004;432(7015):316-23.
17. Sawa M, Masai H. Drug design with Cdc7 kinase: a potential novel cancer therapy target. Drug 
Design, Development and Therapy 2008;2:255–64.
18. Simons CC, Hughes LA, Smits KM, Khalid-de Bakker CA, de Bruine AP, Carvalho B, et al. A 
novel classification of colorectal tumors based on microsatellite instability, the CpG island 
methylator phenotype and chromosomal instability: implications for prognosis. Ann Oncol 
2013;24(8):2048-56.
19. Vilar E, Gruber SB. Microsatellite instability in colorectal cancer-the stable evidence. Nat Rev 
Clin Oncol 2010;7(3):153-62.
20. Common Terminology Criteria for Adverse Events (CTCAE). National Cancer Institute, 
National Institutes of Health, U.S. Department of Health and Human Services Series v4.03. 
June 14, 2010. Publication No. 09-5410.
21. Neuenschwander B, Branson M, Gsponer T. Critical aspects of the Bayesian approach to phase 
I cancer trials. Statistics in Medicine 2008;27(13):2420-39.
22. Babb J, Rogatko A, Zacks S. Cancer phase I clinical trials: efficient dose escalation with 
overdose control. Statistics in Medicine 1998;17(10):1103-20.
23. JSH. JSH Guidelines for the Management of Hepatitis B Virus Infection. Hepatology Research 
44(Suppl. 1):1-58. doi:10.1111/hepr.12269.
24. 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.
25. Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and 
response criteria of the Eastern Cooperative Oncology Group. American Journal of Clinical 
Oncology 1982;5(6):649-55.
26. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
1976;16(1):31-41.
27. 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
Table Aa Schedule of Events for Treatment Cycle 1 (Dosing Schedule A) (14 days on, 7 days off; 21-Day Cycle)
Screening a
Day
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
Informed consent
X
Inclusion/exclusion criteria
X
HBV, HCV, and HIV testing
X
Demographics
X
Medical history b
X
X
Physical examination b,s
X
X
X
X
Height
X
Weight
X
Vital signs c,s
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
(X)
(X)
(X)
(X)
(X)
(X)
(X)
ECOG performance status
X
12-Lead ECG d,e,s
X
X e
X e
X e
Continuous heart rhythm 
monitor f,s
X
X
X
ECHO/MUGA
X
Disease assessment g
X
Monitoring of concomitant 
medications and procedures
Recorded from first dose of study drug through up to 30 days after the last dose of study drug or before initiation of new anticancer
therapy (whichever comes first).
Adverse event reporting
Recorded from first dose of study drug through up to 30 days after the last dose of study drug or before initiation of new anticancer
therapy (whichever comes first).
Serious adverse events h will be reported from signing of the informed consent form through 30 days after the last dose of study drug or before 
initiation of new anticancer therapy (whichever comes first).
TAK-931 administration i
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Footnotes are on last table page.
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Table Aa Schedule of Events for Treatment Cycle 1 (Dosing Schedule A) (14 days on, 7 days off; 21-Day Cycle) (continued)
Screening a
Day
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
Samples/Laboratory Assessments
Pregnancy test j
X
X
Hematology/chemistry k,s
X
X
X
X
X
X
X
Urinalysis l
X
X
Fecal immunochemical testing
X
Blood sample for cardiac 
enzymes m
X
X
X
X
Skin punch o,q
X (or C1D1) (X)
To be obtained postdose on any drug dosing day after 3 consecutive 
dosing days.
Urine and blood sample for PK
Urine and blood samples for PK analysis will be collected on the days and time points specified in Table Ga.
Abbreviations: BP, blood pressure; Cmax, maximum observed plasma concentration; CT, computed tomography; CxDx, Cycle x, Day x; ECG, electrocardiogram; ECHO, 
echocardiogram; ECOG, Eastern Cooperative Oncology Group; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; ICF, informed consent form;
IEC, independent ethics committee; IRB, institutional review board; MRI, magnetic resonance imaging; MUGA, multiple gated acquisition (scan); PK, pharmacokinetic(s); POTS, 
postural orthostatic tachycardia syndrome; QD, once daily.
a Unless otherwise noted, the screening visit must occur within 28 days before administration of the first dose of study drug (C1D1). The ICF may be signed more than 28 days before 
C1D1.
b The C1D1 physical examination and medical history are not required if the screening physical examination was conducted and medical history obtained within 4 days before 
administration of the first dose of study drug (C1D1).
c Perform vital sign measurements including orthostatic measurements before dosing. Also, perform vital sign measurements on C1D1, C1D2, C1D3, and C1D8 at 2, 4, and 8 hours 
postdose (just before PK sampling). On C1D4 to C1D14 (except C1D8), resting and orthostatic heart rate and BP will be assessed and recorded at the estimated Cmax time 
(approximately 2 hours postdose). If the investigator considers that it is otherwise safe, the patient can be discharged after Day 15 assessments making sure that the patient returns for 
C1D18 evaluation. If the investigator considers that it is in the patient’s best interest to remain hospitalized during the third week, then scheduled assessments in parentheses (X) will 
be performed and recorded. Orthostatic measurements of BP and pulse/heart rate should be conducted with the patient in a supine position after the patient has been resting quietly for 
5 minutes followed by a second measurement after the patient has been standing for 2 minutes. At screening, also measure heart rate after 10 minutes of quiet standing to confirm 
POTS. At least 3 separate resting (after 4 to 5 minutes’ rest in sitting position). BP measurements should be taken during the screening and the median of those measurements will be 
utilized as baseline BP reference of individual patient (median of systolic BP and diastolic BP will be evaluated separately).
Property of Takeda: For non-commercia
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 subject to the applicable Terms of Use
le
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screening and on C1D1. Vital sign measurement as well as hematology and chemistry test will be performed at screening and on Days 1, 8, and 15. Continuous heart rhythm 
monitoring is not required. The other tests or examinations will be the same as dose escalation cohorts.
Note: Tests and procedures should be performed on schedule, but occasional changes are allowable (±3 days) with permission of the medical monitor for holidays, vacations, and 
other administrative reasons. If extenuating circumstances prevent a patient from beginning treatment or completing a scheduled procedure or assessment within this time, 
the patient may continue the study only with the written permission of the medical monitor.
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Table Ab Schedule of Events for Treatment Cycle 2 Through PFS Follow-up (Dosing Schedule A) (14 days on, 7 days off; 
21-Day Cycle)
Cycle 2 and Subsequent Cycles
EOT a
PFSFU
Day 1
Day 5
Day 8
Day 12
Day 15
Day 18
Symptom-directed physical examination b
X
X
Weight
X c
X
Vital signs d,s
X
X
X
ECOG performance status e
X
X
12-Lead ECG f
X
X
ECHO/MUGA g
X
X
Disease assessment h
X
(starting at C3 and 
performed between 
D15 and D1 of the 
next cycle, then Q3C 
thereafter)
X i
X j
(Q 12 weeks)
Monitoring of concomitant medications and 
procedures
Recorded from first dose of study drug through up to 30 days after the last dose of study drug or before initiation of new 
anticancer therapy (whichever comes first).
Adverse event reporting
Recorded from first dose of study drug through up to 30 days after the last dose of study drug or before initiation of new 
anticancer therapy (whichever comes first).
Serious adverse events k will be reported from signing of the informed consent form through 30 days after the last 
dose of study drug or before initiation of new anticancer therapy (whichever comes first).
X t
TAK-931 administration l
Days 1 through 14 of each treatment cycle
Samples/Laboratory Assessments
Pregnancy Test m
X
Hematology/Chemistry n,s
X
X o
X o
X o
X
X o
X
Urinalysis p
X p
Fecal immunochemical testing q
X
Blood sample for cardiac enzymes r
X
Abbreviations: BP, blood pressure; C, cycle; CxDx, Cycle x, Day x; CT, computed tomography; ECG, electrocardiogram; ECHO, echocardiogram; ECOG, Eastern Cooperative 
Oncology Group; EOT, End of Treatment; FIT, fusion-inferred threshold; IEC, independent ethics committee; IRB, institutional review board; MRI, magnetic resonance imaging;
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MUGA, multiple gated acquisition (scan); PFSFU, progression-free survival follow-up; Q, every; QD, once daily.
a Patients who discontinue TAK-931 treatment early should complete the EOT visit approximately 30-40 days after the last dose of TAK-931 or before the start of subsequent 
anticancer therapy if that occurs sooner.
b The symptom-directed physical examination will be conducted within 3 days prior to dosing on Day 1 of each treatment cycle and at the EOT visit. The symptom-directed physical 
examination may be performed at other visits during the treatment cycle at the discretion of the investigator.
c Weight will be measured every other cycle, beginning with Cycle 3.
d Perform vital sign measurements including orthostatic measurements prior to dosing. Orthostatic measurements of BP and pulse should be conducted with the patient in a supine 
position after the patient has been resting quietly for 5 minutes, followed by a second measurement after the patient has been standing for 2 minutes. 
e ECOG performance status will be performed within 3 days before the beginning (Day 1) of each treatment cycle and at the EOT visit.
f Predose, single safety ECGs will be collected on Day 1 of Cycle 2 and at the EOT visit. Additional ECGs may be obtained as clinically indicated at the discretion of the investigator. 
ECG assessments are to be performed with the patient supine and rested for 5 minutes.
g ECHO and/or MUGA should be performed predose on C2D1 and at the EOT visit. The same modality should be used as on the screening visit.
h Baseline CT (with contrast) or MRI scan of the chest, abdomen, and pelvis must be at screening, after which CT (with contrast) or MRI may be performed at the end of every third 
cycle (ie, on or before the start of Cycle 4, Day 1; Cycle 7, Day 1; Cycle 10, Day 1, etc), as clinically indicated, according to standard of care. The same imaging modality (CT [with 
contrast] MRI, or bone scan) should be used on a patient as at the screening visit and throughout the study. Bone scans may be performed on patients with bone metastases rather than 
CT or MRI. See Section 10.4.18 for more details.
i At EOT, tumor assessments will be done only on patients who have not previously demonstrated disease progression in the study unless completed within the previous 4 weeks.
j Patients who discontinue study treatment for reasons other than PD will undergo CT/MRI scans every 12 weeks (±1 week) from EOT until the occurrence of PD, the start of 
subsequent antineoplastic therapy, or until 6 months after discontinuation of study treatment, whichever occurs first.
k Including serious pretreatment events; see Section 11.2.
l Initially, TAK-931 will be administered orally QD for 14 days of a 21-day cycle followed by 7 days off. The starting dose will be 30 mg. Study drug will be administered to patients 
on an empty stomach. Patients should not eat for 2 hours before taking the capsules with 8 ounces of water. Patients should be instructed to eat a meal or snack >1 hour after taking 
study drug. See Section 9.1.
m Additional pregnancy testing may be performed during the study at the discretion of the investigator, upon request of an IEC/IRB, or if required by local regulations.
n See Section 9.4. New Grade ≥3 results should be repeated a minimum of every 3 days until recovered to Grade ≤2.
o The hematology and chemistry blood samples on Days 5, 12, and 18 of each cycle starting with Cycle 2 may be waived if there is no evidence of Grade ≥3 analytical toxicity in the 
previous cycle. After Cycle 3, the Day 8 blood samples can also be waived in patients without evidence of Grade ≥3 analytical toxicity in the previous cycle.
p Complete urinalysis with qualitative analysis for protein will be performed at C2D1 and every other cycle thereafter. Positive results may require quantitative analysis (assessment 
of urine protein to creatinine ratio). Refer to Section 10.4.14 for required clinical urinalysis tests.
q A stool sample for fecal immunochemical testing may be collected within 4 days before dosing on C2D1 and C3D1. If a patient has a positive FIT at screening, no further collection 
is required.
r A blood sample will be obtained predose on C2D1 for measurement of cardiac enzymes in serum that monitor for acute injury (ie, troponin I or T) or chronic or progressive failure 
(ie, B-type natriuretic peptide [BNP] or N-terminal pro-brain natriuretic peptide [NT-proBNP]). 
s From Cycle 7 and beyond the hematology and chemistry tests and vital sign measurements will only be conducted on Day 1 of each cycle if in the opinion of the investigators is safe.
t After EOT, only related SAEs must be reported to the sponsor’s Department of Pharmacovigilance or designee.
Note: Tests and procedures should be performed on schedule, but occasional changes are allowable (±3 days) with permission of the medical monitor for holidays, vacations, and 
other administrative reasons. If extenuating circumstances prevent a patient from beginning treatment or completing a scheduled procedure or assessment within this time, 
the patient may continue the study only with the written permission of the medical monitor.
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CONFIDENTIAL
Table Ba Schedule of Events for Treatment Cycle 1 (Dosing Schedule B) (7 days on, 7 days off; 28-Day Cycle)
Screening a
Day
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
Informed consent
X
Inclusion/exclusion criteria
X
HBV, HCV, and HIV testing
X
Demographics
X
Medical history b
X
X
Physical examination b,t
X
X
X
X
X
Height
X
Weight
X
Vital signs c,t
X
X
X
X
X
X
X
X
(X)
(X)
(X)
(X)
(X)
(X)
(X)
X
X
X
X
X
X
X
(X)
(X)
(X)
(X)
(X)
(X)
(X)
ECOG performance status
X
12-Lead ECG d,e,t
X
X e
X e
X e
Continuous heart rhythm 
monitor f,t
X
X
X
ECHO/MUGA
X
Disease assessment g
X
Monitoring of concomitant 
medications and procedures
Recorded from first dose of study drug through up to 30 days after the last dose of study drug or before initiation of new 
anticancer therapy (whichever comes first).
Adverse event reporting
Recorded from first dose of study drug through up to 30 days after the last dose of study drug or before initiation of new 
anticancer therapy (whichever comes first).
Serious adverse events h will be reported from signing of the informed consent form through 30 days after the last dose of study drug or before initiation of new anticancer
therapy (whichever comes first).
TAK-931 administration i
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Footnotes are on last table page.
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TAK-931
Study No. TAK-931-1002
Page 95 of 145
Protocol Incorporating Amendment 04
23 February 2018
CONFIDENTIAL
Table Ba Schedule of Events for Treatment Cycle 1 (Dosing Schedule B) (7 days on 7 days off; 28-Day Cycle) (continued)
Screening a
Day
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
Samples/Laboratory Assessments
Pregnancy test j
X
X
Hematology/chemistry k,t
X
X
X
X
X l
X 
X
X 
X l
Urinalysis m
X
X
Fecal immunochemical testing
X
Blood sample for cardiac 
enzymes n,t
X
X
X
X
X
Skin punch p,r
X (or 
C1D1)
(X)
To be obtained postdose 
on any drug dosing day 
after 3 consecutive 
dosing days
To be obtained postdose 
on any drug dosing day 
after 3 consecutive 
dosing days
Urine and blood sample for PK
Urine and blood samples for PK analysis will be collected on the days and time points specified in Table Gb.
Abbreviations: BID, twice daily; BP, blood pressure; CxDx, Cycle x, Day x; Cmax, maximum observed plasma concentration; CT, computed tomography; ECG, electrocardiogram; ECHO, echocardiogram; 
ECOG, Eastern Cooperative Oncology Group; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; ICF, informed consent form; IEC, independent ethics committee; IRB, 
institutional review board; MRI, magnetic resonance imaging; MUGA, multiple gated acquisition (scan); PK, pharmacokinetic(s); POTS, postural orthostatic tachycardia syndrome; QD, once daily.
a Unless otherwise noted, the screening visit must occur within 28 days before administration of the first dose of study drug (C1D1). The ICF may be signed more than 28 days before C1D1.
b The C1D1 physical examination and medical history are not required if the screening physical examination was conducted and medical history obtained within 4 days before administration of the first dose 
of study drug (C1D1).
c Perform vital sign measurements including orthostatic measurements before dosing. Also, perform vital sign measurements on C1D1, C1D2, C1D3, and C1D7 at 2, 4, and 8 hours postdose (just before PK 
sampling). On C1D4 to C1D6 and C1D15 to C1D21, resting and orthostatic heart rate and BP will be assessed and recorded at the estimated Cmax time (approximately 2 hours postdose). If the investigator 
considers that it is otherwise safe, the patient can be discharged during dose holidays (ie, between Days 8-14 as well as after Day 22 assessments). If the investigator considers that it is in the patient’s best 
interest to remain hospitalized during the second and/or fourth week, then scheduled assessments in parentheses (X) will be performed and recorded. Orthostatic measurements of BP and pulse/heart rate 
should be conducted with the patient in a supine position after the patient has been resting quietly for 5 minutes, followed by a second measurement after the patient has been standing for 2 minutes. At 
screening, also measure heart rate after 10 minutes of quiet standing to confirm POTS. At least 3 separate resting (after 4 to 5 minutes’ rest in sitting position) BP measurements should be taken during the 
screening and the median of those measurements will be utilized as baseline BP reference of individual patient (median of systolic BP and diastolic BP will be evaluated separately).
d The schedule for ECG sampling may be modified based on data from previous cohorts. 
e All 12-lead ECG recordings should be made with the patient in a supine position. On C1D1, C1D7, and C1D21, a 12-lead ECG should be recorded before vital sign measurements and before 
administration of TAK-931; recordings should also be made at 2, 4, and 8 hours postdose on these days. As noted in footnote f, spot 12-lead ECG recordings may be done to assess an abnormal rhythm that 
is detected during monitoring and may require medical intervention. ECG should also be performed for patients experiencing Grade ≥2 hypotension during Cycle 1(See footnote f).
f Continuous patient heart rhythm monitoring while the patient is undergoing inpatient observation will start before the administration of the first dose of TAK-931 on C1D1 to C1D3 inclusive. For patients 
experiencing Grade ≥2 hypotension at any time during Cycle 1, continuous heart rhythm monitoring, and BP and ECG assessment at 2, 4, and 8 hours postdose should be performed in the following 3 
Property of Takeda: For non-commercial
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TAK-931
Study No. TAK-931-1002
Page 96 of 145
Protocol Incorporating Amendment 04
23 February 2018
CONFIDENTIAL
administration days even if they are at a reduced dose level. Spot 12-lead ECG assessments may be done to assess an abnormal rhythm that is detected during monitoring and may require medical 
intervention. Continuous monitoring should not interfere with in-hospital normal patient activities including eating, sleeping, walking, or personal care. 
g Baseline CT (with contrast) or MRI scan of the chest, abdomen, and pelvis must be obtained within 4 weeks before the first dose of TAK-931, according to standard of care. Bone scans may be performed 
on patients with bone metastases rather than CT or MRI. See Section 10.4.18 for more details.
h Including serious pretreatment events; see Section 11.2.
i TAK-931 will be administered orally QD (or BID) for 7 days followed by another 7 days of rest and repeated for a cycle duration of 28 days The starting dose will be 60 mg. Study drug will be 
administered to patients on an empty stomach. Patients should not eat for 2 hours before taking the capsules with 8 ounces of water. Patients should be instructed to eat a meal or snack >1 hour after taking 
the study drug. See Section 9.1. 
j A serum beta-human chorionic gonadotropin (β-hCG) pregnancy test will be performed only for women of childbearing potential during screening and again at C1D1 (baseline) if the screening test was 
performed more than 4 days before the first dose of study drug. The results must be negative within 4 days before the first dose of TAK-931 is administered (ie, within the 4 days before C1D1), or as 
otherwise required by local regulations. If C1D1 serum pregnancy results will not be available before dosing, a urine pregnancy test may be performed. Additional pregnancy testing may be performed 
during the study at the discretion of the investigator, upon request of an IEC/IRB, or if required by local regulations.
k The hematology and chemistry blood samples for C1D1 may be collected within 4 days before dosing to ensure patient eligibility on C1D1. If screening clinical laboratory testing was performed within 
4 days before the C1D1 dose, then testing does not need to be repeated on C1D1. See Section 10.4.14. New clinically significant Grade ≥2 results should be repeated within 3 days and followed until 
recovery.
l If a patient is discharged from hospital during drug holidays, the hematology and chemistry tests on Days 12 and 25 can be waived at investigator discretion.
m Complete urinalysis with qualitative analysis for protein at screening and C1D1. Positive results may require quantitative analysis (assessment of urine protein to creatinine ratio).Refer to Section 10.4.14
for required clinical urinalysis tests. If screening urinalysis was performed within 4 days before the C1D1 dose  urinalysis does not need to be repeated on C1D1.
n A blood sample will be obtained at the screening visit and predose on C1D1, C1D8, and C1D22 for measurement of cardiac enzymes in serum that monitor for acute injury (ie, troponin I or T) or chronic 
or progressive failure (ie, B-type natriuretic peptide [BNP] or N-terminal pro-brain natriuretic peptide [NT-proBNP]). For dose escalation cohorts, the test on C1D15 is not necessary. If screening cardiac 
enzymes measurement was performed within 4 days before the C1D1 dose, it does not need to be repeated on C1D1.
Skin punch biopsies (2-4 mm) will be obtained for all patients either during screening or predose on C1D1 and postdose on any drug dosing day after 3 consecutive dosing days (eg, Days 4-7 or Days 
18-21) in Cycle 1.
r It is strongly recommended that postdose skin biopsies 
 are collected between 4 to 9 hours after study drug administration (simultaneously if possible). 
 
 It is acceptable to use an archival predose biopsy collected before study enrollment if no other anticancer systemic treatment was administered between the 
biopsy collection and the enrollment in the study.
t Patients enrolled in the safety expansion cohorts are not required to be hospitalized for Cycle 1. Physical examination, vital sign measurement as well as hematology, chemistry, and cardiac enzyme 
tests will be performed at screening and on Days 1 and 15. Continuous heart rhythm monitoring is not required. Twelve-lead ECG measurements are required at screening and on C1D1. The other tests or 
examinations will be the same as dose escalation cohorts.
Note: Tests and procedures should be performed on schedule, but occasional changes are allowable (±3 days) with permission of the medical monitor for holidays, vacations, and other administrative 
reasons. If extenuating circumstances prevent a patient from beginning treatment or completing a scheduled procedure or assessment within this time, the patient may continue the study only 
with the written permission of the medical monitor.
Property of Takeda: For non-co
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Page 97 of 145
Protocol Incorporating Amendment 04
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CONFIDENTIAL
Table Bb Schedule of Events for Treatment Cycle 2 Through PFS Follow-up (Dosing Schedule B) (7 days on, 7 days off; 28-Day 
Cycle)
Cycle 2 and Subsequent Cycles
EOT a
PFSFU
Day 1
Day 5
Day 8
Day 15
Day 18
Day 22
Symptom-directed physical examination b
X
X
Weight
X c
X
Vital signs d,s
X
X
X
ECOG performance status e
X
X
12-Lead ECG f
X
X
ECHO/MUGA g
X
X
Disease assessment h
X
(starting at C3 and 
performed between 
D22 and D1 of the 
next cycle, then Q3C 
thereafter)
X i
X j (Q 
12 weeks)
Monitoring of concomitant medications and 
procedures
Recorded from first dose of study drug through up to 30 days after the last dose of study drug or before 
initiation of new anticancer therapy (whichever comes first).
Adverse event reporting
Recorded from first dose of study drug through up to 30 days after the last dose of study drug or before 
initiation of new anticancer therapy (whichever comes first).
Serious adverse events k will be reported from signing of the informed consent form through 30 days after the last 
dose of study drug or before initiation of new anticancer therapy (whichever comes first).
X t
TAK-931 administration l
Days 1 through 7 of each treatment cycle
Days 15 through 21 of each treatment cycle
Samples/Laboratory Assessments
Pregnancy Test m
X
Hematology/Chemistry n,s
X
X o
X o
X
X o
X o
X
Urinalysis p
X p
Fecal immunochemical testing q
X
Blood sample for cardiac enzymes r
X
Abbreviations: BID, twice daily; BP, blood pressure; C, cycle; CxDx, Cycle x, Day x; CT, computed tomography; ECG, electrocardiogram; ECHO, echocardiogram; ECOG, Eastern 
Cooperative Oncology Group; EOT, End of Treatment; FIT, fusion-inferred threshold; IEC, independent ethics committee; IRB, institutional review board; MRI, magnetic resonance 
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Page 98 of 145
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CONFIDENTIAL
imaging; MUGA, multiple gated acquisition (scan); PFSFU, progression-free survival follow-up; Q, every; QD, once daily.
a Patients who discontinue TAK-931 treatment early should complete the EOT visit approximately 30-40 days after the last dose of TAK-931 or before the start of subsequent 
anticancer therapy if that occurs sooner.
b The symptom-directed physical examination will be conducted within 3 days prior to dosing on Day 1 of each treatment cycle and at the EOT visit. The symptom-directed physical 
examination may be performed at other visits during the treatment cycle at the discretion of the investigator.
c Weight will be measured every other cycle, beginning with Cycle 3.
d Perform vital sign measurements including orthostatic measurements prior to dosing. Orthostatic measurements of BP and pulse should be conducted with the patient in a supine 
position after the patient has been resting quietly for 5 minutes followed by a second measurement after the patient has been standing for 2 minutes. 
e ECOG performance status will be performed within 3 days before the beginning (Day 1) of each treatment cycle and at the EOT visit.
f Predose, single safety ECGs will be collected on Day 1 of Cycle 2 and at the EOT visit. Additional ECGs may be obtained as clinically indicated at the discretion of the investigator. 
ECG assessments are to be performed with the patient supine and rested for 5 minutes.
g ECHO and/or MUGA should be performed predose on C2D1 and at the EOT visit. The same modality should be used as on the screening visit.
h Baseline CT (with contrast) or MRI scan of the chest, abdomen, and pelvis must be at screening, after which CT (with contrast) or MRI may be performed at the end of every third 
cycle (ie, on or before the start of Cycle 4, Day 1; Cycle 7, Day 1; Cycle 10, Day 1, etc), as clinically indicated, according to standard of care. The same imaging modality (CT [with 
contrast] MRI, or bone scan) should be used on a patient as at the screening visit and throughout the study. Bone scans may be performed on patients with bone metastases rather than 
CT or MRI. See Section 10.4.18 for more details.
i At EOT, tumor assessments will be done only on patients who have not previously demonstrated disease progression in the study unless completed within the previous 4 weeks.
j Patients who discontinue study treatment for reasons other than PD will undergo CT/MRI scans every 12 weeks (±1 week) from EOT until the occurrence of PD, the start of 
subsequent antineoplastic therapy, or until 6 months after discontinuation of study treatment, whichever occurs first. 
k Including serious pretreatment events; see Section 11.2.
l TAK-931 will be administered orally QD (or BID) for 7 days followed by another 7 days of rest and repeated for a cycle duration of 28 days. The starting dose will be 60 mg. Study 
drug will be administered to patients on an empty stomach. Patients should not eat for 2 hours before taking the capsules with 8 ounces of water. Patients should be instructed to eat 
a meal or snack >1 hour after taking study drug. See Section 9.1.
m Additional pregnancy testing may be performed during the study at the discretion of the investigator, upon request of an IEC/IRB, or if required by local regulations.
n See Section 9.4. New Grade ≥3 results should be repeated a minimum of every 3 days until recovered to Grade ≤2.
o The hematology and chemistry blood samples on Days 5, 8, 18 and 22 of each cycle starting with Cycle 2 may be waived if there is no evidence of Grade ≥3 analytical toxicity in the 
previous cycle.
p Complete urinalysis with qualitative analysis for protein will be performed at C2D1 and every other cycle thereafter. Positive results may require quantitative analysis (assessment 
of urine protein to creatinine ratio). Refer to Section 10.4.14 for required clinical urinalysis tests.
q A stool sample for fecal immunochemical testing may be collected within 4 days before dosing on C2D1 and C3D1. If a patient has a positive FIT at screening, no further collection 
is required.
r A blood sample will be obtained predose on C2D1 for measurement of cardiac enzymes in serum that monitor for acute injury (ie, troponin I or T) or chronic or progressive failure
(ie, B-type natriuretic peptide [BNP] or N-terminal pro-brain natriuretic peptide [NT-proBNP]). 
s From Cycle 7 and beyond the hematology and chemistry tests and vital sign measurements will only be conducted on Day 1 of each cycle if in the opinion of the investigators is safe.
t After EOT, only related SAEs must be reported to the sponsor’s Department of Pharmacovigilance or designee.
Note: Tests and procedures should be performed on schedule, but occasional changes are allowable (±3 days) with permission of the medical monitor for holidays, vacations, and 
other administrative reasons. If extenuating circumstances prevent a patient from beginning treatment or completing a scheduled procedure or assessment within this time, 
the patient may continue the study only with the written permission of the medical monitor.
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TAK-931
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Page 99 of 145
Protocol Incorporating Amendment 04
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CONFIDENTIAL
Table Ca Schedule of Events for Treatment Cycle 1 (Dosing Schedule C) (7 days on, 14 days off; 21-day Cycle)
Screening a
Day
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
Informed consent
X
Inclusion/exclusion criteria
X
HBV, HCV, and HIV testing
X
Demographics
X
Medical history b
X
X
Physical examination b,t
X
X
X
Height
X
Weight
X
Vital signs c,t
X
X
X
X
X
X
X
X
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
ECOG performance status
X
12-Lead ECG d,e,t
X
X e
X e
Continuous heart rhythm 
monitor f,t
X
X
X
ECHO/MUGA
X
Disease assessment g
X
Monitoring of concomitant 
medications and procedures
Recorded from first dose of study drug through up to 30 days after the last dose of study drug or before 
initiation of new anticancer therapy (whichever comes first).
Adverse event reporting
Recorded from first dose of study drug through up to 30 days after the last dose of study drug or before 
initiation of new anticancer therapy (whichever comes first).
Serious adverse events h will be reported from signing of the informed consent form through 30 days after the last dose of study drug or before 
initiation of new anticancer therapy (whichever comes first).
TAK-931 administration i
X
X
X
X
X
X
X
Footnotes are on last table page.
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TAK-931
Study No. TAK-931-1002
Page 100 of 145
Protocol Incorporating Amendment 04
23 February 2018
CONFIDENTIAL
Table Ca Schedule of Events for Treatment Cycle 1 (Dosing Schedule C) (7 days on 14 days off; 21-day Cycle) (continued)
Screening (a)
Day
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
Samples/Laboratory Assessments
Pregnancy testj
X
X
Hematology/chemistryk,t
X
X
X
X
X l
X
X l
Urinalysis m
X
X
Fecal immunochemical 
testing
X
Blood sample for cardiac 
enzymes n,t
X
X
X
X
Skin punch p,r
X (or C1D1)
(X)
To be obtained postdose on 
any drug dosing day after 3 
consecutive dosing days.
Urine and blood sample for 
PK
Urine and blood samples for PK analysis will be collected on the days and time points specified in Table Gc.
Abbreviations: BID, twice daily; BP, blood pressure; CxDx, Cycle x, Day x; Cmax, maximum observed plasma concentration; CT, computed tomography; ECG, electrocardiogram; 
ECHO, echocardiogram; ECOG, Eastern Cooperative Oncology Group; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; ICF, informed consent 
form; IEC, independent ethics committee; IRB, institutional review board; MRI, magnetic resonance imaging; MUGA, multiple gated acquisition (scan); PK, pharmacokinetic(s); 
POTS, postural orthostatic tachycardia syndrome; QD, once daily.
a Unless otherwise noted, the screening visit must occur within 28 days before administration of the first dose of study drug (C1D1). The ICF may be signed more than 28 days before 
C1D1.
b The C1D1 physical examination and medical history are not required if the screening physical examination was conducted and medical history obtained within 4 days before 
administration of the first dose of study drug (C1D1).
c Perform vital sign measurements including orthostatic measurements before dosing. Also, perform vital sign measurements on C1D1, C1D2, C1D3, and C1D7 at 2, 4, and 8 hours 
postdose (just before PK sampling). On C1D4 to C1D6, resting and orthostatic heart rate and BP will be assessed and recorded at the estimated Cmax time (approximately 2 hours 
postdose). If the investigator considers that it is otherwise safe, the patient can be discharged after D8 assessments. If the investigator considers that it is in the patient’s best interest 
to remain hospitalized during the second and third weeks, then scheduled assessments in parentheses (X) will be performed and recorded. Orthostatic measurements of BP and 
pulse/heart rate should be conducted with the patient in a supine position after the patient has been resting quietly for 5 minutes followed by a second measurement after the patient has 
been standing for 2 minutes. At screening, also measure heart rate after 10 minutes of quiet standing to confirm POTS. At least 3 separate resting (after 4 to 5 minutes’ rest in sitting 
Property of Takeda: For non-commer
use o
d subject to the applicable Terms of Use
le
; 21
; 21-day
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TAK-931
Study No. TAK-931-1002
Page 101 of 145
Protocol Incorporating Amendment 04
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CONFIDENTIAL
position) BP measurements should be taken during the screening and the median of those measurements will be utilized as baseline BP reference of individual patient (median of 
systolic BP and diastolic BP will be evaluated separately).
d The schedule for ECG sampling may be modified based on data from previous cohorts. 
e All 12-lead ECG recordings should be made with the patient in a supine position. On C1D1 and C1D7, a 12-lead ECG should be recorded before vital sign measurements and before 
administration of TAK-931; recordings should also be made at 2, 4, and 8 hours postdose on these days. As noted in footnote f, spot 12-lead ECG recordings may be done to assess an 
abnormal rhythm that is detected during monitoring and may require medical intervention. ECG should also be performed for patients experiencing Grade ≥2 hypotension during 
Cycle 1(See footnote f).
f Continuous patient heart rhythm monitoring while the patient is undergoing inpatient observation will start before the administration of the first dose of TAK-931 on C1D1 to C1D3 
inclusive. For patients experiencing Grade ≥2 hypotension at any time during Cycle 1, continuous heart rhythm monitoring, and BP and ECG assessment at 2, 4, and 8 hours postdose 
should be performed in the following 3 administration days even if they are at a reduced dose level. Spot 12-lead ECG assessments may be done to assess an abnormal rhythm that is 
detected during monitoring and may require medical intervention. Continuous monitoring should not interfere with in-hospital normal patient activities including eating, sleeping, 
walking, or personal care. 
g Baseline CT (with contrast) or MRI scan of the chest, abdomen, and pelvis must be obtained within 4 weeks before the first dose of TAK-931, according to standard of care. Bone 
scans may be performed on patients with bone metastases rather than CT or MRI. See Section 10.4.18 for more details.
h Including serious pretreatment events; see Section 11.2.
i TAK-931 will be administered orally QD (or BID) for 7 days of a 21-day cycle followed by 14 days off. The starting dose will be maximum administered dose in Schedule B. Study 
drug will be administered to patients on an empty stomach. Patients should not eat for 2 hours before taking the capsules with 8 ounces of water. Patients should be instructed to eat 
a meal or snack >1 hour after taking the study drug. See Section 9.1. 
j A serum beta-human chorionic gonadotropin (β-hCG) pregnancy test will be performed only for women of childbearing potential during screening and again at C1D1 (baseline) if 
the screening test was performed more than 4 days before the first dose of study drug. The results must be negative within 4 days before the first dose of TAK-931 is administered (ie, 
within the 4 days before C1D1), or as otherwise required by local regulations. If C1D1 serum pregnancy results will not be available before dosing, a urine pregnancy test may be 
performed. Additional pregnancy testing may be performed during the study at the discretion of the investigator, upon request of an IEC/IRB, or if required by local regulations.
k The hematology and chemistry blood samples for C1D1 may be collected within 4 days before dosing to ensure patient eligibility on C1D1. If screening clinical laboratory testing 
was performed within 4 days before the C1D1 dose, then testing does not need to be repeated on C1D1. See Section 10.4.14. New clinically significant Grade ≥2 results should be 
repeated within 3 days and followed until recovery.
l If a patient is discharged from hospital during drug holidays, the hematology and chemistry tests on Days 12 and 18 can be waived at investigator discretion.
m Complete urinalysis with qualitative analysis for protein at screening and C1D1. Positive results may require quantitative analysis (assessment of urine protein to creatinine 
ratio).Refer to Section 10.4.14 for required clinical urinalysis tests. If screening urinalysis was performed within 4 days before the C1D1 dose, urinalysis does not need to be repeated 
on C1D1.
n A blood sample will be obtained at the screening visit and predose on C1D1 and C1D8 for measurement of cardiac enzymes in serum that monitor for acute injury (ie, troponin I or 
T) or chronic or progressive failure (ie, B-type natriuretic peptide [BNP] or N-terminal pro-brain natriuretic peptide [NT-proBNP]). For dose escalation cohorts, the test on C1D15 is 
not necessary  If screening cardiac enzymes measurement was performed within 4 days before the C1D1 dose, it does not need to be repeated on C1D1.
p Skin punch biopsies (2-4 mm) will be obtained for all patients either during screening or before study drug administration on C1D1 and postdose on any drug dosing day after 3 
consecutive dosing days (eg, Days 4-7) in Cycle 1.
It is strongly recommended that postdose skin biopsies 
 are collected between 4 to 9 hours after study drug administration (simultaneously if possible). 
 
 It is acceptable to use an archival predose biopsy collected before study enrollment if no other anticancer 
Property o
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non-commercial use only and subject to the applicable Terms of Use
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TAK-931
Study No. TAK-931-1002
Page 102 of 145
Protocol Incorporating Amendment 04
23 February 2018
CONFIDENTIAL
systemic treatment was administered between the biopsy collection and the enrollment in the study.
Patients enrolled in the safety expansion cohorts are not required to be hospitalized for Cycle 1. Physical examination and 12-lead ECG measurements will be performed at 
screening and on Day 1. Vital sign measurement as well as hematology, chemistry, and cardiac enzyme tests will be performed at screening and on Days 1 and 15. Continuous heart 
rhythm monitoring is not required. The other tests or examinations will be the same as dose escalation cohorts.
Note: Tests and procedures should be performed on schedule, but occasional changes are allowable (±3 days) with permission of the medical monitor for holidays, vacations, and 
other administrative reasons. If extenuating circumstances prevent a patient from beginning treatment or completing a scheduled procedure or assessment within this time, 
the patient may continue the study only with the written permission of the medical monitor.
Property of Takeda: For non-commercial use only and subject to the ap
ble Terms of Use
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TAK-931
Study No. TAK-931-1002
Page 103 of 145
Protocol Incorporating Amendment 04
23 February 2018
CONFIDENTIAL
Table Cb Schedule of Events for Treatment Cycle 2 Through PFS Follow-up (Dosing Schedule C) (7 days on, 14 days off; 
21-Day Cycle)
Cycle 2 and Subsequent Cycles
EOT a
PFSFU
Day 1
Day 5
Day 8
Day 12
Day 15
Day 18
Symptom-directed physical examination b
X
X
Weight
X c
X
Vital signs d
X
X
ECOG performance status e
X
X
12-Lead ECG f
X
X
ECHO/MUGA g
X
X
Disease assessment h
X
(starting at C3 and 
performed between 
D15 and D1 of the 
next cycle, then Q3C 
thereafter).
X i
X j
(Q 12 weeks)
Monitoring of concomitant medications and 
procedures
Recorded from first dose of study drug through up to 30 days after the last dose of study drug or before 
initiation of new anticancer therapy (whichever comes first).
Adverse event reporting
Recorded from first dose of study drug through up to 30 days after the last dose of study drug or before 
initiation of new anticancer therapy (whichever comes first).
Serious adverse events k will be reported from signing of the informed consent form through 30 days after the last dose 
of study drug or before initiation of new anticancer therapy (whichever comes first).
X s
TAK-931 administration l
Days 1 through 7 of each treatment cycle
Samples/Laboratory Assessments
Pregnancy Test m
X
Hematology/Chemistry n
X
X o
X o
X o
X
X o
X
Urinalysis p
X p
Fecal immunochemical testing q
X
Blood sample for cardiac enzymes r
X
Abbreviations: BID, twice daily; BP, blood pressure; C, cycle; CxDx, Cycle x, Day x; CT, computed tomography; ECG, electrocardiogram; ECHO, echocardiogram; ECOG, Eastern 
Cooperative Oncology Group; EOT, End of Treatment; FIT, fusion-inferred threshold; IEC, independent ethics committee; IRB, institutional review board; MRI, magnetic resonance 
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TAK-931
Study No. TAK-931-1002
Page 104 of 145
Protocol Incorporating Amendment 04
23 February 2018
CONFIDENTIAL
imaging; MUGA, multiple gated acquisition (scan); PFSFU, progression-free survival follow-up; Q, every; QD, once daily.
a Patients who discontinue TAK-931 treatment early should complete the EOT visit approximately 30-40 days after the last dose of TAK-931 or before the start of subsequent 
anticancer therapy if that occurs sooner.
b The symptom-directed physical examination will be conducted within 3 days prior to dosing on Day 1 of each treatment cycle and at the EOT visit. The symptom-directed physical 
examination may be performed at other visits during the treatment cycle at the discretion of the investigator.
c Weight will be measured every other cycle, beginning with Cycle 3.
d Perform vital sign measurements including orthostatic measurements prior to dosing. Orthostatic measurements of BP and pulse should be conducted with the patient in a supine 
position after the patient has been resting quietly for 5 minutes followed by a second measurement after the patient has been standing for 2 minutes. 
e ECOG performance status will be performed within 3 days before the beginning (Day 1) of each treatment cycle and at the EOT visit.
f Predose, single safety ECGs will be collected on Day 1 of Cycle 2 and at the EOT visit. Additional ECGs may be obtained as clinically indicated at the discretion of the investigator. 
ECG assessments are to be performed with the patient supine and rested for 5 minutes.
g ECHO and/or MUGA should be performed predose on C2D1 and at the EOT visit. The same modality should be used as on the screening visit.
h Baseline CT (with contrast) or MRI scan of the chest, abdomen, and pelvis must be at screening, after which CT (with contrast) or MRI may be performed at the end of every third 
cycle (ie, on or before the start of Cycle 4, Day 1; Cycle 7, Day 1; Cycle 10, Day 1, etc), as clinically indicated, according to standard of care. The same imaging modality (CT [with 
contrast] MRI, or bone scan) should be used on a patient as at the screening visit and throughout the study. Bone scans may be performed on patients with bone metastases rather than 
CT or MRI. See Section 10.4.18 for more details.
i At EOT, tumor assessments will be done only on patients who have not previously demonstrated disease progression in the study unless completed within the previous 4 weeks.
j Patients who discontinue study treatment for reasons other than PD will undergo CT/MRI scans every 12 weeks (±1 week) from EOT until the occurrence of PD, the start of 
subsequent antineoplastic therapy, or until 6 months after discontinuation of study treatment, whichever occurs first.
k Including serious pretreatment events; see Section 11.2.
l TAK-931 will be administered orally QD (or BID) for 7 days of a 21-day cycle followed by 14 days off. The starting dose will be maximum administered dose in Schedule B. Study 
drug will be administered to patients on an empty stomach. Patients should not eat for 2 hours before taking the capsules with 8 ounces of water. Patients should be instructed to eat 
a meal or snack >1 hour after taking study drug. See Section 9.1.
m Additional pregnancy testing may be performed during the study at the discretion of the investigator, upon request of an IEC/IRB, or if required by local regulations.
n See Section 9.4. New Grade ≥3 results should be repeated a minimum of every 3 days until recovered to Grade ≤2.
o The hematology and chemistry blood samples on Days 5, 8, 12, and 18 of each cycle starting with Cycle 2 may be waived if there is no evidence of Grade ≥3 analytical toxicity in 
the previous cycle. From Cycle 7 and beyond the hematology and chemistry tests will only be conducted on Day 1 of each cycle if in the opinion of the investigators is safe.
p Complete urinalysis with qualitative analysis for protein will be performed at C2D1 and every other cycle thereafter. Positive results may require quantitative analysis (assessment 
of urine protein to creatinine ratio). Refer to Section 10.4.14 for required clinical urinalysis tests.
q A stool sample for fecal immunochemical testing may be collected within 4 days before dosing on C2D1 and C3D1. If a patient has a positive FIT at screening, no further collection 
is required.
r A blood sample will be obtained predose on C2D1 for measurement of cardiac enzymes in serum that monitor for acute injury (ie, troponin I or T) or chronic or progressive failure 
(ie, B-type natriuretic peptide [BNP] or N-terminal pro-brain natriuretic peptide [NT-proBNP]). 
s After EOT, only related SAEs must be reported to the sponsor’s Department of Pharmacovigilance or designee.
Note: Tests and procedures should be performed on schedule, but occasional changes are allowable (±3 days) with permission of the medical monitor for holidays, vacations, and 
other administrative reasons. If extenuating circumstances prevent a patient from beginning treatment or completing a scheduled procedure or assessment within this time, 
the patient may continue the study only with the written permission of the medical monitor.
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TAK-931
Study No. TAK-931-1002
Page 105 of 145
Protocol Incorporating Amendment 04
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CONFIDENTIAL
Table Da Schedule of Events for Treatment Cycle 1 (Dosing Schedule D) (Continuous Schedule; 21-Day Cycle)
Screening a
Day
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
Informed consent
X
Inclusion/exclusion criteria
X
HBV, HCV, and HIV testing
X
Demographics
X
Medical history b
X
X
Physical examination b,q
X
X
Height
X
Weight
X
Vital signs c,q
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECOG performance status
X
12-Lead ECG d,q
X
X d
ECHO/MUGA
X
Disease assessment e
X
Monitoring of concomitant 
medications and procedures
Recorded from first dose of study drug through up to 30 days after the last dose of study drug or before 
initiation of new anticancer therapy (whichever comes first).
Adverse event reporting
Recorded from first dose of study drug through up to 30 days after the last dose of study drug or before 
initiation of new anticancer therapy (whichever comes first).
Serious adverse events f will be reported from signing of the informed consent form through 30 days after the last dose of study drug or before 
initiation of new anticancer therapy (whichever comes first).
TAK-931 administration g
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Footnotes are on last table page.
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TAK-931
Study No. TAK-931-1002
Page 106 of 145
Protocol Incorporating Amendment 04
23 February 2018
CONFIDENTIAL
Table Da Schedule of Events for Treatment Cycle 1 (continued) (Dosing Schedule D) (Continuous Schedule; 21-day Cycle)
Screening a
Day
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
Samples/Laboratory Assessments
Pregnancy test h
X
X
Hematology/chemistry i,q
X
X
X
X
X
X
X
Urinalysis j
X
X
Fecal immunochemical 
testing
X
Blood sample for cardiac 
enzymes k
X
X
Skin punch m,o
X (or C1D1)
(X)
To be obtained postdose on any drug dosing day after 3 consecutive dosing days.
Urine and blood sample for 
PK
Urine and blood samples for PK analysis will be collected on the days and time points specified in Table Gd.
Abbreviations: BID, twice daily; BP, blood pressure; CxDx, Cycle x, Day x; Cmax, maximum observed plasma concentration; CT, computed tomography; ECG, electrocardiogram; 
ECHO, echocardiogram; ECOG, Eastern Cooperative Oncology Group; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; ICF, informed consent 
form; IEC, independent ethics committee; IRB, institutional review board; MRI, magnetic resonance imaging; MUGA, multiple gated acquisition (scan); PK, pharmacokinetic(s); 
POTS, postural orthostatic tachycardia syndrome; QD, once daily.
a Unless otherwise noted, the screening visit must occur within 28 days before administration of the first dose of study drug (C1D1). The ICF may be signed more than 28 days before 
C1D1.
b The C1D1 physical examination and medical history are not required if the screening physical examination was conducted and medical history obtained within 4 days before 
administration of the first dose of study drug (C1D1)
c Perform vital sign measurements including orthostatic and resting measurements at screening. On C1D1 resting heart rate and BP will be measured at predose. On C1D1 through 
C1D21, resting heart rate and BP will be assessed and recorded at the estimated Cmax time (approximately 2 hours postdose). Orthostatic measurements of BP and pulse/heart rate 
should be conducted with the patient in a supine position after the patient has been resting quietly for 5 minutes followed by a second measurement after the patient has been standing 
for 2 minutes. At screening, also measure heart rate after 10 minutes of quiet standing to confirm POTS. At least 3 separate resting (after 4 to 5 minutes’ rest in sitting position) BP 
measurements should be taken during the screening and the median of those measurements will be utilized as baseline BP reference of individual patient (median of systolic BP and 
diastolic BP will be evaluated separately).
d All 12-lead ECG recordings should be made with the patient in a supine position. On C1D1, a 12-lead ECG should be recorded before administration of TAK-931 and before vital 
Property of Takeda: For non-commercial
e o
d subject to the applicable Terms of Use
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TAK-931
Study No. TAK-931-1002
Page 108 of 145
Protocol Incorporating Amendment 04
23 February 2018
CONFIDENTIAL
Table Db Schedule of Events for Treatment Cycle 2 Through PFS Follow-up (Dosing Schedule D) (Continuous Schedule; 
21-day Cycle)
Cycle 2 and Subsequent Cycles
EOT a
PFSFU
Day 1
Day 5
Day 8
Day 12
Day 15
Day 18
Symptom-directed physical examination b
X
X
Weight
X c
X
Vital signs d
X
X
ECOG performance status e
X
X
12-Lead ECG f
X
X
ECHO/MUGA g
X
X
Disease assessment h
X
(starting at C3 and 
performed between 
D15 and D1 of the 
next cycle, then 
Q3C thereafter)
X i
X j
(Q 12 weeks)
Monitoring of concomitant medications and 
procedures
Recorded from first dose of study drug through up to 30 days after the last dose of study drug or before 
initiation of new anticancer therapy (whichever comes first).
Adverse event reporting
Recorded from first dose of study drug through up to 30 days after the last dose of study drug or before 
initiation of new anticancer therapy (whichever comes first).
Serious adverse events k will be reported from signing of the informed consent form through 30 days after the last dose 
of study drug or before initiation of new anticancer therapy (whichever comes first).
X s
TAK-931 administration l
Days 1 through 21 of each treatment cycle
Samples/Laboratory Assessments
Pregnancy Test m
X
Hematology/Chemistry n
X
X o
X
X o
X
X o
X
Urinalysis p
X p
Fecal immunochemical testing q
X
Blood sample for cardiac enzymes r
X
Abbreviations: BID, twice daily; BP, blood pressure; C, cycle; CxDx, Cycle x, Day x; CT, computed tomography; ECG, electrocardiogram; ECHO, echocardiogram; ECOG, Eastern 
Cooperative Oncology Group; EOT, End of Treatment; FIT, fusion-inferred threshold; IEC, independent ethics committee; IRB, institutional review board; MRI, magnetic resonance 
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TAK-931
Study No. TAK-931-1002
Page 109 of 145
Protocol Incorporating Amendment 04
23 February 2018
CONFIDENTIAL
imaging; MUGA, multiple gated acquisition (scan); PFSFU, progression-free survival follow-up; Q, every; QD, once daily.
a Patients who discontinue TAK-931 treatment early should complete the EOT visit approximately 30-40 days after the last dose of TAK-931 or before the start of subsequent 
anticancer therapy if that occurs sooner.
b The symptom-directed physical examination will be conducted within 3 days prior to dosing on Day 1 of each treatment cycle and at the EOT visit. The symptom-directed physical 
examination may be performed at other visits during the treatment cycle at the discretion of the investigator.
c Weight will be measured every other cycle, beginning with Cycle 3.
d Perform resting vital sign measurement (after 4 to 5 minutes’ rest in sitting position) prior to dosing.
e ECOG performance status will be performed within 3 days before the beginning (Day 1) of each treatment cycle and at the EOT visit.
f Predose, single safety ECGs will be collected on Day 1 of Cycle 2 and at the EOT visit. Additional ECGs may be obtained as clinically indicated at the discretion of the investigator. 
ECG assessments are to be performed with the patient supine and rested for 5 minutes.
g ECHO and/or MUGA should be performed predose on C2D1 and at the EOT visit. The same modality should be used as on the screening visit.
h Baseline CT (with contrast) or MRI scan of the chest, abdomen, and pelvis must be at screening, after which CT (with contrast) or MRI may be performed at the end of every third 
cycle (ie, on or before the start of Cycle 4, Day 1; Cycle 7, Day 1; Cycle 10, Day 1, etc), as clinically indicated, according to standard of care. The same imaging modality (CT [with 
contrast] MRI, or bone scan) should be used on a patient as at the screening visit and throughout the study. Bone scans may be performed on patients with bone metastases rather than 
CT or MRI. See Section 10.4.18 for more details.
i At EOT, tumor assessments will be done only on patients who have not previously demonstrated disease progression in the study unless completed within the previous 4 weeks.
j Patients who discontinue study treatment for reasons other than PD will undergo CT/MRI scans every 12 weeks (±1 week) from EOT until the occurrence of PD, the start of 
subsequent antineoplastic therapy, or until 6 months after discontinuation of study treatment, whichever occurs first.
k Including serious pretreatment events; see Section 11.2.
l TAK-931 will be administered orally QD (or BID) continuously in a 21-day cycle. The starting dose will be 20 mg. Study drug will be administered to patients on an empty stomach. 
Patients should not eat for 2 hours before taking the capsules with 8 ounces of water. Patients should be instructed to eat a meal or snack >1 hour after taking study drug. See 
Section 9.1.
m Additional pregnancy testing may be performed during the study at the discretion of the investigator, upon request of an IEC/IRB, or if required by local regulations.
n See Section 9.4. New Grade ≥3 results should be repeated a minimum of every 3 days until recovered to Grade ≤2.
o The hematology and chemistry blood samples on Days 5, 12, and 18 of each cycle starting with Cycle 2 may be waived if there is no evidence of Grade ≥3 analytical toxicity in the 
previous cycle. From Cycle 7 and beyond the hematology and chemistry tests will only be conducted on Day 1 of each cycle if in the opinion of the investigators is safe.
p Complete urinalysis with qualitative analysis for protein will be performed at C2D1 and every other cycle thereafter. Positive results may require quantitative analysis (assessment 
of urine protein to creatinine ratio). Refer to Section 10.4.14 for required clinical urinalysis tests.
q A stool sample for fecal immunochemical testing may be collected within 4 days before dosing on C2D1 and C3D1. If a patient has a positive FIT at screening, no further collection 
is required.
r A blood sample will be obtained predose on C2D1 for measurement of cardiac enzymes in serum that monitor for acute injury (ie, troponin I or T) or chronic or progressive failure 
(ie, B-type natriuretic peptide [BNP] or N-terminal pro-brain natriuretic peptide [NT-proBNP]).
s After EOT, only related SAEs must be reported to the sponsor’s Department of Pharmacovigilance or designee.
Note: Tests and procedures should be performed on schedule, but occasional changes are allowable (±3 days) with permission of the medical monitor for holidays, vacations, and 
other administrative reasons. If extenuating circumstances prevent a patient from beginning treatment or completing a scheduled procedure or assessment within this time, 
the patient may continue the study only with the written permission of the medical monitor.
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TAK-931
Study No. TAK-931-1002
Page 110 of 145
Protocol Incorporating Amendment 04
23 February 2018
CONFIDENTIAL
Table Ea Schedule of Events for Treatment Cycle 1 (Dosing Schedule E) (Daily for 2 Days Followed by 5 Days of Rest per Week 
in a 21-Day Cycle)
Screening a
Day
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
Informed consent
X
Inclusion/exclusion criteria
X
HBV, HCV, and HIV testing
X
Demographics
X
Medical history b
X
X
Physical examination b,q
X
X
X
X
Height
X
Weight
X
Vital signs c,q
X
X
X
(X)
(X)
(X)
(X)
(X)
X
X
(X)
(X)
(X)
(X)
(X)
X
X
(X)
(X)
(X)
(X)
(X)
ECOG performance status
X
12-Lead ECG d,q
X
X d
X
X
ECHO/MUGA
X
Disease assessment e
X
Monitoring of concomitant 
medications and procedures
Recorded from first dose of study drug through up to 30 days after the last dose of study drug or before 
initiation of new anticancer therapy (whichever comes first).
Adverse event reporting
Recorded from first dose of study drug through up to 30 days after the last dose of study drug or before 
initiation of new anticancer therapy (whichever comes first).
Serious adverse events f will be reported from signing of the informed consent form through 30 days after the last dose of study drug or before 
initiation of new anticancer therapy (whichever comes first).
Continuous heart rhythm 
monitor r,q
X
X
X
X
X
X
TAK-931 administration g
X
X
X
X
X
X
Footnotes are on last table page.
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TAK-931
Study No. TAK-931-1002
Page 111 of 145
Protocol Incorporating Amendment 04
23 February 2018
CONFIDENTIAL
Table Ea Schedule of Events for Treatment Cycle 1 (continued) (Dosing Schedule E) (Daily for 2 Days Followed by 5 Days of 
Rest per Week in a 21-Day Cycle)
Screening a
Day
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
Samples/Laboratory Assessments
Pregnancy test h
X
X
Hematology/chemistry i,q
X
X
X
X
X
X
X
Urinalysis j
X
X
Fecal immunochemical 
testing
X
Blood sample for cardiac 
enzymes k
X
X
X
X
Skin punch m,o 
X (or C1D1)
(X)
X
Urine and blood sample for 
PK
Urine and blood samples for PK analysis will be collected on the days and time points specified in Table Ge,f.
Abbreviations: BID, twice daily; BP, blood pressure; CxDx, Cycle x, Day x; Cmax, maximum observed plasma concentration; CT, computed tomography; ECG, electrocardiogram; 
ECHO, echocardiogram; ECOG, Eastern Cooperative Oncology Group; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; ICF, informed consent 
form; IEC, independent ethics committee; IRB, institutional review board; MRI, magnetic resonance imaging; MUGA, multiple gated acquisition (scan); PK, pharmacokinetic(s); 
POTS, postural orthostatic tachycardia syndrome; QD, once daily.
Note: Parentheses indicate the test or procedure is to be performed under certain conditions. 
a Unless otherwise noted, the screening visit must occur within 28 days before administration of the first dose of study drug (C1D1). The ICF may be signed more than 28 days before 
C1D1.
b The C1D1 physical examination and medical history are not required if the screening physical examination was conducted and medical history obtained within 4 days before 
administration of the first dose of study drug (C1D1).
c Perform vital sign measurements including orthostatic measurements before dosing. Also, perform vital sign measurements on C1D1, C1D2, C1D8, C1D9, C1D15, and C1D16 at 2, 
4, and 8 hours postdose (just before PK sampling if on PK sampling day). If the investigator considers that it is otherwise safe, the patient can be discharged during dose holidays. If 
the investigator considers that it is in the patient’s best interest to remain hospitalized, then scheduled assessments in parentheses (X) will be performed and recorded. Orthostatic 
measurements of BP and pulse/heart rate should be conducted with the patient in a supine position after the patient has been resting quietly for 5 minutes followed by a second 
measurement after the patient has been standing for 2 minutes. At screening, also measure heart rate after 10 minutes of quiet standing to confirm POTS. At least 3 separate resting 
Property of Takeda: For non-commerc
u
and subject to the applicable Terms of Use
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TAK-931
Study No. TAK-931-1002
Page 113 of 145
Protocol Incorporating Amendment 04
23 February 2018
CONFIDENTIAL
Note: Tests and procedures should be performed on schedule, but occasional changes are allowable (±3 days) with permission of the medical monitor for holidays, vacations, and 
other administrative reasons. If extenuating circumstances prevent a patient from beginning treatment or completing a scheduled procedure or assessment within this time, 
the patient may continue the study only with the written permission of the medical monitor.
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TAK-931
Study No. TAK-931-1002
Page 114 of 145
Protocol Incorporating Amendment 04
23 February 2018
CONFIDENTIAL
Table Eb Schedule of Events for Treatment Cycle 2 Through PFS Follow-up (Dosing Schedule E) (Daily for 2 Days Followed by 
5 Days of Rest per Week in a 21-Day Cycle)
Cycle 2 and Subsequent Cycles
EOT a
PFSFU
Day 1
Day 5
Day 8
Day 12
Day 15
Day 18
Symptom-directed physical examination b
X
X
Weight
X c
X
Vital signs d
X
X
ECOG performance status e
X
X
12-Lead ECG f
X
X
ECHO/MUGA g
X
X
Disease assessment h
X
(starting at C3 and 
performed between 
D15 and D1 of the 
next cycle, then 
Q3C thereafter)
X i
X j
(Q 12 weeks)
Monitoring of concomitant medications and 
procedures
Recorded from first dose of study drug through up to 30 days after the last dose of study drug or before 
initiation of new anticancer therapy (whichever comes first).
Adverse event reporting
Recorded from first dose of study drug through up to 30 days after the last dose of study drug or before 
initiation of new anticancer therapy (whichever comes first).
Serious adverse events k will be reported from signing of the informed consent form through 30 days after the last dose 
of study drug or before initiation of new anticancer therapy (whichever comes first).
X s
TAK-931 administration l
Days 1, 2, 8, 9, 15, and 16 of each treatment cycle
Samples/Laboratory Assessments
Pregnancy Test m
X
Hematology/Chemistry n
X
X o
X
X o
X
X o
X
Urinalysis p
X p
Fecal immunochemical testing q
X
Blood sample for cardiac enzymes r
X
Abbreviations: BID, twice daily; BP, blood pressure; C, cycle; CxDx, Cycle x, Day x; CT, computed tomography; ECG, electrocardiogram; ECHO, echocardiogram; ECOG, Eastern 
Cooperative Oncology Group; EOT, End of Treatment; FIT, fusion-inferred threshold; IEC, independent ethics committee; IRB, institutional review board; MRI, magnetic resonance 
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TAK-931
Study No. TAK-931-1002
Page 115 of 145
Protocol Incorporating Amendment 04
23 February 2018
CONFIDENTIAL
imaging; MUGA, multiple gated acquisition (scan); PFSFU, progression-free survival follow-up; Q, every; QD, once daily.
a Patients who discontinue TAK-931 treatment early should complete the EOT visit approximately 30-40 days after the last dose of TAK-931 or before the start of subsequent 
anticancer therapy if that occurs sooner.
b The symptom-directed physical examination will be conducted within 3 days prior to dosing on Day 1 of each treatment cycle and at the EOT visit. The symptom-directed physical 
examination may be performed at other visits during the treatment cycle at the discretion of the investigator.
c Weight will be measured every other cycle, beginning with Cycle 3.
d Perform resting vital sign measurement (after 4 to 5 minutes’ rest in sitting position) prior to dosing.
e ECOG performance status will be performed within 3 days before the beginning (Day 1) of each treatment cycle and at the EOT visit.
f Predose, single safety ECGs will be collected on Day 1 of Cycle 2 and at the EOT visit. Additional ECGs may be obtained as clinically indicated at the discretion of the investigator. 
ECG assessments are to be performed with the patient supine and rested for 5 minutes.
g ECHO and/or MUGA should be performed predose on C2D1 and at the EOT visit. The same modality should be used as on the screening visit.
h Baseline CT (with contrast) or MRI scan of the chest, abdomen, and pelvis must be at screening, after which CT (with contrast) or MRI may be performed at the end of every third 
cycle (ie, on or before the start of Cycle 4, Day 1; Cycle 7, Day 1; Cycle 10, Day 1, etc), as clinically indicated, according to standard of care. The same imaging modality (CT [with 
contrast] MRI, or bone scan) should be used on a patient as at the screening visit and throughout the study. Bone scans may be performed on patients with bone metastases rather than 
CT or MRI. See Section 10.4.18 for more details.
i At EOT, tumor assessments will be done only on patients who have not previously demonstrated disease progression in the study unless completed within the previous 4 weeks.
j Patients who discontinue study treatment for reasons other than PD will undergo CT/MRI scans every 12 weeks (±1 week) from EOT until the occurrence of PD, the start of 
subsequent antineoplastic therapy, or until 6 months after discontinuation of study treatment, whichever occurs first.
k Including serious pretreatment events; see Section 11.2.
l TAK-931 will be administered orally QD (or BID only if indicated by the sponsor) on Days 1 and 2 of each week in a 21-day cycle. The starting dose will be 100 mg. Study drug will 
be administered to patients on an empty stomach. Patients should not eat for 2 hours before taking the capsules with 8 ounces of water. Patients should be instructed to eat a meal or 
snack >1 hour after taking study drug. See Section 9.1.
m Additional pregnancy testing may be performed during the study at the discretion of the investigator, upon request of an IEC/IRB, or if required by local regulations.
n See Section 9.4. New Grade ≥3 results should be repeated a minimum of every 3 days until recovered to Grade ≤2.
o The hematology and chemistry blood samples on Days 5, 12, and 18 of each cycle starting with Cycle 2 may be waived if there is no evidence of Grade ≥3 analytical toxicity in the 
previous cycle. From Cycle 7 and beyond the hematology and chemistry tests will only be conducted on Day 1 of each cycle if in the opinion of the investigators is safe.
p Complete urinalysis with qualitative analysis for protein will be performed at C2D1 and every other cycle thereafter. Positive results may require quantitative analysis (assessment 
of urine protein to creatinine ratio). Refer to Section 10.4.14 for required clinical urinalysis tests.
q A stool sample for fecal immunochemical testing may be collected within 4 days before dosing on C2D1 and C3D1. If a patient has a positive FIT at screening, no further collection 
is required.
r A blood sample will be obtained predose on C2D1 for measurement of cardiac enzymes in serum that monitor for acute injury (ie, troponin I or T) or chronic or progressive failure 
(ie, B-type natriuretic peptide [BNP] or N-terminal pro-brain natriuretic peptide [NT-proBNP]).
s After EOT, only related SAEs must be reported to the sponsor’s Department of Pharmacovigilance or designee.
Note: Tests and procedures should be performed on schedule, but occasional changes are allowable (±3 days) with permission of the medical monitor for holidays, vacations, and 
other administrative reasons. If extenuating circumstances prevent a patient from beginning treatment or completing a scheduled procedure or assessment within this time, 
the patient may continue the study only with the written permission of the medical monitor.
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TAK-931
Study No. TAK-931-1002
Page 116 of 145
Protocol Incorporating Amendment 04
23 February 2018
CONFIDENTIAL
Table Fa Schedule of Events for Treatment Cycle 1 (Dosing Schedule F) (Once Weekly in a 21-Day Cycle)
Screening a
Day
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
Informed consent
X
Inclusion/exclusion criteria
X
HBV, HCV, and HIV testing
X
Demographics
X
Medical history b
X
X
Physical examination b,q
X
X
X
X
Height
X
Weight
X
Vital signs c,q
X
X
(X)
(X)
(X)
(X)
(X)
(X)
X
(X)
(X)
(X)
(X)
(X)
(X)
X
(X)
(X)
(X)
(X)
(X)
(X)
ECOG performance status
X
12-Lead ECG d,q
X
X d
X
X
ECHO/MUGA
X
Disease assessment e
X
Monitoring of concomitant 
medications and procedures
Recorded from first dose of study drug through up to 30 days after the last dose of study drug or before 
initiation of new anticancer therapy (whichever comes first).
Adverse event reporting
Recorded from first dose of study drug through up to 30 days after the last dose of study drug or before 
initiation of new anticancer therapy (whichever comes first).
Serious adverse events f will be reported from signing of the informed consent form through 30 days after the last dose of study drug or before 
initiation of new anticancer therapy (whichever comes first).
Continuous heart rhythm 
monitoring r,q
X
X
X
TAK-931 administration g
X
X
X
Footnotes are on last table page.
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TAK-931
Study No. TAK-931-1002
Page 117 of 145
Protocol Incorporating Amendment 04
23 February 2018
CONFIDENTIAL
Table Fa Schedule of Events for Treatment Cycle 1 (continued) (Dosing Schedule F) (Once Weekly in a 21-Day Cycle)
Screening a
Day
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
Samples/Laboratory Assessments
Pregnancy test h
X
X
Hematology/chemistry i,q
X
X
X
X
X
X
X
Urinalysis j
X
X
Fecal immunochemical 
testing
X
Blood sample for cardiac 
enzymes k
X
X
X
X
Skin punch m,o
X (or C1D1)
(X)
X
Urine and blood sample for 
PK
Urine and blood samples for PK analysis will be collected on the days and time points specified in Table Ge,f.
Abbreviations: BID, twice daily; BP, blood pressure; CxDx, Cycle x, Day x; Cmax, maximum observed plasma concentration; CT, computed tomography; ECG, electrocardiogram; 
ECHO, echocardiogram; ECOG, Eastern Cooperative Oncology Group; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; ICF, informed consent 
form; IEC, independent ethics committee; IRB, institutional review board; MRI, magnetic resonance imaging; MUGA, multiple gated acquisition (scan); PK, pharmacokinetic(s); 
POTS, postural orthostatic tachycardia syndrome; QD, once daily.
Note: Parentheses indicate the test or procedure is to be performed under certain conditions. 
a Unless otherwise noted, the screening visit must occur within 28 days before administration of the first dose of study drug (C1D1). The ICF may be signed more than 28 days before 
C1D1.
b The C1D1 physical examination and medical history are not required if the screening physical examination was conducted and medical history obtained within 4 days before 
administration of the first dose of study drug (C1D1).
c Perform vital sign measurements including orthostatic measurements before dosing. Also, perform vital sign measurements on C1D1, C1D8, and C1D15 at 2, 4, and 8 hours 
postdose (just before PK sampling if on PK sampling day). If the investigator considers that it is otherwise safe, the patient can be discharged during dose holidays. If the investigator 
considers that it is in the patient’s best interest to remain hospitalized, then scheduled assessments in parentheses (X) will be performed and recorded. Orthostatic measurements of BP 
and pulse/heart rate should be conducted with the patient in a supine position after the patient has been resting quietly for 5 minutes followed by a second measurement after the 
patient has been standing for 2 minutes. At screening, also measure heart rate after 10 minutes of quiet standing to confirm POTS. At least 3 separate resting (after 4 to 5 minutes’ rest 
in sitting position) BP measurements should be taken during the screening and the median of those measurements will be utilized as baseline BP reference of individual patient 
Property of Takeda: For non-commercia
e
d subject to the applicable Terms of Use
le
ekly in a
ekly in
lic
3
14
14
pp
a p
e a
th
th
th
th
X
to
ctctctct
j ct
je
bj
su
d
e
es for PK a
s for P
erc
x, Day x; 
x, Day 
Group; HB
roup;
review boa
view b
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e daily
 performe
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cur within 
ur with
history ar
istory 
g (C1D1).
g (C1D1
ding orthos
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n PK s
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onducted w
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2 minutes. 
2 minute
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CCI
CCI
CCI




TAK-931
Study No. TAK-931-1002
Page 119 of 145
Protocol Incorporating Amendment 04
23 February 2018
CONFIDENTIAL
Note: Tests and procedures should be performed on schedule, but occasional changes are allowable (±3 days) with permission of the medical monitor for holidays, vacations, and 
other administrative reasons. If extenuating circumstances prevent a patient from beginning treatment or completing a scheduled procedure or assessment within this time, the patient 
may continue the study only with the written permission of the medical monitor.
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TAK-931
Study No. TAK-931-1002
Page 120 of 145
Protocol Incorporating Amendment 04
23 February 2018
CONFIDENTIAL
Table Fb Schedule of Events for Treatment Cycle 2 Through PFS Follow-up (Dosing Schedule F) (Continuous Schedule; Once 
Weekly in a 21-Day Cycle)
Cycle 2 and Subsequent Cycles
EOT a
PFSFU
Day 1
Day 5
Day 8
Day 12
Day 15
Day 18
Symptom-directed physical examination b
X
X
Weight
X c
X
Vital signs d
X
X
ECOG performance status e
X
X
12-Lead ECG f
X
X
ECHO/MUGA g
X
X
Disease assessment h
X
(starting at C3 and 
performed between 
D15 and D1 of the 
next cycle, then 
Q3C thereafter)
X i
X j
(Q 12 weeks)
Monitoring of concomitant medications and 
procedures
Recorded from first dose of study drug through up to 30 days after the last dose of study drug or before 
initiation of new anticancer therapy (whichever comes first).
Adverse event reporting
Recorded from first dose of study drug through up to 30 days after the last dose of study drug or before 
initiation of new anticancer therapy (whichever comes first).
Serious adverse events k will be reported from signing of the informed consent form through 30 days after the last dose 
of study drug or before initiation of new anticancer therapy (whichever comes first).
X s
TAK-931 administration l
Days 1, 8, and 15 of each treatment cycle
Samples/Laboratory Assessments
Pregnancy Test m
X
Hematology/Chemistry n
X
X o
X
X o
X
X o
X
Urinalysis p
X p
Fecal immunochemical testing q
X
Blood sample for cardiac enzymes r
X
Abbreviations: BID, twice daily; BP, blood pressure; C, cycle; CxDx, Cycle x, Day x; CT, computed tomography; ECG, electrocardiogram; ECHO, echocardiogram; ECOG, Eastern 
Cooperative Oncology Group; EOT, End of Treatment; FIT, fusion-inferred threshold; IEC, independent ethics committee; IRB, institutional review board; MRI, magnetic resonance 
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TAK-931
Study No. TAK-931-1002
Page 121 of 145
Protocol Incorporating Amendment 04
23 February 2018
CONFIDENTIAL
imaging; MUGA, multiple gated acquisition (scan); PFSFU, progression-free survival follow-up; Q, every; QD, once daily.
a Patients who discontinue TAK-931 treatment early should complete the EOT visit approximately 30-40 days after the last dose of TAK-931 or before the start of subsequent 
anticancer therapy if that occurs sooner.
b The symptom-directed physical examination will be conducted within 3 days prior to dosing on Day 1 of each treatment cycle and at the EOT visit. The symptom-directed physical 
examination may be performed at other visits during the treatment cycle at the discretion of the investigator.
c Weight will be measured every other cycle, beginning with Cycle 3.
d Perform resting vital sign measurement (after 4 to 5 minutes’ rest in sitting position) prior to dosing.
e ECOG performance status will be performed within 3 days before the beginning (Day 1) of each treatment cycle and at the EOT visit.
f Predose, single safety ECGs will be collected on Day 1 of Cycle 2 and at the EOT visit. Additional ECGs may be obtained as clinically indicated at the discretion of the investigator. 
ECG assessments are to be performed with the patient supine and rested for 5 minutes.
g ECHO and/or MUGA should be performed predose on C2D1 and at the EOT visit. The same modality should be used as on the screening visit.
h Baseline CT (with contrast) or MRI scan of the chest, abdomen, and pelvis must be at screening, after which CT (with contrast) or MRI may be performed at the end of every third 
cycle (ie, on or before the start of Cycle 4, Day 1; Cycle 7, Day 1; Cycle 10, Day 1, etc), as clinically indicated, according to standard of care. The same imaging modality (CT [with 
contrast] MRI, or bone scan) should be used on a patient as at the screening visit and throughout the study. Bone scans may be performed on patients with bone metastases rather than 
CT or MRI. See Section 10.4.18 for more details.
i At EOT, tumor assessments will be done only on patients who have not previously demonstrated disease progression in the study unless completed within the previous 4 weeks.
j Patients who discontinue study treatment for reasons other than PD will undergo CT/MRI scans every 12 weeks (±1 week) from EOT until the occurrence of PD, the start of 
subsequent antineoplastic therapy, or until 6 months after discontinuation of study treatment, whichever occurs first.
k Including serious pretreatment events; see Section 11.2.
l TAK-931 will be administered orally QD (or BID only if indicated by the sponsor) on Days 1 and 2 of each week) in a 21-day cycle. The starting dose will be determined after 
Schedule E dose escalation is completed. Study drug will be administered to patients on an empty stomach. Patients should not eat for 2 hours before taking the capsules with 8 ounces 
of water. Patients should be instructed to eat a meal or snack >1 hour after taking study drug. See Section 9.1.
m Additional pregnancy testing may be performed during the study at the discretion of the investigator, upon request of an IEC/IRB, or if required by local regulations.
n See Section 9.4. New Grade ≥3 results should be repeated a minimum of every 3 days until recovered to Grade ≤2.
o The hematology and chemistry blood samples on Days 5, 12, and 18 of each cycle starting with Cycle 2 may be waived if there is no evidence of Grade ≥3 analytical toxicity in the 
previous cycle. From Cycle 7 and beyond the hematology and chemistry tests will only be conducted on Day 1 of each cycle if in the opinion of the investigators is safe.
p Complete urinalysis with qualitative analysis for protein will be performed at C2D1 and every other cycle thereafter. Positive results may require quantitative analysis (assessment 
of urine protein to creatinine ratio). Refer to Section 10.4.14 for required clinical urinalysis tests.
q A stool sample for fecal immunochemical testing may be collected within 4 days before dosing on C2D1 and C3D1. If a patient has a positive FIT at screening, no further collection 
is required.
r A blood sample will be obtained predose on C2D1 for measurement of cardiac enzymes in serum that monitor for acute injury (ie, troponin I or T) or chronic or progressive failure 
(ie, B-type natriuretic peptide [BNP] or N-terminal pro-brain natriuretic peptide [NT-proBNP]).
s After EOT, only related SAEs must be reported to the sponsor’s Department of Pharmacovigilance or designee.
Note: Tests and procedures should be performed on schedule, but occasional changes are allowable (±3 days) with permission of the medical monitor for holidays, vacations, and 
other administrative reasons. If extenuating circumstances prevent a patient from beginning treatment or completing a scheduled procedure or assessment within this time, 
the patient may continue the study only with the written permission of the medical monitor.
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TAK-931
Study No. TAK-931-1002
Page 122 of 145
Protocol Incorporating Amendment 04
23 February 2018
CONFIDENTIAL
Table Ga
Pharmacokinetic Sample Breakdown (Dosing Schedule A)
Cycle 1
Day 1
Day 8
Day 15
Day Xb
Orthostatics
(BP and HR) a
Plasma
Urine
Orthostatics 
(BP and HR) a
Plasma
Plasma
Plasma
Predose
X
X
X c,d
X
X
X e
X
30 min postdose ()5 min)
X
X
1 hour postdose ()10 min) f
X
X
2 hours postdose ()20 min) 
X
X
X
X
4 hours postdose ()30 min) 
X
X
X
X
6 hours postdose ()60 min)
X
X
8 hours postdose ()60 min) 
X
X
X
X
12 hours postdose ()60 min) g
X
X
24 hours postdose ()3 hours) h
X
X
X
X
1-3 hours postdose
X
4-9 hours postdose
X
Abbreviations: AE, adverse event; BP, blood pressure; BID, twice daily; CxDx, Cycle x, Day x; ECG, electrocardiogram; HR, heart rate; QD, once daily; PK, pharmacokinetic(s).
a Orthostatic measurements should be completed immediately after recording a 12-lead ECG and before collection of the corresponding PK sample.
b If skin biopsy 
 is taken on a non-PK sampling day  sparse PK plasma samples should be collected on that day (Day X). The exact PK sampling date and time will be 
recorded.
c Predose spot urine collection: The patient should be asked to void completely approximately 30 minutes before the administration of the first dose of TAK-931.
d Timed urine collection: The 12-hour urine collection begins on Day 1 at the time of TAK-931 administration and ends 12 hours later when the 12-hour PK plasma specimen is 
collected. See Section 10.4.19.
e After the patient has completed 14 days of continuous dosing, a PK sample should be collected either approximately 12 hours after administration of the last dose of study drug on 
Cycle 1 Day 14 in the BID dosing schedule or approximately 24 hours after administration of the last dose of study drug on Cycle 1 Day 14 in the QD dosing schedule. 
f Patients should be provided food/allowed to eat immediately after the 1-hour PK sample has been obtained.
g The 12-hour PK plasma specimen should be collected before the administration of the evening dose of TAK-931 in the BID dosing schedule.
h For QD dosing only: The 24-hour assessments of orthostatics should be performed and the PK plasma specimen collected before administration of the morning dose of TAK-931.
Note: For any patient who experiences hypotension or other AEs on non-PK sampling days considered to be possibly related to study drug, an additional PK plasma specimen should 
(if feasible) be collected at the time of the event.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
le
lic
pp
Plas
Pla
a
o
t t
ct
jec
X
ubj
X
d s
nd
y a
lylyly
e o
se
l u
cicicicia
ily; CxDx
CxD
r recording
recordi
day  sparse
ay  spar
ed to void 
to voi
begins on 
egins o
nuous dos
uous d
approxim
pproxim
to eat imm
to eat im
uld be colle
d be c
ssessments
sessme
nces hypot
es hypo
ime of the 
me of th
CCI


TAK-931
Study No. TAK-931-1002
Page 123 of 145
Protocol Incorporating Amendment 04
23 February 2018
CONFIDENTIAL
Table Gb
Pharmacokinetic Sample Breakdown (Dosing Schedule B)
Cycle 1
Day 1
Day 7
Day X b
Orthostatics
(BP and HR) a
Plasma
Urine
Orthostatics 
(BP and HR) a
Plasma
Plasma
Predose
X
X
X c,d
X
X
X
30 min postdose ()5 min)
X
X
1 hour postdose ()10 min) e
X
X
2 hours postdose ()20 min) 
X
X
X
X
4 hours postdose ()30 min) 
X
X
X
X
6 hours postdose ()60 min)
X
X
8 hours postdose ()60 min) 
X
X
X
X
12 hours postdose ()60 min) f
X
X
24 hours postdose ()3 hours) g
X
X
X
X
1-3 hours postdose
X
4-9 hours postdose
X
Abbreviations: AE, adverse event; BP, blood pressure; BID, twice daily; CxDx, Cycle x, Day x; ECG, electrocardiogram; HR, heart rate; QD, once daily; PK=pharmacokinetic(s).
a Orthostatic measurements should be completed immediately after recording a 12-lead ECG and before collection of the corresponding PK sample.
b If skin biopsy 
 is taken on a non-PK sampling day, sparse PK plasma samples should be collected on the same day (Day X). The exact PK sampling date and time will 
be recorded.
c Predose spot urine collection: The patient should be asked to void completely approximately 30 minutes before the administration of the first dose of TAK-931.
d Timed urine collection: The 12-hour urine collection begins on Day 1 at the time of TAK-931 administration and ends 12 hours later when the 12-hour PK plasma specimen is 
collected. See Section 10.4.19.
e Patients should be provided food/allowed to eat immediately after the 1-hour PK sample has been obtained.
f The 12-hour PK plasma specimen should be collected before the administration of the evening dose of TAK-931 in the BID dosing schedule.
g For QD dosing only: The 24-hour assessments of orthostatics should be performed and the PK plasma specimen collected before administration of the morning dose of TAK-931.
Note: For any patient who experiences hypotension or other AEs on non-PK sampling days considered to be possibly related to study drug, an additional PK plasma specimen should 
(if feasible) be collected at the time of the event.
Property of Takeda: For non-commercial use only a
e o
e
se
l u
and subject to the applicable Terms of Use
le
lic
Day 7
Day 7
pp
atics
cs 
and HR) 
d HR) a
a
X
o
t t
jec
ub
ub
ubj
ub
cia
ily; CxDx
y; CxD
r recording
recordi
ay, sparse 
y, spars
ed to void 
to voi
begins on 
egins o
immediat
mmedi
collected b
llected
ents of or
ents of 
ypotension
poten
f the event
f the ev
y a
CCI


TAK-931
Study No. TAK-931-1002
Page 124 of 145
Protocol Incorporating Amendment 04
23 February 2018
CONFIDENTIAL
Table Gc
Pharmacokinetic Sample Breakdown (Dosing Schedule C)
Cycle 1
Day 1
Day 7
Day X b
Orthostatics
(BP and HR) a
Plasma
Urine
Orthostatics 
(BP and HR) a
Plasma
Plasma
Predose
X
X
X c,d
X
X
X
30 min postdose ()5 min)
X
X
1 hour postdose ()10 min) e
X
X
2 hours postdose ()20 min) 
X
X
X
X
4 hours postdose ()30 min) 
X
X
X
X
6 hours postdose ()60 min)
X
X
8 hours postdose ()60 min) 
X
X
X
X
12 hours postdose ()60 min) f
X
X
24 hours postdose ()3 hours) g
X
X
X
X
1-3 hours postdose
X
4-9 hours postdose
X
Abbreviations: AE, adverse event; BP, blood pressure; BID, twice daily; CxDx, Cycle x, Day x; ECG, electrocardiogram; HR, heart rate; QD, once daily; PK, pharmacokinetic(s).
a Orthostatic measurements should be completed immediately after recording a 12-lead ECG and before collection of the corresponding PK sample.
b If skin biopsy 
 is taken on a non-PK sampling day, sparse PK plasma samples should be collected on the same day (Day X). The exact PK sampling date and time will 
be recorded.
c Predose spot urine collection: The patient should be asked to void completely approximately 30 minutes before the administration of the first dose of TAK-931.
d Timed urine collection: The 12-hour urine collection begins on Day 1 at the time of TAK-931 administration and ends 12 hours later when the 12-hour PK plasma specimen is 
collected. See Section 10.4.19.
e Patients should be provided food/allowed to eat immediately after the 1-hour PK sample has been obtained.
f The 12-hour PK plasma specimen should be collected before the administration of the evening dose of TAK-931 in the BID dosing schedule.
g For QD dosing only: The 24-hour assessments of orthostatics should be performed and the PK plasma specimen collected before administration of the morning dose of TAK-931.
Note: For any patient who experiences hypotension or other AEs on non-PK sampling days considered to be possibly related to study drug, an additional PK plasma specimen should 
(if feasible) be collected at the time of the event.
Property of Takeda: For non-commercial use only
e o
se
se
se
se
s
l u
y and subject to the applicable Terms of Use
le
lic
Day 7
Day 7
pp
ics
d HR) 
HR) a
a
X
o
t t
jec
ubj
su
s
cia
ily; CxDx
CxD
r recording
recordi
ay, sparse 
y, spars
ed to void 
to voi
begins on 
egins o
immediat
mmedi
collect
llected b
ed
ments of or
ments of 
ypotension
poten
f the event
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Table Gd
Pharmacokinetic Sample Breakdown (Dosing Schedule D)
Cycle 1
Day 1
Day 8
Day X b
Day 21
BP and HR a
Plasma
Urine
Plasma
Plasma
Plasma
Predose
X
X
X c,d
X
X
30 min postdose ()5 min)
X
X
1 hour postdose ()10 min) e
X
X
2 hours postdose ()20 min) 
X
X
X
4 hours postdose ()30 min) 
X
X
6 hours postdose ()60 min)
X
X
8 hours postdose ()60 min) 
X
X
12 hours postdose ()60 min) f
X
X
24 hours postdose ()3 hours) g
X
X
X (h)
1-3 hours postdose
X
4-9 hours postdose
X
Abbreviations: AE, adverse event; BP, blood pressure; BID, twice daily; CxDx, Cycle x, Day x; ECG, electrocardiogram; HR, heart rate; QD, once daily; PK, pharmacokinetic(s).
a Resting BP and HR will be measured. 
b If skin biopsy 
 is taken on a non-PK sampling day, sparse PK plasma samples should be collected on the same day (Day X). The exact PK sampling date and time will 
be recorded.
c Predose spot urine collection: The patient should be asked to void completely approximately 30 minutes before the administration of the first dose of TAK-931.
d Timed urine collection: The 12-hour urine collection begins on Day 1 at the time of TAK-931 administration and ends 12 hours later when the 12-hour PK plasma specimen is 
collected. See Section 10.4.19.
e Patients should be provided food/allowed to eat immediately after the 1-hour PK sample has been obtained.
f The 12-hour PK plasma specimen should be collected before the administration of the evening dose of TAK-931 in the BID dosing schedule.
g For QD dosing only: The PK plasma specimen collected before administration of the morning dose of TAK-931.
h For BID dosing, the PK plasma specimen should be collected 12 hours (±60 min) after the evening dose on Day 21 and before the administration of the morning dose of TAK-931
on Day 22.
Note: For any patient who experiences hypotension or other AEs on non-PK sampling days considered to be possibly related to study drug, an additional PK plasma specimen should 
(if feasible) be collected at the time of the event.
Property of Takeda: For non-commercial use only an
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and subject to the applicable Terms of Use
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Study No. TAK-931-1002
Page 126 of 145
Protocol Incorporating Amendment 04
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CONFIDENTIAL
Table Ge,f
Pharmacokinetic Sample Breakdown (Dosing Schedules E and F)
Cycle 1
Day 1
Day 9 for Schedule E, Day 8 for Schedule F
Day X b
Orthostatic 
BP and HR a
Plasma
Urine
Orthostatic 
BP and HR a
Plasma
Plasma
Predose
X
X
X c,d
X
X
X
30 min postdose ()5 min)
X
X
1 hour postdose ()10 min) e
X
X
2 hours postdose ()20 min) 
X
X
X
X
4 hours postdose ()30 min) 
X
X
X
6 hours postdose ()60 min)
X
X
8 hours postdose ()60 min) 
X
X
X
X
12 hours postdose ()60 min) f
X
X
24 hours postdose ()3 hours) g
X
X
X
X
1-3 hours postdose
X
4-9 hours postdose
X
Abbreviations: AE, adverse event; BP, blood pressure; BID, twice daily; CxDx, Cycle x, Day x; ECG, electrocardiogram; HR, heart rate; QD, once daily; PK, pharmacokinetic(s).
a Orthostatic measurements should be completed immediately after recording a 12-lead ECG and before collection of the corresponding PK sample. 
b If skin biopsy 
 is taken on a non-PK sampling day, sparse PK plasma samples should be collected on the same day (Day X). The exact PK sampling date and time will 
be recorded.
c Predose spot urine collection: The patient should be asked to void completely approximately 30 minutes before the administration of the first dose of TAK-931.
d Timed urine collection: The 12-hour urine collection begins on Day 1 at the time of TAK-931 administration and ends 12 hours later when the 12-hour PK plasma specimen is 
collected. See Section 10.4.19.
e Patients should be provided food/allowed to eat immediately after the 1-hour PK sample has been obtained.
f The 12-hour PK plasma specimen should be collected before the administration of the evening dose of TAK-931 in the BID dosing schedule.
g For QD dosing only: the 24-hour orthostatic assessments should be performed before PK plasma specimen collection in the morning on the following day.
Note: For any patient who experiences hypotension or other AEs on non-PK sampling days considered to be possibly related to study drug, an additional PK plasma specimen should 
(if feasible) be collected at the time of the event. 
Property of Takeda: For non-commercial use only an
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se
l u
cia
and subject to the applicable Terms of Use
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, D
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Page 127 of 145
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CONFIDENTIAL
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, prior to 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 
21 CFR Part 56, 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 21 CFR Part 50, 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 informed consent form 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 informed consent form 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. This responsibility lies on 
the appropriate individual, designated by the site in Japan. 
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
Eastern Cooperative Oncology Group (ECOG) Scale for Performance Status
Grade
Description
0
Normal activity. Fully active, able to carry on all predisease performance without restriction.
1
Symptoms but ambulatory. Restricted in physically strenuous activity, but ambulatory and able to 
carry out work of a light or sedentary nature (eg, light housework, office work).
2
In bed <50% of the time. Ambulatory and capable of all self-care, but unable to carry out any work 
activities. Up and about more than 50% of waking hours.
3
In bed >50% of the time. Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair.
5
Dead
Source: Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and response criteria 
of the Eastern Cooperative Oncology Group. American Journal of Clinical Oncology 1982;5(6):649-55 [25].
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Appendix E
Cockcroft-Gault Equation
For men:
Creatinine Clearance =
(140-age [years])weight [kg]
72(serum creatinine [mg/dL])
OR
Creatinine Clearance =
(140-age [years])weight [kg]
0.81(serum creatinine [µmol/L])
For women:
Creatinine Clearance =
0.85 (140-age [years])weight [kg]
72(serum creatinine [mg/dL])
OR
Creatinine Clearance =
0.85 (140-age [years])weight [kg]
0.81(serum creatinine [µmol/L])
Source: Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
1976;16(1):31-41 [26].
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Appendix F
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. Nomenclature and Criteria for Diagnosis of Diseases 
of the Heart and Great Vessels. 9th Ed. Boston, MA: Little, Brown & Co; 1994:253-256.[27]
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CONFIDENTIAL
Appendix G
Clinically Significant Strong Metabolic Enzyme Inducers
Inducersa
Carbamazepine
Enzalutamide
Mitotane
Phenytoin
Rifampin
St. John’s wort
a This is not an exhaustive list; refer to the following source: 
fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInt
eractionsLabeling/ucm093664 htm#table3-3 (accessed 15 February 2018). 
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CONFIDENTIAL
Appendix H
Detailed Description of Amendments to Text
This document describes changes in reference to Protocol Incorporating Amendment 04. Original 
text that was deleted or revised in Amendment 04 is indicated using strikethrough font. New or 
revised text adopted in Amendment 03 is shown in bold red font.
The primary section(s) of the protocol affected by the changes in Amendment 04 are indicated. 
The corresponding text has been revised throughout the protocol.
Change 1: Added Dosing Schedules E and F.
The primary change occurs in Section 7.1 Overview of Study Design:
Initial 
wording:
…
TAK-931 initially will be administered once daily (QD) for 14 days of each 21-day 
treatment cycle (Dosing Schedule A). The starting dose will be 30 mg. If the 
preliminary PK data from the first 2 dose escalation cohorts in any schedule support 
BID dosing, subsequent cohorts may transition to a BID dosing schedule (by dividing 
the daily dose in 2) either before or when a geometric mean Cmax of 800 ng/mL is 
predicted after a single dose of TAK-931 on C1D1 in a cohort or if Cmax-related AEs 
are observed, or if it is recommended by potential pharmacodynamic effect.
…
To ensure patient safety and to minimize the number of patients exposed to 
non-efficacious doses, the dose escalation in Schedule A will consist of an initial 
accelerated escalation phase in which dose levels are increased by 100%. The 
accelerated escalation phase will transition to modified Fibonacci escalation steps 
after 1 patient experiences a DLT in Cycle 1 or when 2 patients experience ≥Grade 2 
hematologic or non-hematologic related or possibly related drug toxicity (see 
Section 9.2) or when geometric mean plasma Cmax for the cohort reaches or exceeds 
800 ng/mL  For Schedules B, C and D accelerated escalation is not applicable. The 
dose escalation steps will be modified, as needed, based on clinical safety and PK 
results. The escalation steps for Schedules A, B and C may also be modified based on 
accumulating PK data and BLRM that would provide narrower escalation steps and 
potentially decrease the number of patients exposed to doses above the MTD. In 
Schedule D, BLRM will not be applied. Clinical safety, PK and pharmacodynamic 
information will drive escalation (or de-escalation) decisions.
There will be a minimum 1-week interval between C1D1 of the first patient dosed and
C1D1 of the second patient dosed for each dose escalation cohort. Subsequent patient 
dosing (third patient per cohort and beyond) may occur at a shorter interval (eg, 
<7 days from previous patient’s C1D1 dosing) but no more than 1 patient will undergo 
C1D1 dosing within a 1-day period. These intervals are not applicable to patients 
enrolled in Schedule D, to cases of dose de-escalation and to patients enrolled in the 
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CONFIDENTIAL
Change 2: Modified schedule for skin punch 
The primary changes occur in Section 10.4.15 Skin Punch Biopsies
 
Initial 
wording:
Section 10.4.15:
pMCM2 will be detected semiquantitatively by IHC of histologic sections of 
formalin-fixed, paraffin-embedded skin biopsies. Skin punch biopsies (2-4 mm) will 
be obtained for all patients either during screening or predose on C1D1 and postdose 
on any drug dosing day after 3 consecutive dosing days (eg, Day 4 or after) in Cycle 1.
It is strongly recommended that postdose skin biopsies are collected between 4 to 9 
hours after study drug administration
 
. Refer to Section 10.4.21 for sample retention.
Property of Takeda: For
ct t
 applicable Te
ns of
s of
s (2
s (2-4 mm
4 m
C1D1 and
D1 a
4 or 
or aft
aft
Terms of Use
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ed
.
Te
CCI
CCI
CCI
CCI
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Protocol Incorporating Amendment 04
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CONFIDENTIAL
Amended 
or new 
wording:
Section 10.4.15:
pMCM2 will be detected semiquantitatively by IHC of histologic sections of 
formalin-fixed, paraffin-embedded skin biopsies. Skin punch biopsies (2-4 mm) will 
be obtained for all patients either during screening or predose on C1D1, and for 
patients in Schedule A to D postdose on any drug dosing day after 3 consecutive 
dosing days (eg, Day 4 or after) in Cycle 1. A postdose skin biopsy will be obtained 
on Day 9 in Schedule E and on Day 8 in Schedule F. Other time points for biopsy 
collection outside Cycle 1 can be performed if explicitly approved by the sponsor.
It is strongly recommended that postdose skin biopsies are collected between 4 to 9 
hours after study drug administration 
 
. Refer to Section 10.4.21 for sample retention.
Rationale for Change:
Added biopsy schedule for Dosing Schedules E and F. 
The following sections also contain this change:
!
Section 2.0 STUDY SUMMARY.
!
Section 7.1 Overview of Study Design.
Property of Ta
The fo
The follo
l
!
Takeda:
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TAK-931
Study No. TAK-931-1002
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CONFIDENTIAL
Change 3: Clarified method of calculation for the TAK-931 accumulation ratio.
The primary change occurs in Section 14.1.4 Pharmacokinetic Analysis:
Initial 
wording:
Rac
Amended 
or new 
wording:
Rac Rac(AUC)
Rationale for Change:
Clarified the method used to calculate the accumulation ratio.
Various other sections also contain this change. 
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TAK-931
Study No. TAK-931-1002
Page 142 of 145
Protocol Incorporating Amendment 04
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CONFIDENTIAL
Change 4: Updated nonclinical data.
The primary change occurs in Section 4.1.1 Nonclinical Experience:
Initial 
wording:
…
The in vivo antitumor activity of TAK-931 was further characterized utilizing up to 59
primary human xenograft tumors. In this preclinical “phase 2-like” study, mice with 
xenografted human primary tumors received TAK-931 60 mg/kg PO for 3 days on and 
4 days off weekly for 21 days (a dose and schedule shown to be efficacious across 
multiple tumor models [Figure 4.a]). Response characterized by tumor growth 
inhibition and survival was then analyzed relative to the underlying mutation status of 
the primary human tumors as well as gene expression profile to identify potential 
genetic biomarkers associated with resistance and sensitivity to TAK-931. 
…
…
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CONFIDENTIAL
Rationale for Change:

This data was updated to provide more recent information. 
Change 5: Added appendix of clinically significant strong metabolic enzyme inducers.
The primary change occurs in Appendix G, Clinically Significant Strong Metabolic Enzyme 
Inducers:
New 
wording:
Rationale for Change:
Clarified which compounds are strong metabolic enzyme inducers.
The following sections also contain this change:

Section 8.2 Exclusion Criteria.

Section 9.6 Excluded Concomitant Medications and Procedures.
Change 6: Revised criteria for beginning or delaying a subsequent treatment cycle.
The primary changes occur in Section 9.4.2 Criteria for Beginning or Delaying a Subsequent 
Treatment Cycle:
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Study No. TAK-931-1002
Page 145 of 145
Protocol Incorporating Amendment 04
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CONFIDENTIAL
Amended 
or new 
wording:
Before starting a new treatment cycle, TAK-931–related AEs or laboratory 
abnormalities that require dose modification must have returned to Grade ≤1 or 
baseline levels. For Schedule B these criteria also apply to Day 15 dosing. For 
Schedules E and F, in general these criteria also apply to Day 8 and Day 15 dosing; 
however, for patients with Grade 2 neutropenia on Day 8 or Day 15, treatment 
can be administered at the investigator’s discretion. For Schedule D, this 
requirement is applicable also for restarting treatment after an interruption due to 
toxicity.
…
Rationale for Change:
Added greater latitude for investigator to treat patients with Grade 2 neutropenia on Day 8 or 
Day 15. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

SAP_000.pdf: 
Title: An Open-Label, Phase 1, Dose-Escalation Study to Evaluate the Safety, Tolerability, 
and Pharmacokinetics of TAK-931, a Cell Division Cycle 7 (CDC7) Inhibitor, in Adult 
Patients With Advanced Nonhematologic Tumors 
NCT Number: NCT02699749 
Statistical analysis plan Approve Date: 15-MAR-2020 
Certain information within this statistical analysis plan has been redacted (ie, specific 
content is masked irreversibly from view with a black/blue bar) to protect either 
personally identifiable information or company confidential information. 
This may include, but is not limited to, redaction of the following: 
z
Named persons or organizations associated with the study.
z
Patient identifiers within the text, tables, or figures or in by-patient data listings.
z
Proprietary information, such as scales or coding systems, which are considered
confidential information under prior agreements with license holder.
z
Other information as needed to protect confidentiality of Takeda or partners,
personal information, or to otherwise protect the integrity of the clinical study.
If needed, certain appendices that contain a large volume of personally identifiable 
information or company confidential information may be removed in their entirety if it 
is considered that they do not add substantially to the interpretation of the data (eg, 
appendix of investigator’s curriculum vitae). 


TAK931 
Statistical Analysis Plan, Study C1002 
Confidential 
1
STATISTICAL ANALYSIS PLAN
TAK-931
An Open-Label, Phase 1, Dose-Escalation Study to Evaluate the Safety, Tolerability, and 
Pharmacokinetics of TAK-931, a Cell Division Cycle 7 (CDC7) Inhibitor, in Adult 
Patients with Advanced Nonhematologic Tumors
Protocol #:  1002
Protocol Amendment 4
SAP Version:
Date of Statistical Analysis Plan:
Final
15 MAR 2020
Property of 
 applicable Term
e T rms of Use
erm
PPD






TAK931 
Statistical Analysis Plan, Study C1002 
Confidential 
1 
STATISTICAL ANALYSIS PLAN
TAK-931
An Open-Label, Phase 1, Dose-Escalation Study to Evaluate the Safety, Tolerability, and 
Pharmacokinetics of TAK-931, a Cell Division Cycle 7 (CDC7) Inhibitor, in Adult 
Patients with Advanced Nonhematologic Tumors
Protocol #:  1002
Protocol Amendment 4
SAP Version:
Date of Statistical Analysis Plan:
Final
15 MAR 2020
Property
 applicable Ter
e Terms of Use
er
PPD


TAK931 
Statistical Analysis Plan, Study C1002 
Confidential 
1
STATISTICAL ANALYSIS PLAN 
TAK-931 
An Open-Label, Phase 1, Dose-Escalation Study to Evaluate the Safety, Tolerability, and 
Pharmacokinetics of TAK-931, a Cell Division Cycle 7 (CDC7) Inhibitor, in Adult 
Patients with Advanced Nonhematologic Tumors 
Protocol #:  1002 
Protocol Amendment 4 
 
SAP Version:  
Date of Statistical Analysis Plan: 
 
Final   
 
15 MAR 2020 
Property 
 applicable Terms of Use
e Ter
PPD




TAK931 
Statistical Analysis Plan, Study C1002 
Confidential 
2
TABLE OF CONTENTS
1. LIST OF ABBREVATION..................................................................................................3 
2. INTRODUCTION ................................................................................................................4 
2.1 Study Design...................................................................................................................4 
2.2 Study Objectives.............................................................................................................5 
2.2.1 Primary Objectives ................................................................................................ .5 
2.2.2 Secondary Objectives ........................................................................................... ..5 
 
3. POPULATIONS FOR ANALYSIS ....................................................................... ............6 
3.1 Safety population....................................................................................... . . ................6 
3.2 Pharmacokinetic population .................................................................. . ....................6 
3.3 Pharmacodynamics population........................................................... . .........................6 
3.4 Response-Evaluable Population ................................................... . . .............................7 
3.5 DLT-Evaluable Population.......................................................... ..................................7 
4. HYPOTHESES AND DECISION RULES................................. .......................................7 
5. INTERIM ANALYSIS.......................................................... ..............................................7 
6. STATISTICAL METHODOLOGY.............................. . . .................................................7 
6.1 Sample Size Justification........................................ .. ....................................................8 
6.2 Randomization and Stratification ..................... ............................................................9 
6.3 Unblinding.................................................... ... .............................................................9 
6.4 Data Handling.......................................... ......................................................................9 
6.4.1 Methods for Handling Missing Data . .....................................................................9 
6.4.2 Definition of Baseline Values.... . .........................................................................11 
6.4.3 Windowing of Visits........... . ................................................................................11 
6.4.4 Justification of Pooling. .... ..................................................................................11 
6.5 Patient Disposition............ . .........................................................................................11 
6.6 Demographics and Baseline Disease Characteristics ...................................................12 
6.6.1 Demographics .. .. ..................................................................................................12 
6.6.2 Medical History .....................................................................................................12 
6.6.3 Baseline Disease Status .........................................................................................12 
6.6.4 Concomitant Medications......................................................................................12 
6.6.5 Study Treatments ...................................................................................................12 
6.6.6 Efficacy Analysis...................................................................................................13 
6.6.7 Pharmacokinetic Analyses.....................................................................................14 
6.6.8 Pharmacodynamic Analysis...................................................................................15 
 
6.6.10 Safety Analyses....................................................................................................15 
6.6.11 Laboratory Data ...................................................................................................17 
6.6.12 Electrocardiograms..............................................................................................18 
6.6.13 Vital Signs............................................................................................................18 
7. PROGRAMMING CONSIDERATIONS ..........................................................................19 
7.1 Statistical Software.......................................................................................................19 
7.2 Rules and Definitions ...................................................................................................19 
8. REFERENCES:..................................................................................................................19 
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TAK931 
Statistical Analysis Plan, Study C1002 
Confidential 
3
1.  LIST OF ABBREVATION 
AE                     adverse event 
ALP                   alkaline phosphatase 
ALT                   alanine aminotransferase 
ANC                  absolute neutrophil count 
AST                   aspartate aminotransferase 
ATP                   adenosine triphosphate 
AUC                  area under the plasma concentration-time curve 
AUC12                       area under the plasma concentration-time curve from the time 0 to 12 hours 
AUC24                        area under the plasma concentration-time curve from the time 0 to 24 hours 
AUClast                      area under the plasma concentration-time curve from time 0 to the time of the last 
                           quantifiable concentration 
BID                    twice daily 
BLRM                Bayesian Logistic Regression Modeling 
BNP                    B-type natriuretic peptide 
CDC7                 cell division cycle 7 
CL/F                   apparent oral clearance 
CLr                     renal clearance 
Cmax                               maximum observed plasma concentration 
CR                      complete response 
CSR                    clinical study report 
                
 
DLT                    dose-limiting toxicity 
DOR                   duration of response 
ECG                   electrocardiogram 
ECOG                Eastern Cooperative Oncology Group 
EOT                    end of treatment 
MCM2                minichromosome maintenance complex-2 
MedDRA            Medical Dictionary for Regulatory Activities 
MTD                   maximum tolerated dose 
NCI CTCAE       National Cancer Institute Common Terminology Criteria for Adverse Events 
ORR                    overall response rate 
PD                       progressive disease (disease progression) 
PFS                      progression-free survival 
PK                       pharmacokinetics 
PR                        partial response 
QD                       once daily 
Rac(AUC)                          accumulation ratio based on AUC 
RECIST               Response Evaluation Criteria in Solid Tumors 
RP2D                    recommended Phase 2 dose(s) 
SAE                      serious adverse event 
SAP                      statistical analysis plan 
TEAE                   treatment-emergent adverse event 
TK                        toxicokinetic 
tmax                                    time to first occurrence of maximum (peak) concentration 
WHO                    World Health Organization 
pMCM2               phosphorylation of minichromosome maintenance complex-2 
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TAK931 
Statistical Analysis Plan, Study C1002 
Confidential 
4
 
 
2. INTRODUCTION 
The purpose of the Statistical Analysis Plan (SAP) is to provide a framework that addresses 
the protocol objectives in a statistically rigorous fashion, with minimized bias or analytical 
deficiencies.  Specifically, this plan has the following purpose:
To prospectively (a priori) outline the types of analyses and data presentations that will 
address the study objectives outlined in the protocol, and to explain in detail how the data will 
be handled and analyzed, adhering to commonly accepted standards and practices of 
biostatistical analysis in the pharmaceutical industry.
2.1     Study Design 
This is a phase 1, open-label, dose-escalation study designed to evaluate the safety, 
tolerability, and PK and to determine the MTD or a maximum tested dose of TAK-931, a 
CDC7 inhibitor, in adult patients with histologically confirmed, nonhematologic (solid) 
tumors. Dose escalation of TAK-931 will be cohort based with an adaptive design using 
Bayesian Logistic Regression Modeling (BLRM) with PK guidance. 
Approximately 100 patients will be enrolled into this study in up to 8 to 9 dose cohorts. A 
minimum of 3 patients will be enrolled in each cohort to support safety and PK guidance.
Once the MTD is defined, a safety expansion cohort of 15 patients will be initiated including 
patients treated at the MTD.
TAK-931 initially will be administered for 14 days of each 21-day treatment cycle. TAK-931 
will be given as a single daily dose (QD). The starting dose will be 30 mg. If the PK from the 
first 2 dose escalation cohorts supports BID dosing, then study drug administration in 
subsequent cohorts may transition to a BID dosing schedule either before or when a geometric 
mean Cmax of 400 ng/mL is predicted after a single dose of TAK-931 on C1D1 in a cohort. 
Study drug may be discontinued early if a patient experiences study drug-related toxicities, if 
a patient requires prolonged treatment interruption to recover from a toxicity, or if the toxicity 
recurs upon retreatment. Patients will attend the End-of-Study visit 30 to 40 days after 
receiving their last dose of study drug or before initiating new anti-cancer therapy (whichever 
comes first).
To ensure patient safety and to minimize the number of patients exposed to non-efficacious 
doses, the dose escalation will consist of an initial accelerated escalation phase in which dose 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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TAK931 
Statistical Analysis Plan, Study C1002 
Confidential 
5
levels are increased by 100%. The accelerated escalation phase will transition to modified 
Fibonacci escalation steps after 1 patient experiences a DLT in Cycle 1 or when 2 patients 
experience ≥Grade 2 hematologic or non-hematologic related or possibly related drug toxicity 
or when geometric mean plasma Cmax for the cohort reaches or exceeds 400 ng/mL. The dose 
escalation steps will be modified, as needed, based on clinical safety and PK results. The 
escalation steps may also be modified based on accumulating PK data and BLRM that would 
provide narrower escalation steps and potentially decrease the number of patients exposed to 
doses above the MTD. In addition, there will be a minimum of 1 week interval between C1D1 
of the first patient dosed and C1D1 of the second patient dosed for each dose escalation cohort. 
Subsequent patient dosing (third patient per cohort and beyond) may occur at a shorter interval 
(eg, <7 days from previous patient’s C1D1 dosing) but no more than 1 patient will undergo 
C1D1 dosing within a 1-day period. At the MTD dose level, an expansion cohort of 15 patients 
(including patients treated at the MTD) will be treated to better define the safety and 
tolerability of TAK-931.
2.2     Study Objectives 
2.2.1 Primary Objectives 
The primary objectives are:
x
To evaluate the safety and tolerability of TAK-931. 
x
To identify the MTD or maximum tested dose of TAK-931 in adult patients with 
nonhematologic tumors.
2.2.2 Secondary Objectives 
The secondary objectives are:
x
To characterize the PK of TAK-931 in adult patients with nonhematologic tumors.
x
To assess the pharmacodynamic effect of TAK-931 by measuring basal and 
postdose levels of phosphorylated MCM2 (Ser40), a CDC7 substrate, in skin.
x
To assess preliminary clinical activity of TAK-931 as measured by Response 
Evaluation Criteria in Solid Tumors (RECIST) guidelines (Version 1.1).
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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TAK931 
Statistical Analysis Plan, Study C1002 
Confidential 
6
 
3.     POPULATIONS FOR ANALYSIS 
3.1  
Safety population 
The safety population is defined as all patients who receive any amount of study drug.
All safety analyses will be based on the safety population.
3.2       Pharmacokinetic population 
The pharmacokinetic population is defined as all patients for whom there are sufficient 
dosing and TAK-931 concentration-time data to reliably estimate the PK parameter(s). 
PK analyses will be performed using the PK population.
3.3       Pharmacodynamics population 
The pharmacodynamics population is defined as all patients who receive at least the first 
dose of TAK-931, have a baseline skin punch 
 biopsy sample, and have at least 1 
additional skin punch 
biopsy taken during Cycle 1 of treatment. The skin 
 
biopsies must contain detectable basal pMCM2 signals to permit an estimate of pMCM2 
(Ser40) levels. Pharmacodynamic analyses will be performed using the pharmacodynamics 
population.
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TAK931 
Statistical Analysis Plan, Study C1002 
Confidential 
7
3.4      Response-Evaluable Population 
The response-evaluable population is defined as patients who receive at least 1 dose of study 
drug, have measurable disease at baseline, and at least 1 post-baseline response assessment. 
The response-evaluable population will be used for the analysis of ORR and DOR. 
3.5      DLT-Evaluable Population 
The DLT-evaluable population is defined as all patients who receive at least 75% of their 
planned TAK-931 doses (ie, 11 QD doses or 21 BID doses) for their first cycle of treatment 
(unless interrupted by related AEs) and who have sufficient follow-up data to allow the 
investigators and sponsor to determine whether DLT occurred. Patients who receive <75% 
of doses of TAK-931 (ie, 11 QD doses or 21 BID doses) in Cycle 1 for reasons other than 
related AEs are not evaluable for DLT and will be replaced  Patients will be analyzed by the 
dose level to which they were originally assigned, including those who receive subsequent 
treatment at a lower or higher dose level. The DLT-Evaluable population will be used for 
analysis of DLT. 
4.     HYPOTHESES AND DECISION RULES 
Statistical analyses will be descriptive and graphical in nature and no formal hypothesis 
testing will be performed.
5.
INTERIM ANALYSIS
As this is a phase 1 study there is no formal interim analysis.  There will be an ongoing 
review of safety data with the medical monitor and study investigators.
6.
STATISTICAL METHODOLOGY
Analyses will be primarily descriptive in nature. No formal statistical tests will be performed. 
Summary tabulations will be presented that display the number of observations, mean, 
standard deviation, median, minimum, and maximum for continuous variables, and the 
number and percent (calculated using non-missing values) per category for categorical data, 
unless specified otherwise. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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TAK931 
Statistical Analysis Plan, Study C1002 
Confidential 
8
Subjects will be analyzed at the dose level to which they were originally assigned, including 
those who receive subsequent treatment at a lower dose level.
6.1 Sample Size Justification
It is anticipated that approximately 36 to 40 patients will be enrolled in up to 8 to 9 dose
escalation cohorts. Once the MTD is determined, a safety expansion cohort of 15 patients 
(including patients treated at the MTD) will be initiated. 
An adaptive approach with BLRM will be used for dose escalation. BLRM implements dose 
escalation with overdose control principle [1,2] that informs dose escalation decisions and 
MTD estimation, along with clinical safety data evaluation and PK guidance (ie, the
projected geometric mean Cmax for the subsequent cohort does not exceed 800 ng/mL to 
allow dose escalation). 
The 2-parameter model used is as follows: 
where πi is the DLT rate for dose i and doseref is a reference dose. A quantile-based, 
non-informative, bivariate normal prior will be used for ln(α) and ln(β). This prior will be 
assigned based on pre-study estimates of the DLT rate at each dose level, as described in
Neuenschwander, et al. [1].
The model will be updated after each group of 3 patients enrolled in the current dose level. 
For each dose level, the posterior probability of having DLT rates that fall into the following 
intervals will be estimated:
[0, 0.16): underdosing.
[0.16, 0.33): target toxicity.
[0.33, 1.00]: excessive toxicity.
The next recommended dose will be selected as described in Section Error! Reference s
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The accuracy of the BLRM recommendation relies on the true DLT rate, thus the clinical 
PK guidance and safety evaluation are combined to support the dose escalation. 
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TAK931 
Statistical Analysis Plan, Study C1002 
Confidential 
9
6.2
Randomization and Stratification 
No randomization or stratification will be performed in this study.  During dose escalation, 
subjects will be enrolled in successive dose cohorts. 
6.3 Unblinding
Not applicable. 
6.4
Data Handling
6.4.1 Methods for Handling Missing Data
All available efficacy and safety data will be included in data listings and tabulations.  Data 
that are potentially spurious or erroneous will be examined under the auspices of standard data 
management operating procedures.
In general, missing data will be treated as missing and no data imputation will be applied, 
unless otherwise specified.  
6.4.1.1 Missing/Partial Dates in Screening Visit  
The following rules apply to dates recorded in the screening visits, with the exception of 
prior therapies (Section 6.4.1.2)
x
If only the day-component is missing, the first day of the month will be used if the
year and the month are the same as those for the first treatment. Otherwise, the 15
th
will be used.
x
If only a year is present, and it is the same as the year of the first treatment, the 15
th
of January will be used unless it is later than the first treatment, in which case the 
date of the first of January will be used.
x
If only a year is present, and it is not the same as the year of the first treatment, the 
15
th
of June will be used, unless other data indicates that the date is earlier, in which 
case the 15th of January will be used.  .  
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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TAK931 
Statistical Analysis Plan, Study C1002 
Confidential 
10
6.4.1.2     Missing/Partial Dates in Adverse Events/Concomitant 
Therapies/Subsequent Therapies 
Every effort will be made to avoid missing/partial dates in on-study data. If the resolution 
date of a resolved adverse event (AE) or the stop date of a concomitant therapy is missing, 
the following rules are to be used unless conflicting data exists: if month and year are 
present and the day of the month is missing, the last day of the month is imputed. If only a 
year is present, the 31st of December is used. After imputation, the imputed dates will be 
compared against the date of death, if available. If the date is later than the date of death, 
the date of death will be used as the imputed date instead.
In cases where the onset date of an adverse event is completely or partially missing, the 
following imputation rules will be used: 
1. When month and year are present and the day of the month is missing, 
x
If the onset month and year are the same as the month and year of first treatment 
with study drug, the day of first treatment or the day-component of the resolution 
date are imputed, whichever is earliest
x
If the onset month and year are not the same as the month and year of first 
treatment with study drug, the first day of the month is imputed.
2. When only a year is present, or no components of the onset date are present, 
x
If the resolution date is available, the earlier of the resolution date (possibly 
imputed) and the date of first treatment will be used.
x
If the resolution date is missing, and the onset-year is the same as the year of first 
treatment with study drug, then the date of first treatment with study drug is used.
x
Otherwise if only a year is present, the 1st of January of that year is imputed.
3. If none of the previous rules can be applied, then the date of first treatment with 
study drug is imputed as the onset date.
The imputation rules for missing/partial start dates of concomitant therapies will be the same 
as the above with the exception as follows: 
For prior therapy data, no imputation will be done for start dates.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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TAK931 
Statistical Analysis Plan, Study C1002 
Confidential 
11
The imputation rules for missing/partial start dates of subsequent therapies recorded as 
concomitant medications will be the same as the above with exceptions as follows.
1. When month and year are present and the day of the month is missing, 
a.
If the month and year of the start date are the same as the month and year of 
treatment termination, the day of treatment termination or the day-component 
of the stop date is imputed, whichever is earliest.
b. If the start month and year are not the same as the month and year of 
treatment termination, the first day of the month is imputed.
2. When only a year is present, or no components of the start date are present, the date 
will not be imputed.
6.4.2  Definition of Baseline Values 
Unless otherwise specified, the baseline value is defined as the value collected at the time 
closest to, but prior to, the start of study drug administration. For the ECG summaries, the 
baseline is defined as the average of the triple 12-lead ECG measurements at the time closest 
to, but prior to, the start of TAK-931 administration.
6.4.3 Windowing of Visits 
All data will be categorized based on the scheduled visit at which they were collected.  
These visit designators are pre-defined values that appear as part of the visit tab in the eCRF. 
6.4.4 Justification of Pooling 
All data from all sites will be pooled.  Study center or treatment-by-center interaction will 
not be included in any statistical analysis.
6.5 Patient Disposition 
A disposition of patients includes the number and percentage of patients for the following 
categories:  patients in each of the study population, primary reason to discontinue from the 
treatment, patients discontinued from the study, and primary reason to discontinue from the 
study.  All percentages will be presented by dose level and be based on the number of 
patients in the safety population.  
A listing will present data concerning patient disposition.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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TAK931 
Statistical Analysis Plan, Study C1002 
Confidential 
12
6.6 Demographics and Baseline Disease Characteristics 
6.6.1     
Demographics 
Demographics and baseline characteristics will be summarized by treatment dose group in a 
descriptive fashion for the ITT population.  Baseline demographic data to be evaluated will 
include age, sex, race, ethnicity, height, weight, and other parameters as appropriate.  
Demographic data will also be presented in a by-patient listing. 
6.6.2     
Medical History  
Medical history will be presented in a by-patient listing, including the medical and surgical 
history, date of onset and the status (whether it is resolved or ongoing). 
6.6.3 Baseline Disease Status  
Baseline disease characteristics will be summarized by the number and percentage of 
patients by dose escalation patients and total. Time since initial diagnosis (months) will be 
included in the summary as well as the stage of the disease. Eastern Cooperative Oncology 
Group (ECOG) performance status will be summarized similarly in the same table.
Separate by-patient listing will be presented for baseline disease and ECOG performance 
status.
6.6.4 Concomitant Medications 
Concomitant medications will be coded by preferred term using the World Health 
Organization (WHO) Drug Dictionary for patients in the safety population.  The number and 
percentage of subjects taking concomitant medications will be tabulated by WHO drug 
generic term, from the first dose of study treatment through 30 days after the last dose of 
study medication or until the start of subsequent antineoplastic therapy, whichever occurs 
first   
Concomitant procedures will not be coded, but will be presented in a by-patient listing.
6.6.5 Study Treatments 
TAK-931 initially will be administered for 14 days of each 21-day treatment cycle. TAK-
931 will be given as a single daily dose (QD). The starting dose will be 30 mg. If the PK 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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TAK931 
Statistical Analysis Plan, Study C1002 
Confidential 
13
from the first 2 dose escalation cohorts supports BID dosing, then study drug administration 
in subsequent cohorts may transition to a BID dosing schedule either before or when a 
geometric mean Cmax of 400 ng/mL is predicted after a single dose of TAK-931 on C1D1 
in a cohort.
6.6.5.1 Extent of Exposure 
Extent of exposure to TAK-931 will be characterized by total amount of dose taken in mg, 
total number of dose taken, number of treated cycles, numbers and percentages of patients 
who had ≥1, ≥2, …, and ≥12 treated cycles, and relative dose intensity (%)  Duration of 
treatment (days), and number and percentages of patients who had >=3, >=6, … weeks of 
treatment will be summarized for patients in the safety population. 
A treated cycle is defined as a cycle in which the patient received any amount of any treatment 
drug. Relative dose intensity (%) is defined as 100 x (total dose received in mg) / (sum of 
prescribed dose over all treated cycles). Prescribed dose is determined by the dose level to 
which a patient is enrolled at the onset of the study. 
Dosing data will also be presented in a by-patient listing.
6.6.5.2 Treatment Modifications 
The actions on TAK-931 (reduce prescribed, reduce non-prescribed, increased prescribed, 
increased non-prescribed, held, missed, interrupted, delayed, discontinued permanently) will 
be summarized over all treatment periods, and by each of Cycle.
Reasons for dose 
modification may also be tabulated similarly. 
6.6.6 Efficacy Analysis 
The secondary efficacy parameters include ORR (CR + PR), PFS, and DOR.
The ORR is defined as the proportion of patients who achieved PR or CR. The estimate of 
the ORR will be presented with 2-sided 95% exact binomial confidence intervals for each 
dose cohort. ORR will be analyzed using the response-evaluable population.
Progression-free survival is defined as the time from the date of first dose to the date of first 
documentation of progressive disease or death due to any cause, whichever occurs first. The 
Kaplan-Meier survival curves, 25th, 50th (median), and 75th percentiles (if estimable), 
along with their 2-sided 95% confidence intervals will be provided for each dose cohort. 
PFS will be analyzed using safety population.
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TAK931 
Statistical Analysis Plan, Study C1002 
Confidential 
14
The DOR is defined as the time from the date of first documentation of a response (PR or 
better) to the date of first documentation of progressive disease. Patients without 
documentation of progressive disease at the time of analysis will be censored at the date of 
their last response assessment that is stable disease or better. The DOR will be analyzed 
using the Kaplan-Meier method. The DOR will be analyzed based on the responders in the 
response-evaluable population.
6.6.7 Pharmacokinetic Analyses  
PK parameters will be estimated using non-compartmental methods with WinNonlin®
Professional Version 6.1 or higher (Pharsight Corp., Mountain View, CA). The plasma PK 
parameters will be estimated from the concentration-time profiles for all PK population 
patients. In estimating the PK parameters, BQL values at the beginning of the profile will be 
set to zero. BQL values that occur after the first quantifiable point will be considered 
missing. Values that are embedded between BQLs, or quantifiable values occurring after 
two or more BQLs, will be set to missing at the discretion of the pharmacokineticist. Actual 
sampling times, rather than scheduled sampling times, will be used in all computations 
involving sampling times.
Concentration data that are identified as anomalous may be excluded from the concentration 
summaries and plots and will not be used in the calculation of PK parameters. Evidence or 
explanations will be provided to justify the exclusion of data.
The plasma and urine PK of TAK-931 after the first dose on C1D1 and after multiple doses 
on C1D8 will be determined based on the PK parameters below, as permitted by data.
x
Area under the plasma concentration-time curve from time 0 to time of last 
measurable concentration (AUC0-last )
x
Area under the plasma concentration-time curve from time 0 to infinity (AUC0-inf)
x
Area under the plasma concentration-time curve from time 0 to 24 hr (AUC24)
x
Area under the plasma concentration-time curve from time 0 to 12 hr (AUC12 for 
BID dosing on C1D1 and after administration of multiple doses on C1D8))
x
Observed maximum plasma concentration (Cmax)
x
Time to observed maximum plasma concentration (Tmax)
x
Terminal disposition phase rate constant (Oz)
x
Terminal phase half-life (t1/2)
x
Apparent oral clearance (CL/F)
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TAK931 
Statistical Analysis Plan, Study C1002 
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15
x
Apparent terminal phase volume of distribution (Vz/F)
Individual TAK-931 concentration versus time data and individual PK parameters will be 
presented in listings and also tabulated using summary statistics by dose group.  Individual 
and mean plasma concentration-time profiles will be plotted by dose group. 
Descriptive statistics (number of patients, arithmetic mean, arithmetic standard deviation, 
arithmetic coefficient of deviation, geometric mean, median, minimum value, and maximum 
value) will be used to summarize the calculated PK parameters. For Tmax, only median, 
minimum value, and maximum value will be calculated only if quantifiable and/or 
reportable values are available for at least 50% of the observations.  A minimum of 2 
patients are required to show the mean and geometric mean, and at least 3 patients are 
required to show the standard deviation and CV. The number of observations above the limit 
of quantification will be shown for plasma concentration-time data.
The overall summary statistics will be calculated across dose groups for PK parameters will
be provided that there is no readily apparent nonlinear pharmacokinetics across dosing 
groups.
TAK-931 plasma concentration-time data will be listed using the PK-Evaluable population.  
6.6.8 Pharmacodynamic Analysis 
The change from baseline of pMCM2 (Ser40) levels in skin on C1D8 will be descriptively 
summarized by dose cohort  The change from baseline of pMCM2 (Ser40) levels may also 
be descriptively summarized in skin 
 biopsies on C1D15 at the MTD or maximum 
tested dose.
 
6.6.10      Safety Analyses 
Safety evaluations will be based on the incidence, severity, type of AEs, clinically
significant changes, or abnormalities in the subject’s physical examination, vital signs, ECG, 
and clinical laboratory results.
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TAK931 
Statistical Analysis Plan, Study C1002 
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16
These analyses will be performed using the safety population. 
6.6.10.1     Dose Limiting Toxicities (DLTs) 
A by-subject listing of DLTs which occur during Cycle 1 of treatment will be presented by 
schedule and dose level for all subjects enrolled during the dose escalation portion of this 
study. Subjects will be grouped by the dose level to which they were originally assigned, 
including those who receive subsequent treatment at a lower dose level. 
6.6.10.2    Adverse Events 
AEs will be coded using the MedDRA dictionary, version 18.0. All AEs will be presented 
in a by-patient listing. Treatment-emergent AEs will be tabulated where treatment-emergent 
is defined as any AE that occurs after administration of the first dose of study treatment and 
up through 30 days after the last dose of study medication or until the start of subsequent 
antineoplastic therapy, whichever occurs first, any event that is considered drug related 
regardless of the start date of the event, or any event that is present at baseline but worsens 
in severity after baseline or is subsequently considered drug-related by the investigator. 
Treatment-emergent AEs will be tabulated according to the MedDRA by system organ class, 
high level terms and preferred terms and will include the categories listed below. Patients 
with the same AE more than once will have that event counted only once within each body 
system, once within each high level term, and once within each preferred term.   
x
Treatment-emergent AEs
x
Drug-related treatment-emergent AEs
x
Grade 3 or higher treatment-emergent AEs
x
Grade 3 or higher drug-related treatment-emergent AEs
The most commonly reported treatment-emergent AEs (ie, those events reported by t10% of 
all patients in the safety population) will be tabulated by system organ class and preferred 
term. Patients with the same AE more than once will have that event counted only once 
within each system organ class and once within each preferred term.
6.6.10.3     
Serious Adverse Events 
The number and percentage of patients experiencing at least one treatment emergent serious 
AE (SAE) will be summarized by MedDRA primary system organ class, high level term, 
and preferred term. Drug-related SAE will be summarized similarly.
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TAK931 
Statistical Analysis Plan, Study C1002 
Confidential 
17
In addition, a by-patient listing of the SAEs will be presented (the patient listing will contain 
all SAEs regardless of treatment emergent AE status).
6.6.10.4     
Deaths 
A by-patient listing of the deaths will be presented.  All deaths occurring on-study and 
during follow-up will be displayed (regardless of treatment emergent AE status). An on
study death is defined as a death that occurs between the first dose of study drug and 30 days 
of the last dose of study drug.
6.6.10.5     
Adverse Events Resulting in Discontinuation of Study Drug 
A by-patient listing of treatment-emergent AEs resulting in discontinuation of study drug 
will be presented.  
6.6.11     Laboratory Data 
For the purposes of summarization in both the tables and listings, all laboratory values will 
be converted to standardized units.  If a laboratory value is reported using a non-numeric 
qualifier (e.g., less than (<) a certain value, or greater than (>) a certain value), the given 
numeric value will be used in the summary statistics, ignoring the non-numeric qualifier.
Laboratory test results from the central laboratory will be used when they are available.  
Laboratory test results from local laboratory will only be used when no central laboratory 
test results exist at the same scheduled sample collection time point.
If a patient has repeated laboratory values for a given time point, the value from the last 
evaluation will be used. In case more than one assessment is available on the same date, the 
later assessment will be used.
Laboratory test results will be summarized descriptively according to the scheduled sample 
collection time points. Actual values and change from baseline will be summarized over 
time.  Laboratory data will also be presented in listings. Unscheduled laboratory test results 
will be listed and included in laboratory shift tables.
Shift tables will be constructed for laboratory parameters to tabulate changes in NCI 
CTCAE for toxicity from baseline to post baseline worst CTCAE grade.  Parameters to be 
tabulated will include:
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TAK931 
Statistical Analysis Plan, Study C1002 
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18
x
Hematology: hemoglobin, hematocrit, platelets, absolute neutrophil counts (ANC), 
lymphocytes, eosinophils, and WBC
x
Clinical chemistry: ALT/SGPT, AST/SGOT, alkaline phosphatase, bilirubin (total),
calcium, creatinine, glucose, hemoglobin A1c, magnesium, phosphate, potassium, 
and sodium
Box plots over time for liver function tests will be produced.
E-dish plots for ALT/bilirubin and AST/bilirubin will also be produced.
By-patient listings to be presented include hematology, clinical chemistry and urinalysis.
Urinalysis parameters include turbidity and Color, pH, specific gravity, protein, ketones, 
bilirubin, occult blood, nitrite, urobilinogen, glucose, leukocytes.
Change from baseline in below parameters will be provided
x
Metabolic panel – Cholesterol, Triglycerides, high density lipoprotein (HDL) 
cholesterol, low density protein (LDL) cholesterol, and hemoglobin A1c
x
Fasting serum glucose
By-patient listings to be presented include cholesterol, triglycerides, high density lipoprotein 
(HDL) cholesterol, low density protein (LDL) cholesterol, fasting plasma glucose and 
hemoglobin A1c.
The incidence of all Cycle 1 ≥Grade 2 hepatic toxicities with a duration >72 hours and 
≥Grade 3 hematologic toxicities with a duration >72 hours will also be tabulated for each 
dose cohort.
6.6.12     Electrocardiograms 
Electrocardiogram actual results including abnormalities will be listed in a by-patient listing.
6.6.13     Vital Signs 
The actual values and changes from baseline of vital sign parameters including oral 
temperature, heart rate, systolic and diastolic blood pressure, and weight, will be 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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TAK931 
Statistical Analysis Plan, Study C1002 
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19
summarized over time for both Phase 1b and Phase 2 analyses, and will also be presented in 
a by-patient listing. 
7. PROGRAMMING CONSIDERATIONS
7.1
Statistical Software 
SAS version 9.2 (or higher) will be used for all analyses.
7.2
Rules and Definitions
Subject populations are defined in Section 3.
Baseline values are defined in Section Error! Reference source not found..
8.  REFERENCES: 
1. Neuenschwander B, Branson M, Gsponer T. Critical aspects of the Bayesian approach to 
phase I cancer trials. Stat Med 2008;27(13):2420-39.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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