Clinical trial NCT03708211
Conditions: Neoplasms, Advanced Solid
Keywords: Drug Therapy
Sponsor: Millennium Pharmaceuticals, Inc.
Start date: 2019-03-28; Completion date: 2019-12-03
Enrollment: 20 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to estimate the relative bioavailability of TAK-931 tablets in reference to powder-in capsule (PIC) and to assess the effect of food and esomeprazole on the pharmacokinetics (PK) of TAK-931 as a tablet.

Detailed description:
The drug being tested in this study is called TAK-931. TAK 931 is being tested to treat participants who have advanced solid tumors. This study will look at relative bioavailability, effect of food and gastric pH modification on the PK of TAK-931.

The study will enroll approximately 44 participants. The study will be conducted in 2 parts: Part 1 and Part 2. In Part 1 and Part 2, participants will be randomly assigned (by chance, like flipping a coin) in a crossover design. In Part 1, participants will be assigned to 1 of the 2 following treatment sequences:

* TAK-931 80 mg PIC + TAK-931 80 mg Tablet
* TAK-931 80 mg Tablet + TAK-931 80 mg PIC

Part 2 of the study will be initiated, once the preliminary PK data from Part 1 is available to determine the relative bioavailability of the tablet formulation in reference to PIC and to calculate the single dose of TAK-931 tablet to be used in Part 2.In Part 2, participants will be assigned to 1 of the 2 following treatment sequences:

* TAK-931 TBD Fed + TAK-931 TBD Fasted
* TAK-931 TBD Fasted + TAK-931 TBD Fed

This multi-center trial will be conducted in the Netherlands. The overall time to participate in this study is approximately 2 years. Participants will make multiple visits to the clinic and will be contacted for approximately 30 days after receiving their last dose of study drug or until the start of subsequent anticancer therapy, whichever occurs first for a follow up assessment.

Arms: arm 1: TAK-931 80 milligram (mg), PIC, orally, once on Day 1 Cycle 0 (16-day treatment cycle), followed by TAK-931 80 mg, tablet, orally, once on Day 3 Cycle 0, further followed by TAK-931 50 mg, PIC, orally, once daily from Day 5 to Day 16 Cycle 0. Participants will receive TAK-931 50 mg PIC, orally, once daily for up to 14 days in 21-day treatment cycles until progressive disease (PD), or unacceptable toxicity or any treatment discontinuation is determined. arm 2: TAK-931 80 mg, tablet, orally, once on Day 1 of Cycle 0 (16-day treatment cycle), followed by TAK-931 80 mg, PIC, orally, once on Day 3 Cycle 0, further followed by TAK-931 50 mg, PIC, orally, once daily from Day 5 to Day 16 Cycle 0. Participants will receive TAK-931 50 mg PIC, orally, once daily for up to 14 days in 21-day treatment cycles until PD, or unacceptable toxicity or any treatment discontinuation is determined. arm 3: TAK-931 tablet, orally, once under fed state on Day 1 Cycle 0 (22-day treatment cycle), followed by TAK-931 tablet, orally, once under fasted state on Day 3 Cycle 0, further followed by esomeprazole 40 mg, tablet, orally, once daily from Day 5 to Day 13 Cycle 0 and TAK-931 tablet, orally, once on Day 12, Day 14 to Day 22. Participants will receive TAK-931 tablets, orally, once daily for up to 14 days in 21-day treatment cycles until PD, unacceptable toxicity or any treatment discontinuation is determined. Dose of TAK-931 in Part 2 will be determined based on relative bioavailability data available from Part 1 of the study. arm 4: TAK-931 tablet, orally, once under fasted state on Day 1 Cycle 0 (22-day treatment cycle), followed by TAK-931 tablet, orally, once under fed state on Day 3 Cycle 0, further followed by esomeprazole 40 mg, tablet, orally, once daily from Day 5 to Day 13 Cycle 0 and TAK-931 tablet, orally, once on Day 12, Day 14 to Day 22. Participants will receive TAK-931 tablets, orally, once daily for up to 14 days in 21-day treatment cycles until PD, unacceptable toxicity or any treatment discontinuation is determined. Dose of TAK-931 in Part 2 will be determined based on relative bioavailability data available from Part 1 of the study.
Interventions: intervention 1: TAK-931 PIC intervention 2: TAK-931 Tablet intervention 3: Esomeprazole
Intervention descriptions: intervention 1: TAK-931 PICs. intervention 2: TAK-931 Tablets. intervention 3: Esomeprazole Tablets.

Protocol documents:
Prot_000.pdf: 



Title: A Phase 1, Open-Label Study to Assess the Relative Bioavailability, Effect of Food, and 
Gastric pH Modification on the Pharmacokinetics of TAK-931 in Patients with Advanced Solid 
Tumors 
NCT Number: NCT03708211
Protocol Approve Date: 21 June 2018
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
view with a black/blue bar) to protect either personally identifiable information (PPD) or company 
confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal information, or 
to otherwise protect the integrity of the clinical study.


1.0 TITLE PAGE
PROTOCOL
A Phase 1, Open-Label Study to Assess the Relative Bioavailability, Effect of Food, and 
Gastric pH Modification on the Pharmacokinetics of TAK-931 in Patients With Advanced 
Solid Tumors
Sponsor:
Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda 
Pharmaceutical Company Limited
40 Landsdowne Street
Cambridge, MA 02139 USA
Telephone: +1 (617) 679-7000 
Please note: Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda 
Pharmaceutical Company Limited, may be referred to in this protocol as “Millennium,” 
“Sponsor,” or “Takeda”. 
Study Number:
TAK-931-1003
IND Number:
127,176 
EudraCT Number:
2017-004629-34
Compound:
TAK-931
Date:
21 June 2018
Version/Amendment 
Number:
Original
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Protocol 
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1.0
ADMINISTRATIVE 
1.1
Contacts 
A separate contact information list will be provided to each site.
Serious adverse event (SAE) and pregnancy reporting information is presented in Section 10.2, 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 Sections 10.2 and 10.4
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Protocol 
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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 (ICH) E6 Good Clinical Practice (GCP): 
Consolidated Guideline.
!
All applicable laws and regulations, including, without limitation, data privacy laws, clinical 
study disclosure laws, and regulations.
SIGNATURES
The signature of the responsible Takeda medical officer (and other signatories, as applicable) can 
be found on the signature page.
Electronic Signatures may be found on the last page of this document.
PPD
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
dance
ance
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wing:
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e (GCP
a privac
priva
other s
other 
f thi
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Protocol 
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INVESTIGATOR AGREEMENT 
I confirm that I have read and that I understand this protocol, the investigator’s brochure, and any 
other product information provided by the sponsor. I agree to conduct this study in accordance 
with the requirements of this protocol and also to protect the rights, safety, privacy, and well-being 
of study subjects in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

ICH, E6 GCP: Consolidated Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting serious adverse events defined in Section 10.2 of this 
protocol.

Terms outlined in the clinical study site agreement.

Responsibilities of the investigator (Appendix B).
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix C of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Province)
Location of Facility (Country)
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Protocol 
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TABLE OF CONTENTS
1.0
ADMINISTRATIVE.......................................................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
2.0
STUDY SUMMARY ....................................................................................................10
3.0
STUDY REFERENCE INFORMATION ......................................................................15
3.1
Study-Related Responsibilities.................................................................................15
3.2
Principal Investigator/Coordinating Investigator ......................................................15
3.3
List of Abbreviations ...............................................................................................16
3.4
Corporate Identification...........................................................................................18
4.0
INTRODUCTION.........................................................................................................19
4.1
Background .............................................................................................................19
4.1.1
Nonclinical Experience ......................................................................................19
4.1.2
Clinical Experience............................................................................................22
4.1.3
Benefits and Risks..............................................................................................23
4.2
Rationale for the Proposed Study.............................................................................24
4.2.1
Part 1: Assessment of Relative Bioavailability of TAK-931 Tablets in 
Reference to PIC................................................................................................24
4.2.2
Part 2: Assessment of the Effect of Food and Esomeprazole on PK of TAK-931 
as Tablet ............................................................................................................24
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................26
5.1
Objectives................................................................................................................26
5.1.1
Primary Objectives.............................................................................................26
5.1.2
Secondary Objectives.........................................................................................26
5.1.3
Exploratory Objectives.......................................................................................27
5.2
Endpoints.................................................................................................................27
5.2.1
Primary Endpoints .............................................................................................27
5.2.2
Secondary Endpoints..........................................................................................28
5.2.3
Exploratory Endpoints .......................................................................................29
6.0
STUDY DESIGN..........................................................................................................30
6.1
Overview of Study Design.......................................................................................30
6.1.1
Part 1: Assessment of Relative Bioavailability of TAK-931 Tablet in Reference 
to PIC ................................................................................................................30
6.1.2
Part 2: Assessment of the Effect of Food and Esomeprazole, a PPI, on the PK of 
TAK-931 as a Tablet..........................................................................................31
6.2
Number of Patients ..................................................................................................32
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6.3
Duration of Study ....................................................................................................33
6.3.1
Duration of an Individual Patient’s Study Participation ......................................33
6.3.2
End of Study/Study Completion Definition and Planned Reporting....................33
6.3.3
Time Frames for Primary and Secondary Endpoints to Support Disclosures.......33
6.3.4
Total Study Duration..........................................................................................36
7.0
STUDY POPULATION................................................................................................37
7.1
Inclusion Criteria .....................................................................................................37
7.2
Exclusion Criteria ....................................................................................................38
8.0
STUDY DRUG .............................................................................................................40
8.1
Study Drug Administration......................................................................................40
8.1.1
Day 1 and Day 3 of Cycle 0, Part 1 Relative Bioavailability Assessment............40
8.1.2
Day 1 and Day 3 of Cycle 0, Part 2 Food Effect Assessment..............................40
8.1.3
Day 12 of Cycle 0, Part 2 Esomeprazole DDI Assessment..................................41
8.1.4
TAK-931 Multiple-Dose Administration in Cycle 0 and Beyond........................41
8.2
Reference/Control Therapy......................................................................................41
8.3
Dose Modification Guidelines..................................................................................41
8.3.1
Criteria for Beginning or Delaying a Subsequent Treatment Cycle.....................42
8.3.2
Criteria for Dose Interruption During a Cycle.....................................................42
8.3.3
Criteria for Discontinuation of TAK-931............................................................43
8.4
Excluded Concomitant Medications and Procedures ................................................44
8.5
Permitted Concomitant Medications and Procedures................................................44
8.6
Precautions and Restrictions ....................................................................................45
8.6.1
Pregnancy and Contraception.............................................................................45
8.6.2
Females Who are Lactating or Breastfeeding......................................................46
8.6.3
Patients With Prior Exposure to Hepatitis B or Hepatitis C.................................46
8.6.4
Photosafety ........................................................................................................46
8.7
Management of Specific AE ....................................................................................46
8.7.1
Hematologic Toxicities ......................................................................................46
8.7.2
GI AEs...............................................................................................................47
8.7.3
Hepatobiliary Disorders .....................................................................................48
8.7.4
Cardiac Toxicities ..............................................................................................48
8.7.5
Hypotension.......................................................................................................49
8.8
Blinding and Unblinding..........................................................................................49
8.9
Description of Investigational Agents ......................................................................49
8.10
Preparation, Reconstitution, and Dispensation..........................................................50
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8.11
Packaging and Labeling...........................................................................................50
8.12
Storage, Handling, and Accountability.....................................................................50
8.12.1 TAK-931 ...........................................................................................................50
8.12.2 Esomeprazole.....................................................................................................51
8.13
Other Protocol-Specified Materials ..........................................................................51
9.0
STUDY CONDUCT......................................................................................................52
9.1
Study Personnel and Organizations..........................................................................52
9.2
Arrangements for Recruitment of Patients................................................................52
9.3
Treatment Group Assignments.................................................................................52
9.3.1
Part 1 .................................................................................................................52
9.3.2
Part 2 .................................................................................................................52
9.4
Study Procedures.....................................................................................................52
9.4.1
Informed Consent...............................................................................................53
9.4.2
Patient Demographics ........................................................................................53
9.4.3
Medical History .................................................................................................53
9.4.4
Physical Examination.........................................................................................53
9.4.5
Patient Height and Weight .................................................................................53
9.4.6
Vital Signs .........................................................................................................53
9.4.7
Pregnancy Test...................................................................................................53
9.4.8
Concomitant Medications and Procedures..........................................................54
9.4.9
AEs....................................................................................................................54
9.4.10 Enrollment .........................................................................................................54
9.4.11 ECG...................................................................................................................54
9.4.12 ECHO or MUGA Scan.......................................................................................55
9.4.13 ECOG Performance Status.................................................................................55
9.4.14 Clinical Laboratory Evaluations .........................................................................55
9.4.15 Disease Assessment ...........................................................................................56
9.4.16
 Pharmacodynamic, and PK Samples ................................................56
9.4.17 PK Measurements..............................................................................................56
9.4.18
..........................................................................................57
9.5
Completion of Study Treatment (for Individual Patients) .........................................57
9.6
Completion of Study (for Individual Patients)..........................................................57
9.7
Discontinuation of Treatment With Study Drug and Patient Replacement................57
9.8
Withdrawal of Patients From Study .........................................................................58
9.9
Study Compliance....................................................................................................58
CCI
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9.10
Posttreatment Follow-up Assessments (PFS) ...........................................................59
10.0
ADVERSE EVENTS ....................................................................................................60
10.1
Definitions...............................................................................................................60
10.1.1 PTE Definition...................................................................................................60
10.1.2 AE Definition ....................................................................................................60
10.1.3 SAE Definition ..................................................................................................60
10.2
Procedures for Recording and Reporting AEs and SAEs..........................................61
10.3
Monitoring of AEs and Period of Observation .........................................................62
10.4
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events.........62
10.5
Procedures for Reporting Product Complaints or Medication Errors (Including 
Overdose) ................................................................................................................63
10.6
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities...........63
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................64
12.0
DATA HANDLING AND RECORDKEEPING............................................................65
12.1
eCRFs......................................................................................................................65
12.2
Record Retention .....................................................................................................65
13.0
STATISTICAL METHODS..........................................................................................67
13.1
Statistical and Analytical Plans ................................................................................67
13.1.1 Populations for Analysis ....................................................................................67
13.1.2 Procedures for Handling Missing, Unused, and Spurious Data ...........................67
13.1.3 Analysis of Demographics and Other Baseline Characteristics...........................67
13.1.4 Antitumor Activity Analysis ..............................................................................67
13.1.5 PK Analysis .......................................................................................................68
13.1.6
............................................................................................69
13.1.7 Safety Analysis ..................................................................................................69
13.2
Determination of Sample Size..................................................................................70
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................71
14.1
Study-Site Monitoring Visits ...................................................................................71
14.2
Protocol Deviations..................................................................................................71
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................71
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................72
15.1
IRB and/or IEC Approval ........................................................................................72
15.2
Subject Information, Informed Consent, and Subject Authorization .........................73
15.3
Subject Confidentiality ............................................................................................74
15.4
Publication, Disclosure, and Clinical Study Registration Policy ...............................74
15.4.1 Publication.........................................................................................................74
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15.4.2 Clinical Study Registration.................................................................................74
15.4.3 Clinical Study Results Disclosure.......................................................................75
15.5
Insurance and Compensation for Injury....................................................................75
16.0
REFERENCES..............................................................................................................76
LIST OF IN-TEXT TABLES
Table 6.a
Primary and Secondary Endpoints for Disclosures .............................................34
Table 8.a
Approximate Composition of High-Fat Breakfast...............................................40
Table 8.a
Dose Modification Recommendations for TAK-931 Toxicities ..........................43
Table 8.b
TAK-931 Dose Adjustments for Hematologic Toxicities....................................47
Table 9.a
Clinical Chemistry and Hematology Tests..........................................................55
Table 9.b
Primary Specimen Collection.............................................................................56
LIST OF IN-TEXT FIGURES
Figure 6.a
Part 1: Relative Bioavailability of TAK-931 Tablets in Reference to PIC...........30
Figure 6.b
Part 2: Assessment of Effects of High-Fat Meal and Esomeprazole on TAK-931 
Tablet PK Profile ...............................................................................................32
LIST OF APPENDICES
Appendix A
Schedule of Events.............................................................................................78
Appendix B
Responsibilities of the Investigator.....................................................................83
Appendix C
Investigator Consent to Use of Personal Information..........................................85
Appendix D
Eastern Cooperative Oncology Group Scale for Performance Status ..................86
Appendix E
Cockcroft-Gault Equation ..................................................................................87
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2.0
STUDY SUMMARY
Name of Sponsor:
Millennium Pharmaceuticals, Inc.
Compound:
TAK-931
Title of Protocol:
A Phase 1, Open-Label Study to Assess the Relative 
Bioavailability, Effect of Food, and Gastric pH 
Modification on the Pharmacokinetics of TAK-931 in 
Patients With Advanced Solid Tumors
IND No.:
127,176
EudraCT No.:
2017-004629-34
Study Number: TAK-931-1003
Phase: 1
Study Design:
Part 1: Assessment of Relative Bioavailability of TAK-931 Tablets in Reference to Powder-in-Capsule
Approximately 20 patients (to ensure 14-16 patients evaluable for pharmacokinetics [PK]) will be randomized in a 
crossover fashion to receive in Cycle 0 a single dose of TAK-931 80 mg powder-in-capsule (PIC) or tablet on Day 1 
and a single dose of TAK-931 80 mg with the alternate formulation on Day 3 (PIC to tablet, or tablet to PIC; 
n of ~10/sequence). Blood samples will be collected predose and up to 48 hours postdose at predetermined time points 
to measure plasma drug concentrations to evaluate the relative bioavailability of TAK-931 tablets in reference to the 
PIC formulation. There will be no TAK-931 dosing on Day 2 or Day 4. Starting on Day 5, patients will continue to 
receive TAK-931 50 mg PIC once daily (QD) for 12 days followed by a 7-day rest period. 
Starting at Cycle 1, patients will 50 mg PIC QD for 14 days, followed by 7-day rest period, in 21-day treatment cycles 
until one of the discontinuation criteria is met.
Part 2: Assessment of the Effect of Food and Esomeprazole, a Proton Pump Inhibitor, on the PK of TAK-931 as a 
Tablet
After the preliminary PK data from part 1 have been analyzed to estimate the relative bioavailability of the tablet 
formulation in reference to PIC, the dose of TAK-931 tablet will be calculated to provide total exposure (area under 
the concentration-time curve [AUC]) comparable to the 80-mg dose of PIC. In part 2, approximately 24 patients (to 
ensure 14-16 patients evaluable for PK) will be randomized in a crossover fashion to receive in Cycle 0 a single dose 
of the TAK-931 tablet formulation with or without a standard high-fat breakfast on Day 1, with the alternate food 
intake condition and dosing on Day 3 (fasted to fed or fed to fasted; n of ~12/sequence). Blood samples will be 
collected predose and for up to 48 hours postdose at predetermined time points to measure plasma drug concentrations 
to characterize the effect of food on the PK profile of TAK-931 tablet. Starting from Day 5, patients will receive 
esomeprazole 40 mg QD through Day 13. On Day 12, each patient will receive a single dose of the TAK-931 tablet 
formulation, and PK samples will be collected up to 48 hours postdose (Day 14 predose). Starting on Day 14, patients 
will continue to receive TAK-931 tablets at a dose expected to achieve exposures comparable to 50 mg PIC QD for 
11 days, followed by a 7-day rest period, until a discontinuation criterion is met. 
Starting at Cycle 1, patients will receive the TAK-931 tablet formulation at a dose expected to achieve exposures 
comparable to 50 mg PIC QD for 14 days, followed by 7-day rest period, in 21-day treatment cycles.
Primary Objectives:
Part 1

Estimate the relative bioavailability of the tablet formulation of TAK-931 in reference to the PIC 
formulation. 
Part 2

Assess the effect of a high-fat meal on the single dose PK of TAK-931 administered as the tablet formulation. 

Assess the effect of esomeprazole, a proton pump inhibitor (PPI) on the single dose PK of TAK-931 
administered as the tablet formulation.
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Secondary Objectives:
Part 1

Further characterize the PK of TAK-931 administered as PIC or the tablet formulation. 

Assess the safety and tolerability of TAK-931 administered as the tablet and PIC formulations. 

Assess the antitumor activity of TAK-931 in patients with locally advanced or metastatic solid tumors.
Part 2

Further characterize the PK of TAK-931 administered as the tablet formulation under fasted and fed 
conditions. 

Further characterize the PK of TAK-931 administered as the tablet formulation in the presence or absence of 
esomeprazole, a PPI. 

Assess the safety and tolerability of TAK-931 administered as the tablet formulation under fed and fasted 
conditions.

Assess the antitumor activity of TAK-931 in patients with locally advanced or metastatic solid tumors.
Subject Population: Adult patients with histologically or cytologically confirmed metastatic or locally advanced or 
metastatic solid tumors for whom there is no available standard treatment with proven survival benefit, this therapy is 
not indicated, or it is refused by the patient.
Number of Patients:
A total of approximately 44 patients: 20 patients to obtain 
14 to 16 evaluable patients in part 1 and 24 patients to obtain 
14 to 16 evaluable patients in part 2.
Number of Sites: 
Estimated total: 3 to 4 sites in The Netherlands
Doses:
Part 1: 80 mg single dose on Day1 and Day 3 respectively 
followed by 50 mg QD thereafter. 
Part 2: Tablet single dose providing an AUC comparable to 
the 80-mg single dose of PIC on Day 1, Day 3, and Day 12 
followed by a tablet QD dose providing an AUC 
comparable to 50-mg dose of PIC.
Route of Administration:
Oral
Duration of Treatment:
Patients may receive TAK-931 until they experience 
progressive disease or unacceptable toxicity or until any 
other discontinuation criterion is met. The maximum 
scheduled duration of treatment will be 1 year; however, 
patients receiving clinical benefit (per the investigator and 
as agreed by the sponsor’s medical monitor) can continue 
on treatment beyond 1 year with the explicit approval of the 
sponsor’s medical monitor.
Period of Evaluation:
Patients will be followed for safety for approximately 
30 days after their last dose of study drug or until the 
start of subsequent anticancer therapy, whichever 
occurs first. 
All patients will be followed for progression-free 
survival (PFS).
It is anticipated that this study will last for 
approximately 24 months. 
Main Criteria for Inclusion:

Adult patients with histologically or cytologically confirmed metastatic or locally advanced or metastatic solid 
tumors for whom there is no available standard treatment with proven survival benefit, this therapy is not 
indicated, or it is refused by the patient. 

Eastern Cooperative Oncology Group performance status of 0 to 1.

Adequate bone marrow reserve and renal and hepatic function based on the following laboratory parameters: 
–
Absolute neutrophil count ≥1.5 × 109/L, platelet count ≥75.0 × 109/L, and hemoglobin ≥85 g/L.
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–
Total bilirubin ≤1.5 times the institutional upper limit of the normal range (ULN) or total bilirubin <3.0 times 
ULN in patients with well documented Gilbert´s Syndrome.
–
Serum alanine aminotransferase or aspartate aminotransferase ≤3.0 times the ULN (<5 times ULN if liver 
enzyme elevations are due to hepatocellular cancer, biliary tract cancer, or metastatic disease in the liver).
–
Creatinine <1.5 times the institutional ULN or estimated creatinine clearance using the Cockcroft-Gault 
formula ≥30 mL/min for patients with serum creatinine concentrations above institutional limits.

Left ventricular ejection fraction ≥50% as measured by echocardiogram or multiple gated acquisition scan within 
4 weeks before receiving the first dose of study drug.

Recovered to Grade 1 or baseline from all toxic effects of previous therapy (except alopecia or neuropathy).
Main Criteria for Exclusion:

Patients who require continuous use of PPIs or histamine-2 receptor antagonists and patients who are taking PPIs 
within 5 days before the first dose of study drug.

Treatment with clinically significant enzyme inducers, such as phenytoin, carbamazepine, enzalutamide, 
mitotane, ritonavir, rifampin, or St John's wort within 14 days before the first dose of study drug. 

Treatment with systemic anticancer treatments or any investigational products within 28 days before the first dose 
of study drug or 5 half-lives, whichever is shorter. 

Patients with hypertension that is unstable or not controlled despite appropriate medical therapy.

Patients with treated brain metastases are eligible if there is no evidence of progression for at least 4 weeks after 
central nervous system-directed treatment, as ascertained by clinical examination and brain imaging (magnetic 
resonance imaging or computed tomography) during the screening period. 

Known history of HIV infection.

Known hepatitis B (HBV) surface antigen seropositive or detectable hepatitis C infection viral load. Note: 
Patients who have positive hepatitis B core antibody or hepatitis B surface antigen antibody can be enrolled but 
must have an undetectable hepatitis B viral load. 

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 or GI transit.
Main Criteria for Evaluation and Analyses:
Primary:
Part 1

Ratio of geometric mean of the following PK parameters for TAK-931 tablets in reference to PIC and 
associated 90% CIs:
–
Maximum observed concentration (Cmax).
–
AUC from time 0 to time of the last quantifiable concentration (AUClast).
–
AUC from time 0 to infinity (AUC∞).
Part 2

Ratio of geometric mean of the following PK parameters for TAK-931 tablets under fed and fasted conditions 
and associated 90% CIs: 
–
Cmax. 
–
AUClast.
–
AUC∞. 

Ratio of geometric mean of the following PK parameters for TAK-931 tablets in the presence and absence of 
esomeprazole and associated 90% CIs: 
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–
Cmax. 
–
AUClast. 
–
AUC∞. 

Summary statistics of the following PK parameters for TAK-931: 
–
Cmax. 
–
AUClast. 
–
AUC∞. 
Secondary:
Part 1

PK parameters of TAK-931 following single-dose administrations as PIC and tablets at 80 mg: 
–
Time of first occurrence of Cmax (tmax).
–
Apparent clearance after extravascular administration (CL/F).
–
Terminal disposition phase half-life (t1/2z). 

Antitumor activity: 
–
Overall response rate (ORR). 
–
PFS.
–
Disease control rate (DCR).
–
Duration of response (DOR).

Safety: 
–
Percentage of serious adverse events (SAEs), treatment-emergent adverse events (TEAEs), Grade ≥3 
TEAEs, TEAEs leading to discontinuation or dose modification, and percentage of laboratory 
abnormalities. 
Part 2

PK parameters: 
–
tmax, CL/F, and t1/2z of TAK-931 tablets following single-dose administration under fasting and fed 
conditions. 
–
tmax, CL/F, and t1/2z of TAK-931 tablets following single-dose administration in the absence and in the 
presence of esomeprazole. 

Antitumor activity:
–
ORR. 
–
PFS.
–
DCR.
–
DOR. 

Safety: 
–
Percentage of serious adverse events (SAEs), treatment-emergent adverse events (TEAEs), Grade ≥3 
TEAEs, TEAEs leading to discontinuation or dose modification, and percentage of laboratory 
abnormalities. 
Statistical Considerations:
A total of approximately 44 patients: (20 patients to obtain 14-16 evaluable patients in part 1 and 24 patients to obtain 
14-16 evaluable patients in part 2) will be enrolled in study. Results will be summarized using descriptive statistics.
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Sample Size Justification:
The sample size calculation is based on the expected 2-sided 90% CI for the difference in the paired, log transformed 
AUC (or Cmax) means of TAK-931 administered as tablet and PIC formulations. On the basis of preliminary data 
obtained from Study TAK-931-1002, the within-subject coefficient of variation was estimated to be 35.0% for AUC 
and 36.9% for Cmax. Assuming the true/assumed AUC (or Cmax) ratio is 1.0, with a sample size of 14 evaluable 
patients, the 90% CI of the ratio of geometric means is expected to be (0.795-1.257) for AUC and (0.786-1.272) for 
Cmax on the basis of the previously discussed variance assumptions. If the ratio is X, the 90% CI of the ratio of 
geometric means is expected to be within (0.795X-1.257X) for AUC and (0.786X-1.272X) for Cmax. Patients who are 
not PK-evaluable may be replaced to ensure the availability of 14 to 16 PK-evaluable patients for the final analysis of 
part 1 and part 2, respectively. 
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3.0
STUDY REFERENCE INFORMATION
3.1
Study-Related Responsibilities 
The sponsor will perform all study-related activities except for 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
%CV
coefficient of variation
AE
adverse event
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
ATP
adenosine triphosphate
AUC
area under the plasma concentration-time curve
AUC∞
area under the concentration-time curve from time 0 to infinity
AUC24
area under the plasma concentration-time curve from time 0 to 24 hours
AUClast
area under the plasma concentration-time curve from time 0 to time of the last quantifiable 
concentration
BP
blood pressure
CDC7
cell division cycle 7
CL/F
Apparent clearance after extravascular administration
Cmax
maximum observed plasma concentration
CRO
contract research organization
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CYP
cytochrome P-450
DCR
disease control rate
DDI
drug-drug interaction
DDR
DNA damage response
DLT
dose-limiting toxicity
DOR
duration of response
ECG
electrocardiogram
ECHO
echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
EOT
end-of-treatment
FDA
Food and Drug Administration
FIH
first-in-human
GCP
Good Clinical Practice
G-CSF
granulocyte colony-stimulating factor
GI
gastrointestinal
H2
histamine-2
HBV
hepatitis B virus
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HCV
hepatitis C virus
HR
heart rate
IB
investigator’s brochure
IC50
concentration producing 50% inhibition
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IHC
immunohistochemistry
IRB
institutional review board
MCM2
minichromosome maintenance complex 2
MedDRA
Medical Dictionary for Regulatory Activities
MHRA
Medicines and Healthcare products Regulatory Agency
MRI
magnetic resonance imaging
MSI
microsatellite instability
MSI-H
microsatellite instability-high
MSS
microsatellite stability
MTD
maximum tolerated dose
MUGA
multiple-gated acquisition 
NCI
National Cancer Institute 
ORR
overall response rate
OTC
over-the-counter
PD
progressive disease/disease progression
PDX
primary tumor xenograft
PFS
progression-free survival
P-gp
P-glycoprotein
PIC
powder-in-capsule (formulation)
PK
pharmacokinetic(s)
pMCM2
phosphorylation of MCM2 at serine-40
PMDA
Pharmaceuticals and Medical Devices Agency of Japan
PPI
proton pump inhibitor
PR
partial response
PTE
pretreatment event
QD
once daily
QTc
QT interval corrected for heart rate
RBC
red blood cell
RECIST
Response Evaluation Criteria in Solid Tumors
SAE
serious adverse event
SD
stable disease
SOE
schedule of events
SUSAR
suspected unexpected serious adverse reaction
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t1/2z
terminal disposition phase half-life
TEAE
treatment-emergent adverse event
TGI
tumor growth inhibition
tmax
time of first occurrence of maximum observed plasma concentration
ULN
upper limit of the normal range
WBC
white blood cell
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 DNA replication by 
phosphorylating the minichromosome maintenance complex 2 (MCM2) [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) and 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, 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 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. Given the dual 
mechanism of action of CDC7, inhibitors of CDC7 may also produce clinical activity both as 
single agents and in combination with other DNA-damaging drugs. 
4.1.1
Nonclinical Experience
4.1.1.1
Nonclinical Pharmacology
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4.1.1.2
Nonclinical Pharmacokinetics and Pharmacodynamics
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TAK-931 exhibited nonlinear PK following oral dosing in rats and dogs with single-dose 
maximum observed concentration (Cmax) and ea under the plasma concentration-time curve 
(AUC) from time 0 to 24 hours (AUC24) increasing in a greater-than-dose-proportional manner at 
higher doses. No accumulation of TAK-931 was observed in either species. 
TAK-931 has high permeability and is a substrate for breast cancer resistance protein, but is not 
likely a substrate for P-glycoprotein (P-gp) on the basis of 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, 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 showed that the compound is metabolized through glucuronidation 
by liver microsomes from all species except dogs (mice, rats, monkeys, and humans).
Investigations into cytochrome P450 (CYP) enzyme-mediated metabolism showed that CYP2D6 
and CYP3A are the main CYPs involved in the metabolism of TAK-931. There is a DDI potential 
with uridine 5'-diphospho-glucuronosyltransferase inducers; however, the DDI potential with 
CYP inhibitors, though they are involved in metabolism, is unlikely. TAK-931 is unlikely to cause 
DDIs with concomitant medications metabolized via CYP isozymes at Cmax values <800 ng/mL. 
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Details on these studies are provided in the current TAK-931 Investigator’s Brochure (IB).
4.1.1.3
Nonclinical Toxicology
The TK profile and systemic toxic potential of TAK-931 has 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 observed cardiovascular changes. The effects on blood 
pressure (BP) and heart rate (HR) 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. It has been confirmed that the effects of TAK-931 on HR and BP are 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 monitorable with clinical chemistry, and renal tubular damage is considered to 
be reversible.
The target organ toxicities after repeated dosing of TAK-931 were largely similar in rats and dogs 
and were generally consistent with inhibition of CDC7 activity. Test article-related findings 
included the hematopoietic and lymphoid systems, gastrointestinal (GI) mucosa, and reproductive 
organs. Decreased white blood cell (WBC) count or single cell necrosis in the GI mucosa appeared 
with minimal degree at lower doses and severity increased with dose level. All target organ 
toxicities observed in the repeat-dose studies were generally monitorable and reversible, except for 
the effect on 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 considered to be monitorable and reversible. 
The primary Cmax-related toxicity was cardiovascular effects (decreased BP with reflecting 
tachycardia). The DLTs related to total exposure were effects on the GI mucosa and lymphoid 
systems consistent with pharmacology-mediated CDC7 inhibition. 
Details of these studies are provided in the current TAK-931 IB. 
4.1.2
Clinical Experience
TAK-931 is being evaluated in 2 ongoing studies: TAK-931-1002, a phase 1 first-in-human (FIH) 
study in adult Japanese patients with histologically confirmed solid tumors; and TAK-931-2001, a 
phase 2 study in patients with metastatic pancreatic cancer or metastatic colon cancer. After 
TAK-931 50 mg once daily (QD) was established as the maximum tolerated dose (MTD) under 
Schedule A (14 days of treatment followed by 7 days of rest in a 21-day cycle) in study 
TAK-931-1002, an expansion cohort was added at that dose and 16 additional patients were 
enrolled. As of 04 January 2018, a total of 49 patients had received at least 1 dose of TAK-931, 
administered as a single agent in Schedule A (n = 25), Schedule B (n=12, QD for 7 consecutive 
days followed by another 7 days of rest and repeated in a 28-day cycle), and Schedule D (n = 12, 
QD continuously in a 21-day cycle). 
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4.1.2.1
Safety
DLTs occurred in 5 patients in Study TAK-931-1002. Two DLTs were Grade 4 neutropenia at 
60 mg QD for 14 days in a 21-day cycle. Three DLTs were febrile neutropenia events (all 
Grade 3): 1 occurred at 50 mg under dosing Schedule A and the other 2 at 80 mg under dosing 
Schedule B. Four of these 5 DLTs were serious, and all 5 resolved. 
A total of 20 serious treatment-emergent adverse events (TEAEs), regardless of causality, were 
reported in 12 patients treated in Study TAK-931-1002, as of the 04 January 2018 cutoff date. Of 
these, 3 SAEs were reported in 2 patients in the 60 mg cohort (neutropenia, nausea, decreased 
appetite), and 1 SAE was reported in the 40 mg cohort (pleural effusion). 
Grade ≥3 TEAEs reported in 2 or more patients in Study TAK-931-1002 as of 04 January 2018 
included neutropenia (37%), leukopenia (12%), WBC count decreased (10%), febrile neutropenia 
(6%), anemia (4%), and decreased appetite (4%). Seven of the 23 total patients treated developed 
at least 1 Grade ≥3 TEAE. There were no deaths. 
The most common TEAEs regardless of causality reported in at least 2 patients in Study 
TAK-931-1002 as of the 04 January 2018 cutoff date included nausea (49%), neutropenia (43%), 
WBC count decreased (29%), decreased appetite (27%), alopecia (22%), vomiting (20%), 
diarrhoea (18%), anaemia (16%), leukopenia (16%), uncoded (16%), malaise (14%), pyrexia 
(14%), oedema peripheral (12%), constipation (10%), fatigue (10%), and hypoalbuminaemia 
(10%). Forty-eight of the 49 total patients treated developed at least 1 TEAE. 
Refer to the IB for additional information. 
4.1.2.2
PK
Absorption of TAK-931 was fast following single or multiple oral dose administrations, with a 
median time of first occurrence of Cmax (tmax) of 1 to 4 hours. Systemic exposures (AUC) of 
TAK-931 increased in approximately a dose-proportional manner over the range of 20 to 80 mg 
QD. The interpatient variability (coefficient of variation [%CV]) in TAK-931 Cmax was <50% and 
AUC ≤30%. TAK-931 showed minimal accumulation following multiple-dose administration, 
consistent with a mean terminal disposition phase half-life (t1/2z) of 4.3 to 6.2 hours. 
4.1.3
Benefits and Risks
The current study is an open-label clinical pharmacology study to assess the relative 
bioavailability, effect of food, and gastric pH modification on the PK of TAK-931 in patients with 
advanced solid tumors. Some tumor indications are suggested as preferred based on the 
information in Section 4.1.1.1. Regardless, patients should have exhausted available standard 
therapeutic options with a proven survival benefit. Because Studies TAK-931-1002 and 
TAK-931-2001 are in progress and only a limited number of patients have been treated with 
TAK-931, there are no established benefits of this drug and the available safety information for the 
proposed dose is described in Section 4.1.2.1. 
Based on the available clinical and preclinical data, it is reasonable to consider this trial for patients 
with advanced solid tumors for whom there is no available standard treatment with proven survival 
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benefit. Based on the nonclinical data in Section 4.1.1.1, some indications may have a higher 
probability of clinical benefit: high-grade serous ovarian cancer, uterine carcinosarcoma, 
squamous esophageal cancer, squamous NSCLC, squamous head and neck cancers, rectal 
adenocarcinoma, and in general tumors with known TP53 gene mutations. For any of these 
preferred indications, patients should have exhausted standard therapeutic options with a proven 
survival benefit.
4.2
Rationale for the Proposed Study
This study will enroll approximately 44 patients. In part 1, approximately 20 patients will be 
enrolled to obtain 14 to 16 evaluable patients to assess the relative bioavailability of the TAK-931 
tablet formulation in reference to the powder-in-capsule (PIC) formulation. In part 2, 
approximately 24 patients will be enrolled to obtain 14 to 16 evaluable patients to assess the effects 
of food and esomeprazole on the PK of TAK-931 tablets. 
4.2.1
Part 1: Assessment of Relative Bioavailability of TAK-931 Tablets in Reference to 
PIC
In addition to the PIC formulation, a tablet formulation of TAK-931 has been developed for 
clinical use. The rationale for conducting this study is to characterize the relative bioavailability of 
TAK-931 administered as a tablet in reference to the PIC formulation. A tablet of 80 mg is the 
highest dose strength being evaluated in clinical studies. The prototype tablet was designed as an 
immediate-release formulation and possesses a similar rapid dissolution profile to the PIC 
formulation under acidic conditions. In vitro dissolution profiles for 10, 25, and 80 mg tablets and 
capsules are considered similar at low pH. Part 1 of this study will estimate the relative 
bioavailability of the tablet in reference to the PIC formulation to enable the transition from PIC to 
tablet in clinical development. 
4.2.2
Part 2: Assessment of the Effect of Food and Esomeprazole on PK of TAK-931 as 
Tablet
Food can alter the rate or extent of absorption or both of orally administered antineoplastic agents, 
which can have clinical implications in the treatment of patients with cancer. Ingestion of food has 
several physiologic GI effects including delayed gastric emptying, stimulated bile flow, changed 
GI pH, and increased splanchnic blood flow. Food may also alter the bioavailability of a drug by 
physically or chemically interacting with a dosage form or a drug substance. Because food may 
change the bioavailability of a drug, a food effect study is being conducted to assess the effects of 
food on the rate and extent of drug absorption when the drug is administered after a high-calorie 
and high-fat meal has been ingested. This part of the study will therefore evaluate the effect of a 
high-fat meal on the PK of TAK-931 administered as the tablet formulation.
TAK-931 (basic pKa of 6.23 and an acidic pKa of 11.1) exhibits pH-dependent solubility with low 
aqueous solubility at basic pH. Therefore, it is possible that concomitant administration of gastric 
acid-reducing agents, such as proton pump inhibitors (PPIs) and histamine-2 (H2) receptor 
antagonists, could decrease TAK-931 systemic exposures. This part of the study is therefore 
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designed to additionally evaluate the effect of multiple-dose administrations of esomeprazole, a 
PPI, on the PK of TAK-931 administered as a tablet formulation.
Part 2 of this study will be initiated only after the preliminary data from part 1 are available to 
estimate the relative bioavailability of the tablet formulation in reference to PIC. Based on this 
estimate, the dose of TAK-931 tablets will be calculated to provide total exposure (AUC) 
comparable to that achieved at the 80 mg dose of PIC. Part 2 will evaluate the effect of food and 
esomeprazole, a PPI, on the PK of the tablet formulation at the above calculated dose level to 
ensure that assessment of food effect and the effect of esomeprazole are being performed at a 
clinically relevant dose of TAK-931 as tablet formulation. 
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5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objectives
The primary objectives are:
Part 1

Estimate the relative bioavailability of the tablet formulation of TAK-931 in reference to the 
PIC formulation. 
Part 2

Assess the effect of a high-fat meal on the single dose PK of TAK-931 administered as the 
tablet formulation. 

Assess the effect of esomeprazole, a PPI on the single dose PK of TAK-931 administered as 
the tablet formulation. 
5.1.2
Secondary Objectives
The secondary objectives are:
Part 1

Further characterize the PK of TAK-931 administered as PIC or the tablet formulations. 

Assess the safety and tolerability of TAK-931 administered as the tablet and PIC formulations. 

Assess the antitumor activity of TAK-931 in patients with locally advanced or metastatic solid 
tumors.
Part 2

Further characterize the PK of TAK-931 administered as the tablet formulation under fasted 
and fed conditions. 

Further characterize the PK of TAK-931 administered as the tablet formulation in the presence 
or absence of esomeprazole, a PPI. 

Assess the safety and tolerability of TAK-931 administered as the tablet formulations under 
fed and fasted conditions.

Assess the antitumor activity of TAK-931 in patients with locally advanced or metastatic solid 
tumors.
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5.1.3
Exploratory Objectives
5.2
Endpoints
5.2.1
Primary Endpoints
The primary endpoints are:
Part 1
!
Ratio of geometric mean of the following PK parameters for TAK-931 tablets in reference to 
PIC and associated 90% CIs:
–
Cmax.
–
AUC from time 0 to time of the last quantifiable concentration (AUClast). 
–
AUC from time 0 to infinity (AUC∞).
Part 2
!
Ratio of geometric mean of the following PK parameters for TAK-931 tablets under fed and 
fasted conditions and associated 90% CIs: 
–
Cmax. 
–
AUClast.
–
AUC∞. 
!
Ratio of geometric mean of the following PK parameters for TAK-931 tablets in the presence 
and absence of esomeprazole and associated 90% CIs: 
–
Cmax. 
–
AUClast. 
–
AUC∞. 
!
Summary statistics of the following PK parameters for TAK-931: 
–
Cmax. 
–
AUClast.
–
AUC∞. 
CCI
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable T
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Terms of Us


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5.2.2
Secondary Endpoints
The secondary endpoints are:
Part 1

PK parameters of TAK-931 following single-dose administrations as PIC and tablets at 80 mg: 
–
tmax. 
–
Apparent clearance after extravascular administration (CL/F).
–
t1/2z. 

Antitumor activity: 
–
Overall response rate (ORR). 
–
Progression-free survival (PFS).
–
Disease control rate (DCR).
–
Duration of response (DOR). 

Safety:
–
Percentage of SAEs, TEAEs, Grade ≥3 TEAEs, TEAEs leading to discontinuation or dose 
modification, and percentage of laboratory abnormalities. 
Part 2

PK parameters: 
–
tmax, CL/F, and t1/2z of TAK-931 tablets following single-dose administration under fasted 
and fed conditions. 
–
tmax, CL/F, and t1/2z of TAK-931 tablets following single-dose administration in the 
absence and presence of esomeprazole. 

Antitumor activity:
–
ORR. 
–
PFS.
–
DCR.
–
DOR. 
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!
Safety:
–
Percent of SAEs, TEAEs, Grade ≥3 TEAEs, TEAEs producing discontinuation or dose 
modification, percent of laboratory abnormalities. 
5.2.3
Exploratory Endpoints
CCI
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6.0
STUDY DESIGN
6.1
Overview of Study Design
6.1.1
Part 1: Assessment of Relative Bioavailability of TAK-931 Tablet in Reference to PIC
Approximately 20 patients (to ensure 14-16 patients evaluable for PK) will be randomized in a 
crossover fashion to receive a single dose of TAK-931 80 mg PIC or tablet on Cycle 0 Day 1 and a 
single dose of TAK-931 80 mg with the alternate formulation on Day 3 (PIC to tablet, or tablet to 
PIC; n of ~10/sequence). Blood samples will be collected predose and up to 48 hours postdose at 
predetermined time points to measure plasma drug concentrations to evaluate the relative 
bioavailability of TAK-931 tablets in reference to the PIC formulation. There will be no TAK-931 
dosing on Day 2 or Day 4. Starting on Day 5, patients will continue to receive TAK-931 50 mg 
PIC QD for 12 days followed by a 7-day rest period. 
Starting at Cycle 1, patients will receive 50 mg PIC QD for 14 days followed by 7-day rest period 
in 21-day treatment cycles until one of the discontinuation criteria is met.
Figure 6.a
Part 1: Relative Bioavailability of TAK-931 Tablets in Reference to PIC
Abbreviations: D, Day; PIC, powder-in-capsule; PK, pharmacokinetics; QD, once daily.
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6.1.2
Part 2: Assessment of the Effect of Food and Esomeprazole, a PPI, on the PK of 
TAK-931 as a Tablet
After the preliminary PK data from part 1 have been analyzed to estimate the relative 
bioavailability of the tablet formulation in reference to PIC, the single dose of TAK-931 tablet to 
be used on Cycle 0 Day 1, Day 3, and Day 12 will be calculated to provide total exposure (AUC) 
comparable to the 80-mg dose of PIC. In part 2, approximately 24 patients (to ensure 
14-16 patients evaluable for PK) will be randomized in a crossover fashion to receive a single dose 
of the TAK-931 tablet formulation with or without a standard high-fat breakfast on Cycle 0 Day 1, 
with the alternate food intake condition and dosing on Day 3 (fasted to fed or fed to fasted; n of
~12/sequence). Blood samples will be collected predose and for up to 48 hours postdose at 
predetermined time points to measure plasma drug concentrations to characterize the effect of food 
on the PK of TAK-931 tablet. Starting from Day 5, patients will receive esomeprazole 40 mg QD 
through Day 13. On Day 12, each patient will receive a single dose of the TAK-931 tablet 
formulation, and PK samples will be collected up to 48 hours postdose (Day 14 predose). Starting 
on Day 14, patients will continue to receive TAK-931 tablets at a dose expected to achieve 
exposures comparable to 50 mg PIC QD for 9 days followed by a 7-day rest period until a 
discontinuation criterion is met. 
Starting at Cycle 1, patients will receive the TAK-931 tablet formulation at a dose expected to 
achieve exposures comparable to 50 mg PIC QD for 14 days followed by 7-day rest period in 
21-day treatment cycles. 
This study is an open-label, multicenter, phase 1 study of TAK-931 in adult patients with locally 
advanced or metastatic solid tumors. The patient population will consist of adults previously 
diagnosed with any form of locally advanced or metastatic solid tumor for whom there is no 
available standard treatment with proven survival benefit. Based on the nonclinical data in 
Section 4.1.1.1, some indications may have a higher probability of clinical benefit with TAK-931: 
high-grade serous ovarian cancer, uterine carcinosarcoma, squamous esophageal cancer, 
squamous NSCLC, squamous head and neck cancers, rectal adenocarcinoma, and in general 
tumors with known TP53 gene mutations. For any of these preferred indications, patients should 
have exhausted standard therapeutic options with a proven survival benefit.
Toxicity will be evaluated according to NCI CTCAE, version 5.0, effective date 27 November 
2017 [18]. 
Adverse events (AEs) will be assessed and laboratory values, vital signs, and electrocardiograms 
(ECGs) will be obtained to evaluate the safety and tolerability of TAK-931.
Serial blood samples for determination of the plasma concentration of TAK-931 and 
corresponding triplicate ECGs (part 1 only) will be obtained during Cycle 0 at prespecified time 
points as described in the schedule of events (SOE) (Appendix A) and in Section 9.4. 
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Figure 6.b
Part 2: Assessment of Effects of High-Fat Meal and Esomeprazole on 
TAK-931 Tablet PK Profile
Abbreviations: AUC, area under the plasma concentration-time curve; BA, bioavailability; D, Day; PIC, 
powder-in-capsule; PK, pharmacokinetics; QD, once daily.
6.2
Number of Patients
A total of approximately 44 patients will be enrolled in this study (approximately 20 patients to 
obtain 14 to 16 evaluable patients in part 1 and approximately 24 patients to obtain 14 to 16 
evaluable patients in part 2 [see Section 13.1.1 for definition of evaluable]). These patients will be 
enrolled at approximately 3-4 study centers in the Netherlands. Enrollment is defined as signing of 
the informed consent form (ICF). 
Patients are considered PK evaluable if they complete the protocol-specified dosing and PK 
assessments in Cycle 0 (see Section 13.1.1). Patients may be replaced if they are not evaluable for 
PK. Specifically, patients will not be considered evaluable if 1 of the following occurs during 
Cycle 0:
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
Vomit within 2 hours of taking the Day 1 or Day 3 dose of TAK-931 in Cycle 0 (part 1 and part 
2).

Vomit within 2 hours of taking the Day 12 dose of TAK-931 in Cycle 0 (part 2).

Fail to consume at least 75% of the meal (part 2 food effect assessment).

Miss 1 or more doses of esomeprazole (part 2 esomeprazole DDI assessment).

Take any excluded medication that, in the assessment of the Takeda clinical pharmacologist, 
may compromise PK evaluability for the assessment of relative bioavailability and effects of 
food or PPIs on TAK-931 PK.
6.3
Duration of Study
6.3.1
Duration of an Individual Patient’s Study Participation
Patients may receive TAK-931 until they experience progressive disease (PD) or unacceptable 
toxicity or until any other discontinuation criterion is met (see Section 8.3.3). The maximum 
scheduled duration of treatment will be 1 year; however, patients receiving clinical benefit (per the 
investigator and as agreed by the sponsor’s medical monitor) can continue on treatment beyond 
1 year with the explicit approval of the sponsor’s medical monitor. 
All patients will attend an end-of-treatment (EOT) visit 30 days (+10 days) after receiving their 
last dose of study drug or before the start of subsequent systemic anticancer therapy, whichever 
occurs first, to permit detection of any delayed TEAEs and resolution of ongoing events. Patients 
with unresolved TEAEs will continue the periodic safety follow-up until complete resolution or 
stabilization (established as squealae) occurs. Patients who discontinue study treatment for reasons 
other than PD will continue PFS follow-up every 12±1 weeks from the EOT visit until the 
occurrence of PD, loss to follow-up, consent withdrawal, death, the start of subsequent systemic 
antineoplastic therapy, or study termination (Section 9.7). 
6.3.2
End of Study/Study Completion Definition and Planned Reporting
Patients will be followed for safety for approximately 30 days after their last dose of study drug or 
until the start of subsequent anticancer therapy, whichever occurs first. All patients will be 
followed for PFS. It is anticipated that this study will last for approximately 24 months. 
6.3.3
Time Frames for Primary and Secondary Endpoints to Support Disclosures
The final data cutoff for the clinical study report will be conducted after all patients have been 
discontinued treatment or transferred to a long-term safety study, a single-patient investigational 
new drug application, or a similar program. 
Refer to Table 6.a for disclosures information for all primary and secondary endpoints. 
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Table 6.a
Primary and Secondary Endpoints for Disclosures
Endpoint
Definition
Maximum Time Frame
Primary: 
Part 1:
Ratio of geometric mean of the 
following PK parameters for 
TAK-931 tablets in reference to 
PIC and associated 90% CIs: 
–
Cmax.
–
AUClast.
–
AUC∞.
See Section 5.2.1
30 days
Part 2:

Ratio of geometric mean of the 
following PK parameters for 
TAK-931 tablets under fed and 
fasted conditions and associated 
90% CIs: 
–
Cmax.
–
AUClast.
–
AUC∞.

Ratio of geometric mean of the 
following PK parameters for 
TAK-931 tablets in the presence 
and absence of esomeprazole and 
associated 90% CIs:
–
Cmax.
–
AUClast.
– AUC∞.

Summary statistics of the 
following PK parameters for 
TAK-931: 
–
Cmax.
–
AUClast.
–
AUC∞.
See Section 5.2.1
30 days
Secondary: 
Part 1:
PK parameters of TAK-931 
following single-dose 
administrations as PIC and tablets 
at 80 mg: 
–
tmax.
–
CL/F.
–
t1/2z. 
See Section 5.2.2
30 days
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Table 6.a
Primary and Secondary Endpoints for Disclosures (continued)
Endpoint
Definition
Maximum Time Frame
Antitumor activity:
–
ORR.
–
PFS.
–
DCR.
–
DOR.
See Section 5.2.2
1 year
Safety: percentage of SAEs, 
TEAEs, Grade ≥3 TEAEs, TEAEs 
leading to discontinuation or dose 
modification, and percentage of 
laboratory abnormalities using 
NCI CTCAE version 5.0.
See Section 5.2.2
1 year
Part 2: 
PK parameters following 
single-dose TAK-931 
administration under fasted and 
fed conditions: 
–
tmax.
–
CL/F.
–
t1/2z.
See Section 5.2.2
30 days
PK parameters following 
single-dose TAK-931 
administration in the presence and 
absence of esomeprazole: 
–
tmax.
–
CL/F.
–
t1/2z.
See Section 5.2.2
30 days
Antitumor activity 
–
ORR.
–
PFS.
–
DCR.
–
DOR.
See Section 5.2.2
1 year
Safety: percentage of SAEs, 
TEAEs, Grade ≥3 TEAEs, TEAEs 
leading to discontinuation or dose 
modification, and percentage of 
laboratory abnormalities using 
NCI CTCAE version 5.0.
See Section 5.2.2
1 year
Abbreviations: AUC∞, area under the concentration-time curve from time 0 to infinity; AUClast, area under the plasma 
concentration-time curve from time 0 to the time of the last quantifiable concentration; CL/F, apparent clearance after 
extravascular administration; Cmax, maximum observed plasma concentration; DCR, disease control rate; DOR, 
duration of response; NCI CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events;
ORR, overall response rate; PIC, powder-in-capsule; PFS, progression-free survival; PK, pharmacokinetic(s); SAE, 
serious adverse event; t1/2z, terminal disposition phase half-life; TEAE, treatment-emergent adverse event; tmax, time of 
first occurrence of maximum observed plasma concentration. 
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6.3.4
Total Study Duration
Patients will be followed for safety for approximately 30 days after their last dose of study drug or 
until the start of subsequent anticancer therapy, whichever occurs first. All patients will be 
followed for PFS. It is anticipated that this study will last for approximately 24 months. 
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7.0
STUDY POPULATION
This study will include adult patients with histologically or cytologically confirmed metastatic or 
locally advanced solid tumors for whom there is no available standard treatment with proven 
survival benefit, this therapy is not indicated, or it is refused by the patient. 
7.1
Inclusion Criteria
Each patient must meet all the following inclusion criteria to be enrolled in the study:
1. Male or female patients aged 18 years or older.
2. Adult patients with histologically or cytologically confirmed metastatic or locally advanced 
solid tumors for whom there is no available standard treatment with proven survival benefit, 
this therapy is not indicated, or it is refused by the patient. Based on the nonclinical data in 
Section 4.1.1.1, the following indications may have a higher probability of clinical benefit: 
high-grade serous ovarian cancer, uterine carcinosarcoma, squamous esophageal cancer, 
squamous NSCLC, squamous head and neck cancers, rectal adenocarcinoma, and in general 
tumors with known TP53 gene mutations. For any of these preferred indications, patients 
should have exhausted standard therapeutic options with a proven survival benefit. 
3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. 
4. Adequate bone marrow reserve and renal and hepatic function based on the following 
laboratory parameters: 
–
Absolute neutrophil count (ANC) ≥1.5 × 109/L, platelet count ≥75 × 109/L, and hemoglobin 
≥85 g/L.
–
Total bilirubin ≤1.5 times the institutional upper limit of the normal range (ULN) or total 
bilirubin <3.0 times the ULN in patients with well-documented Gilbert syndrome.
–
Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤3.0 times the 
ULN (<5 times the ULN if liver enzyme elevations are due to hepatocellular cancer, biliary 
tract cancer, or metastatic disease in the liver).
–
Creatinine <1.5 times the institutional ULN or estimated creatinine clearance using the 
Cockcroft-Gault formula ≥30 mL/min for patients with serum creatinine concentrations 
above institutional limits.
5. Left ventricular ejection fraction ≥50% as measured by echocardiogram (ECHO) or multiple 
gated acquisition (MUGA) scan within 4 weeks before receiving the first dose of study drug.
6. Recovered to Grade 1 or baseline from all toxic effects of previous therapy (except alopecia or 
neuropathy).
7. Female patients who:

Are postmenopausal for at least 1 year before the screening visit, OR

Are surgically sterile, OR
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
If they are of childbearing potential, agree to practice 1 highly effective method of 
contraception and 1 additional effective (barrier) method at the same time, from the time of 
signing the ICF 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 patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 
methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable 
methods of contraception. Female and male condoms should not be used together.)
8. Male patients, even if surgically sterilized (ie, 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 patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 
methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable 
methods of contraception. Female and male condoms should not be used together.) AND

Agree not to donate sperm during this study and for 120 days after receiving their last dose 
of study drug. 
9. 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.
10. Suitable venous access for the study-required blood sampling including PK and 
pharmacodynamic sampling.
11. Patients must have a radiographically or clinically evaluable tumor, but measurable disease as 
defined by Response Evaluation Criteria in Solid Tumors (RECIST) (version 1.1) [19] is not 
required for participation in this study.
7.2
Exclusion Criteria
Patients meeting any of the following exclusion criteria are not to be enrolled in the study.
1. 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.
2. Treatment with systemic anticancer treatments or investigational products within 28 days 
before the first dose of study drug or 5 half-lives, whichever is shorter.
3. Patients who require continuous use of PPIs or H2 receptor antagonists and patients who are 
taking PPIs within 5 days before the first dose of study drug.
4. Treatment with clinically significant enzyme inducers, such as phenytoin, carbamazepine, 
enzalutamide, mitotane, ritonavir, rifampin, or St John's wort within 14 days before the first 
dose of study drug. 
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5. Patients with hypertension that is unstable or not controlled despite appropriate medical 
therapy.
6. Patients with treated brain metastases are eligible if there is no evidence of progression for at 
least 4 weeks after central nervous system-directed treatment, as ascertained by clinical 
examination and brain imaging (magnetic resonance imaging [MRI] or computed tomography 
[CT]) during the screening period. 
7. Known history of HIV virus infection.
8. Known hepatitis B virus (HBV) surface antigen seropositive or detectable hepatitis C virus 
(HCV) infection viral load. Note: Patients who have positive hepatitis B core antibody or 
hepatitis B surface antigen antibody can be enrolled but must have an undetectable HBV viral 
load. 
9. Known 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 or GI 
transit. 
10. Part 2 only: known hypersensitivity to PPIs (eg, angioedema or anaphylaxis have occurred). 
11. Part 2 only: not being able or willing to take one high fat breakfast as indicated in the protocol. 
12. Any serious medical or psychiatric illness that could, in the investigator’s opinion, potentially 
interfere with the completion of treatment according to this protocol. 
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8.0
STUDY DRUG
8.1
Study Drug Administration
All protocol-specific criteria for administration of study drug must be met and documented before 
drug administration. Study drug will be administered only to eligible patients under the 
supervision of the investigator or identified subinvestigator(s).
8.1.1
Day 1 and Day 3 of Cycle 0, Part 1 Relative Bioavailability Assessment
TAK-931 will be administered to patients on an empty stomach except water from 2 hours before 
taking the study drug until completion of collection of the 4-hour ECG/PK samples on Day 1 and 
Day 3 of Cycle 0. Each dose of the study drug will be given orally with at least 8 ounces (230 mL) 
of water. Accordingly, patients will be instructed to eat a meal or snack at least 2 hours before 
dosing, and to eat a meal or snack after the 4-hour triplicate ECG and blood sample for PK analysis 
are collected. 
8.1.2
Day 1 and Day 3 of Cycle 0, Part 2 Food Effect Assessment
For the fasted treatment, the Day 1 or Day 3 dose of TAK-931 will be administered with 240 mL 
(8 fluid ounces) of water following an overnight fast, including no medications, of approximately 
10 hours. In addition, no food will be allowed for 2 hours after the Day 1 or Day 3 dose. Water is 
allowed as desired except for 1 hour before and after TAK-931 administration. For the fed 
treatment, following an overnight fast (including no medications) of approximately 10 hours, 
patients will start the recommended meal 30 minutes before administration of the Day 1 or Day 3 
dose. Table 8.a shows the approximate composition of a high-fat breakfast. Patients should finish 
the entire meal in 30 minutes or less; TAK-931 will be administered 30 minutes after start of the 
meal with 240 mL (8 fluid ounces) of water. No food will be allowed for at least 2 hours postdose. 
Water is allowed as desired except for 1 hour before and 1 hour after TAK-931 administration. 
Patients will be randomized to receive a standard high-fat meal before dosing on Day 1 or Day 3 of 
Cycle 0. 
Table 8.a
Approximate Composition of High-Fat Breakfast
Kcal
Protein (g)
Fat (g)
Carbohydrate (g)
2 slices whole-wheat bread (approx 70 g)
154
6.2
1.8
28.4
15 g halvarine a
112
0.1
12.3
0.2
2 fried eggs in 15 g halvarine a
220
14.4
17.6
0.9
40 g bacon b
151
7.2
13.6
0.0
115 g fried potatoes
130
2.5
5.2
18.3
240 mL whole milk
151
8.4
8.2
10.8
TOTAL
918
38.8
58.7
58.6
a Reduced-fat margarine. 
b Vegetarians may substitute 50 g of brie cheese for bacon.  
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8.1.3
Day 12 of Cycle 0, Part 2 Esomeprazole DDI Assessment
TAK-931 will be administered to patients with esomeprazole on an empty stomach except water 
from 2 hours before and 2 hours after taking the study drug. Each dose of the study drug will be 
given orally with at least 8 ounces (230 mL) of water. 
8.1.4
TAK-931 Multiple-Dose Administration in Cycle 0 and Beyond
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), that dose 
should be skipped. Patients should record any skipped doses in their dosing diary (see the 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) or tablets are 
visible in the vomitus, replacement capsule(s) or tablets should be taken; otherwise the dose will 
not be readministered, 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, patients should never repeat a dose or double-up on 
doses.
Beginning with Cycle 1 and after, TAK-931 will be administered only during Days 1 to 14 of each 
21-day cycle of study participation. TAK-931 doses missed due to any reason, including treatment 
interruption due to toxicity, will not be made up by extending the 14-day treatment period during 
the 21-day cycle. Patients in part 1 will receive 50 mg PIC. Patients in part 2 will receive the tablet 
formulation at a dose that produces comparable exposure to 50 mg PIC as determined in part 1.
8.2
Reference/Control Therapy
No reference or control therapy will be used. Esomeprazole will be used in Cycle 0 of part 2 to 
assess the effects of modifying gastric pH on the PK of TAK-931. 
8.3
Dose Modification Guidelines
Dose modification guidelines for toxicities, based on the type and severity of AEs and causality 
determination by investigators, are described below for TAK-931. Further clarification can be 
obtained in consultation with the sponsor clinician (or designee). In general it is recommended to 
reduce the dose of TAK-931 in 10-mg increments (for example from 50 mg to 40 mg). Reductions 
below 30 mg (PIC or tablets) are not recommended unless the investigator believes that the patient 
is deriving benefit from treatment. 
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8.3.1
Criteria for Beginning or Delaying a Subsequent Treatment Cycle
Before starting a new treatment cycle, TAK-931–related AEs or laboratory abnormalities must 
have returned to Grade ≤1 or baseline levels or to a level considered acceptable by the physician 
(eg, hypophosphatemia that can be managed by oral replacement).
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 the patient is receiving clinical benefit as assessed by the 
investigator, with agreement by the sponsor’s medical monitor. TAK-931 dosing may be 
continued at a reduced dose level.
For Cycle 1 onward, treatment with TAK-931 will use a cycle length of 21 days. For a new cycle 
of treatment to begin, the patient must meet the following criteria:

ANC must be ≥1.5 × 109/L.

Platelet count must be ≥75.0 × 109/L.
If the patient fails to meet the above-cited criteria for retreatment, initiation of the next cycle of 
treatment should be delayed until the criteria for re-treatment have been met. The patient has to be 
re-tested or re-evaluated at least once a week at the investigator's discretion. The patient can be 
re-treated once recovery is achieved. 
8.3.2
Criteria for Dose Interruption During a Cycle
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 or a subsequent occurrence.
Refer to Table 8.b for general dose modification recommendations. When the dose of TAK-931 is 
withheld according to 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. For transient laboratory abnormalities that, per 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 8.7. 
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Table 8.b
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 treatment 
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 a reduced dose level. 
Grade 3 and Grade 4 
non–life-threatening AEs
Hold TAK-931 until resolution to Grade ≤1 or baseline, then resume treatment at 
either the same dose or a reduced dose level at the discretion of the investigator and 
after discussion with the sponsor.
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 the patient is receiving 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.
Abbreviation: AE, adverse event. 
If initial dose adjustment does not provide sufficient relief, the dose of TAK-931 can be further 
reduced by an additional dose level if the treating physician believes that the patient is receiving 
clinical 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. Up to 2 dose level reductions of TAK-931 due to AE are generally 
recommended. If a third dose reduction is needed, it must first be discussed with and approved by 
the sponsor’s medical monitor. 
8.3.3
Criteria for Discontinuation of TAK-931
TAK-931 should be discontinued for patients experiencing an AE 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 a reduced dose level when toxicity recovers to Grade ≤1 or 
baseline.
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, study treatment should be discontinued unless 
the investigator believes that the patient will benefit from continuing in the study. Further dose 
reduction must be discussed with and approved by the sponsor’s medical monitor. If treatment 
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discontinuation is determined, the EOT visit should be completed within 30 to 40 days after the 
last administration of TAK-931 or before initiation of new anti-cancer therapy (whichever occurs 
first). 
8.4
Excluded Concomitant Medications and Procedures
All prescription and over-the-counter (OTC) medications, including influenza vaccines, taken by a 
patient since signing the ICF through the EOT visit or before initiation of new anti-cancer therapy 
(whichever occurs first) will be recorded in the designated electronic case report forms (eCRFs). 
Patients must be instructed not to take any medications, including OTC medications and herbal 
supplements, without first consulting with the investigator.
The following medications and procedures are prohibited during the study:

Patients currently on chronic erythropoietin support for anemia may continue to receive 
erythropoietin, but initiation of new erythropoietin therapy is not allowed during Cycle 0 [20]. 

Any investigational agent other than TAK-931.

Any concurrent antineoplastic therapy (eg, chemotherapy, hormonal therapy, immunotherapy, 
radiation therapy except for palliative radiation therapy and once PD is ruled out), or standard 
or investigational agents for treatment of cancer. 

Clinically significant CYP enzyme inducers, such as phenytoin, carbamazepine, enzalutamide, 
mitotane, ritonavir, rifampin, or St John's wort, within 14 days before the first dose of 
TAK-931 and during the study.

Chronic concomitant administration of any PPI is not allowed during the study except for the 
esomeprazole indicated in Cycle 0 of part 2. Patients receiving PPI therapy 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 require treatment with PPIs 
should be discussed with the sponsor to determine the dose, 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 the first dose (Day -1) through the last day of TAK-931 dosing in the treatment 
cycle. Intermittent use may be considered especially during the 1-week rest 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 the dose, 
schedule, and suitability of the patient for continued study participation. During Cycle 0 in 
part 2, OTC antacid preparations such as calcium carbonate are not allowed.
8.5
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 in the eCRF. Use of myeloid growth factors (eg, 
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granulocyte colony-stimulating factor [G-CSF], granulocyte-macrophage colony-stimulating 
factor) may be administered to manage patients who experience severe and/or febrile neutropenia 
if clinically indicated in accordance with the American Society of Clinical Oncology (ASCO) 
guidelines and/or institutional practices. For the first episode of neutropenia, dose reduction is 
preferred [21]. 
During Cycle 0 in part 1 and from Cycle 1 and after in both parts, OTC antacid preparations are 
allowed but should not be taken from 2 hours before and until 2 hours after administration of 
TAK-931. They are allowed as needed on non-dosing days. 
8.6
Precautions and Restrictions
Patients must be educated about adequate and safe storage of TAK-931 at home. They must be 
informed about safe self-administration of the drug following the directions given in Section 8.1. 
and Section 8.12. 
Because of the risk of neutropenia, patients should be instructed to measure axillary temperature at 
least daily and to follow local procedures if their body temperature reaches 38ºC or above. 
8.6.1
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 and male patients should use effective methods of contraception throughout 
defined periods during and after study treatment as specified below. 
Female patients must meet 1 of the following:

Postmenopausal for at least 1 year before the screening visit, OR

Surgically sterile, OR

If they are of childbearing potential, agree to practice 1 highly effective method of 
contraception and 1 additional effective (barrier) method at the same time, from the time of 
signing of the ICF 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 patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 
methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable 
methods of contraception. Female and male condoms should not be used together.)
Male patients, even if surgically sterilized (eg, status postvasectomy) must agree to 1 of the 
following:

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 patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 
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methods for the female partner], withdrawal spermicides only, and lactational amenorrhea are 
not acceptable methods of contraception. Female and male condoms should not be used 
together.) AND

Agree not to donate sperm during the study and for 120 days after receiving their last dose of 
study drug.
8.6.2
Females Who are Lactating or Breastfeeding
Female patients who are lactating must refrain from breastfeeding from the start of study 
participation (Section 7.2, exclusion criterion #1) through 30 days after the last dose of study drug.
8.6.3
Patients With Prior Exposure to Hepatitis B or Hepatitis C
Patients who have detectable HBV or HCV viral loads are excluded from study participation (see 
Section 7.2, exclusion criterion #8). 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 per 
institutional guidelines, and 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 nucleoside antagonist 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. 
8.6.4
Photosafety
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. A 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).
8.7
Management of Specific AE
Therapies that are required to manage AEs and control cancer symptoms are allowed per standard 
clinical practice, unless specifically excluded. Supportive care agents, such as erythropoietin and 
G-CSF are permitted as needed per the ASCO [20,21] guidelines. Blood products (red blood cell 
[RBC] and platelet transfusions), and pain medications are permitted per local institutional 
practice. Each treatment intervention should be clearly documented.
8.7.1
Hematologic Toxicities
Refer to Table 8.c for dose delay and reduction recommendations for hematologic toxicities. 
Dosing with TAK-931 should be held if 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 (RBC or platelet) 
and hematopoietic or thrombopoietic stimulating factors may be used to treat cytopenia/ 
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thrombocytopenia at the discretion of the investigator per standard clinical practice. For a first 
event, a dose reduction is preferred over the use of myeloid growth factors [20].
Table 8.c
TAK-931 Dose Adjustments for Hematologic Toxicities
Criteria
Action
Neutropenia (ANC)
Grade 1 (ANC <LLN to 1.5 × 109 cells/L)
Continue TAK-931 at the same dose level.
Grade 2 (ANC 1.0 to <1.5 × 109 cells/L)
Continue TAK-931 at the same dose level.
Grade 3 (ANC 0.5 to <1 × 109cells/L) 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 <0.5 × 109 cells/L) without 
fever.
Withhold dose until resolved to Grade ≤1 or baseline, then resume 
treatment at a reduced dose level.
Febrile neutropenia (ANC <1.0 × 109 cells/L, 
with a single temperature of >38.3°C or 
sustained temperature of ≥38°C for more than 
1 h)
Withhold dose until fever/infection have recovered and ANC is 
Grade ≤1 or baseline, then resume treatment at a reduced dose level.
Thrombocytopenia (PLT)
Grade 1 (PLT <LLN to 75.0 × 109 cells/L)
Continue TAK-931 at the same dose level.
Grade 2 (PLT <75.0 to 50.0 × 109 cells/L)
Continue TAK-931 at the same dose level.
Grade 3 (PLT <50.0 to 25.0 × 109 cells/L) 
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 <25.0 × 109cells/L) without 
bleeding
Withhold dose until resolved to Grade ≤1 or baseline, then 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.
8.7.2
GI AEs
Nausea and/or Vomiting
This study will not initially employ prophylactic antiemetics; however, a patient who develops 
nausea and/or vomiting will be actively managed by employing optimal antiemetic treatment per 
local standard practice. Additionally, antiemetics could be used prophylactically as clinically 
indicated following the occurrence of the first event of TAK-931–related or possibly related 
nausea and/or vomiting. An optimal antiemetic regimen is defined as one that employs both a 
5-hydroxytryptamine 3 serotonin antagonist and a corticosteroid given in standard doses and 
according to standard schedules. PPIs and H2 receptor antagonists are not allowed during 
treatment. 
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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.
8.7.3
Hepatobiliary Disorders
Liver function tests should be monitored throughout participation in the study (AST, ALT, 
alkaline phosphatase, and bilirubin). If abnormalities are observed, the patient should be assessed 
for causes other than TAK-931. Transaminase elevations should be managed according to locally 
accepted clinical practice, including frequent monitoring of appropriate laboratory functions 
(2-3 times per week). If possible, hepatotoxic concomitant medications should be discontinued in 
patients who develop elevated transaminases.
Dose interruption should be considered in any patient who develops Grade 2 elevated 
transaminases lasting longer than 2 weeks or any time a patient develops Grade ≥3 elevated 
transaminases. Treatment should be restarted at a reduced dose level (after transaminase levels 
resolve to Grade ≤1 or baseline), provided that this occurs within 14 days of dose interruption.
Patients who develop AST or ALT >3 times the ULN in conjunction with bilirubin >1.5 times the 
ULN must be permanently discontinued from study treatment, unless a correctable non–
drug-related cause of hepatic injury is identified. 
8.7.4
Cardiac Toxicities
A MUGA scan or ECHO will be performed as indicated in the SOE. ECHO or MUGA scan will 
also be performed if symptoms of heart failure are noted. Patients with significant abnormalities 
should be treated per standard of care at their institution and the treatment should be documented 
in the eCRFs. If Grade ≥2 decrease in cardiac ejection fraction occurs, treatment should be 
discontinued until resolution to Grade ≤1, then the study drug will be resumed at a reduced dose 
level. 
If Grade 3 QT interval corrected for heart rate (QTc) prolongation or arrhythmia occur, 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 
necessary) should be put in place immediately after observation of a QTc prolongation or 
arrhythmia. Review of concomitant medications and electrolyte abnormalities 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 approval from the sponsor (see Section 8.3.3).
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8.7.5
Hypotension
Transient hypotension with reflex tachycardia was observed in toxicology studies with dogs at 
tmax. This risk has not been substantiated in Japanese patients dosed up to 80 mg in the FIH study.
If a hypotensive event occurs, the patient should be advised to contact the site for instructions. BP 
and HR monitoring should be performed at home, if indicated by the investigator, and values 
recorded in the patient’s diary. 
If a hypotensive event occurs at the site, the patient can be discharged only if no clinically relevant 
BP or HR changes occurred during the observation period. If the investigator notes changes in 
BP/HR and/or symptoms of concern, subsequent doses of TAK-931 should be administered at the 
site with the same monitoring as for Days 1 and 3 of Cycle 0 until the risk is confirmed or 
discharged. 

Grade 1 hypotension: hypotension (at least 20 mmHg systolic BP drop and/or at least 
10 mmHg diastolic BP drop vs individual patient’s baseline BP) without symptoms and no 
reflex tachycardia at rest. No treatment modification or monitoring is indicated. 

Grade 2 hypotension: hypotension with compatible symptoms and/or reflex tachycardia (or 
Grade 2 presyncope). BP, HR, ECG, and blood draw for TAK-931 concentration will be 
performed promptly. Repeated assessments should be performed as clinically indicated. 
Treatment should follow local practice. After recovery and normalization to baseline, the 
patient can continue receiving treatment at the same dose if it is the first occurrence or at a 
reduced dose if it is a reoccurrence. 

Grade ≥3 hypotension: Stop treatment. Treatment for the event should follow local practice. 
Consider continuous electronic monitoring of HR, BP, and ECG until complete normalization 
of vital signs. Take a blood sample for measurement of TAK-931 concentration. Depending on 
the seriousness of the event, associated pathologies, and recovery, consider either 
discontinuing the patient’s treatment or continuing treatment at a reduced dose level. 
8.8
Blinding and Unblinding
This is an open-label study. 
8.9
Description of Investigational Agents
TAK-931 will be supplied as PIC for oral administration in part 1 as indicated. TAK-931 PIC is 
available in 3 dose strengths, 10, 25, and 80 mg of TAK-931 in addition to the following inactive 
ingredients: mannitol (filler), colloidal silicon dioxide (flow aid), and hard gelatin capsule. 
The dose strength of each capsule is differentiated by size and color:

10 mg TAK-931 capsules: white opaque color, size 4 capsule.

25 mg TAK-931 capsules: Swedish orange opaque color, size 4 capsule.

80 mg TAK-931 capsules: Swedish orange opaque color, size 3 capsule.
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TAK-931 will be supplied as tablets for oral administration in parts 1 and 2 as indicated. TAK-931 
tablets are available in 3 dose strengths, 10, 25, and 80 mg of TAK-931 in addition to the following 
inactive ingredients: mannitol (filler), microcrystalline cellulose (filler), and croscarmellose 
sodium (disintegrant)
The dose strength of each tablet is differentiated by size:

10 mg TAK-931 tablets: white, round, approximately 5.5 mm in diameter.

25 mg TAK-931 tablets: white, round, approximately 6.4 mm in diameter.

80 mg TAK-931 tablets: white, round, approximately 9.5 mm in diameter.
Refer to the TAK-931 IB for full details.
8.10
Preparation, Reconstitution, and Dispensation
TAK-931 dosage forms will be provided in labeled bottles in accordance with all applicable 
regulations. Materials provided by the sponsor should be dispensed to patients with clear 
administration instructions from the investigator. 
TAK-931 is an anticancer drug, and as with other potentially toxic compounds, caution should be 
exercised when handling TAK-931 capsules and tablets. 
8.11
Packaging and Labeling
TAK-931 will be provided by Takeda and will be handled at the investigative site as open-label 
material.
TAK-931 will be provided in high-density polyethylene bottles with polypropylene, 
child-resistant caps and an induction seal.
TAK-931 is packaged and labeled in accordance with all applicable regulations.
The clinical sites will obtain esomeprazole and will apply study labels provided by the sponsor. 
The precautions, warnings, contraindications, and adverse events associated with esomeprazole 
are included in the prescribing information [22].
8.12
Storage, Handling, and Accountability
8.12.1 TAK-931
Upon receipt at the investigative site, TAK-931 should be stored in the original bottles until use. 
Capsules should be stored at 2°C to 8°C (refrigerated) and tablets should be stored at 15°C to 25°C 
(room temperature). All temperature excursions at the site pharmacy will be reported to the 
sponsor for assessment and authorization for continued use. All investigational supplies must be 
stored in a secure area with controlled access and will be stored in original packaging. All 
TAK-931 should be used before the retest expiry date.
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A drug dispensing log, including records of drug received from the sponsor and drug dispensed to 
the patients, will be provided and kept at the study site. Storage area temperature conditions must 
be monitored and recorded daily. A daily temperature log will also be kept at the study site.
Because TAK-931 is an investigational agent, it should be handled with due care. If contact with a 
broken capsules occurs, 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 cleanup is complete. The spilled material should be disposed of as hazardous 
medical waste in compliance with federal, state, and local regulations. If contact with the powder 
(eg, from a broken capsule) occurs, skin should be washed immediately with soap and copious 
amounts of water for at least 15 minutes. If contact with the eyes occurs, 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.
8.12.2 Esomeprazole
The container should be stored at the investigative site at controlled room temperature (25°C; 
excursions permitted from 15°C to 30°C) and used before the expiration date indicated on the label 
or accompanying documentation. Tablets are not intended to be broken or manipulated in any way. 
Dispense in a tight container if the product package is subdivided. For complete storage and 
handling information, refer to documentation provided with the commercial product [22]. 
8.13
Other Protocol-Specified Materials
Not applicable. 
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9.0
STUDY CONDUCT
This study will be conducted in compliance with the protocol, GCP, applicable regulatory 
requirements, and ICH guidelines.
9.1
Study Personnel and Organizations
The contact information for the 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.
9.2
Arrangements for Recruitment of Patients
Recruitment and enrollment strategies for this study may include recruitment from the 
investigator’s local practice or referrals from other physicians. If advertisements become part of 
the recruitment strategy, they will be reviewed by the institutional review board (IRB)/ 
independent ethics committee (IEC). 
9.3
Treatment Group Assignments
Central randomization (non–center-specific) will be used. Additional instructions are available in 
the study manual. 
9.3.1
Part 1
Patients will be randomly assigned in a 1:1 ratio with a block size of 2 to receive a single dose of 
TAK-931 either as PIC or tablet on Day 1 of Cycle 0. These patients will then be administered in 
the alternate formulation on Day 3 of Cycle 0. Details of treatments are in Section 6.1.1.
9.3.2
Part 2
Patients will be randomly assigned in a 1:1 ratio with a block size of 2 to receive a single dose of 
TAK-931 with or without a standard high-fat breakfast (see Section 8.1.2) on Day 1 of Cycle 0. 
These patients will then be administered in the alternate food intake condition on Day 3 of Cycle 0. 
Details of treatments are in Section 6.1.2. 
9.4
Study Procedures
Refer to the SOE (Appendix A) for timing of assessments. Additional details are provided as 
necessary in the sections that follow. 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 
procedures should be performed on schedule for all visits. The timing of PK assessments is 
specified in Appendix A, Tables 1, 2, and 4. All EOT evaluations should occur 30 to 40 days after 
the last dose of study drug. 
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Refer to the SOE (Appendix A) for timing of assessments. Additional details are provided as 
necessary in the sections that follow.
9.4.1
Informed Consent
Each patient must provide written informed consent before any study-required procedures are 
conducted, unless those procedures are performed as part of the patient’s standard care.
9.4.2
Patient Demographics
The date of birth, race, ethnicity, and sex of the patient are to be recorded during screening.
9.4.3
Medical History
During the screening period, a complete medical history 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, with a breakdown by treatment intention (neoadjuvant, adjuvant, or 
metastatic); line of therapy for metastatic disease, regimen, and drug(s); treatment start and stop 
dates (including at least month and year); best response; and PD date. Known genetic and serum 
tumor biomarkers previously analyzed at the site should be recorded. In addition, concomitant 
medications will be recorded as specified in Section 9.4.8.
9.4.4
Physical Examination
A physical examination will be completed per standard of care at the times specified in the SOE 
(Appendix A). Any clinically relevant findings are to be documented. 
9.4.5
Patient Height and Weight
Height and weight will be measured only once during screening (within 28 days before the first 
dose of TAK-931). 
9.4.6
Vital Signs
Standard vital signs should be obtained at least once during each visit specified in the SOE 
(Appendix A) and will include temperature (may be oral or axillary temperature), BP, and HR. 
9.4.7
Pregnancy Test
A serum pregnancy test will be performed for women of childbearing potential at screening and 
again at Cycle 0 Day 1 if the screening test was performed more than 4 days before 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
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
Those who have not had natural menopause for 12 consecutive months or longer (eg, 
follicle-stimulating hormone >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 Cycle 0, Day 1 serum pregnancy results will not be available before dosing, a 
urine pregnancy test may be performed. 
Pregnancy tests may also be repeated during the study at the discretion of the investigator, if 
requested by an IEC/IRB, or if required by local regulations.
9.4.8
Concomitant Medications and Procedures
Medications used by the patient and therapeutic procedures completed by the patient will be 
recorded in the eCRF from the ICF signature through the EOT visit or before initiation of new 
anti-cancer therapy, whichever occurs first. See Sections 8.4 and 8.5 for a list of medications and 
therapies that are prohibited or allowed during the study.
9.4.9
AEs
Monitoring of AEs, serious and nonserious, will be conducted throughout the study as specified in 
the SOE (Appendix A). Refer to Section 10.0 for details regarding definitions, documentation, and 
reporting of pretreatment events (PTEs), AEs, and SAEs.
9.4.10
Enrollment
Enrollment is defined as the randomization date. Procedures for completing the enrollment 
information are described in the study manual. Information regarding patients who do not meet the 
study entry criteria will be collected in a separate log. 
9.4.11
ECG
9.4.11.1 Safety ECGs
Standard 12-lead ECGs will be performed at the time points specified in the SOE (Appendix A). 
All machine-generated tracings should be acquired in the supine position after patients have been 
resting for 5 minutes. A qualified person will interpret the ECGs locally. Additional ECGs may be 
obtained as clinically indicated at the discretion of the investigator (see Section 8.7.5). 
9.4.11.2 Triplicate ECGs
Time-matched triplicate ECGs and PK samples will be collected during Cycle 0 on Days 1 and 3 
of part 1 (Appendix A, Table 4). Triplicate ECGs will be recorded electronically and transmitted to 
a central vendor for storage.
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Before each nominal triplicate ECG sampling time point, patients must maintain a supine position 
for 15 minutes. Each ECG recording of the triplicate ECGs should occur within 3 minutes of the 
previous recording and over a 10-minute window.
For these matched PK/triplicate ECG collections, the PK blood sample should be collected only 
after completion of the triplicate ECG collection. It is recommended that patients refrain from 
eating or limit themselves to bland food for 2 hours before and until completion of the 4-hour 
triplicate ECG measurements. The PK blood draws will occur immediately following the 
completion of the triplicate ECG extractions on Days 1 and 3 of Cycle 0. 
9.4.12
ECHO or MUGA Scan
A MUGA scan or ECHO will be administered at the time points specified in the SOE 
(Appendix A).
9.4.13
ECOG Performance Status
ECOG performance status (Appendix D) will be assessed at the times specified in the SOE.
9.4.14
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 9.a will be obtained as specified in the SOE.
Table 9.a
Clinical Chemistry and Hematology Tests
Hematology
Serum Chemistry
Hemoglobin
Leukocytes with differential
Neutrophils
Platelets
Alanine aminotransferase
Albumin
Alkaline phosphatase 
Aspartate aminotransferase
Bicarbonate
Bilirubin (total)
Blood urea nitrogen
Calcium
Chloride 
Creatinine
Glucose
Lactate dehydrogenase 
Magnesium
Phosphate
Potassium
Sodium
Creatinine clearance will be estimated using the Cockroft-Gault formula as follows:
	
 
	
 
		
 
=  [(140 −
) ∗	() ] / [72 ∗
! 
	
(/")] 
For female patients, the result of the formula above should be multiplied by 0.85. 
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9.4.15
Disease Assessment
Patients will undergo CT scan, with contrast as appropriate (areas of known or clinically suspected 
disease), or MRI scan to monitor and assess PD, using RECIST, version 1.1 [19] as outlined in the 
SOE (Appendix A). Brain CT scan evaluation at screening is not required in the absence of 
symptoms.
Primary determination of disease status will be based on local investigator assessment. The 
collection and central storage of scans are planned in case more detailed analysis of imaging data, 
as determined by the sponsor, is needed. 
Tests will be repeated at the frequency specified in the SOE. 
9.4.16
Biomarker, Pharmacodynamic, and PK Samples
9.4.16.1 Primary Specimen Collection for PK 
Blood samples will be collected at the time points detailed in the SOE (Appendix A) for plasma 
concentration measurements of TAK-931 
. The primary specimen 
collection is presented in Table 9.b.
Details on sample handling, storage, shipment, and analysis are provided in the laboratory manual.
Table 9.b
Primary Specimen Collection
Specimen Name in Schedule of Events
Primary 
Specimen
Intended Use
Sample Collection
Plasma sample for TAK-931 PK
Plasma
PK measurements
Mandatory
Abbreviations: 
 circulating tumor DNA; PK, pharmacokinetic. 
9.4.16.2
9.4.17
PK Measurements
Serial blood specimens for PK analysis of TAK-931 will be collected at the time points specified 
in the SOE (Appendix A, Table 4). The dates and exact times of administration of TAK-931 before 
collection of the blood sample for PK analysis and the dates and exact times of the postdose PK 
sample collection will be recorded in the eCRF.
Plasma samples may be stored for possible future analysis of TAK-931 metabolites and to test for 
inversion of the single chiral center within TAK-931. 
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PK parameters to be assessed are described in Section 5.2.2 and samples will be collected 
according to the SOE (Appendix A, Table 4). 
If the timing of PK and ECGs coincide, the ECGs should be acquired first followed by the PK 
sample collection. 
9.4.18
 
9.5
Completion of Study Treatment (for Individual Patients)
Patients will be considered to have completed study treatment if they discontinue study drug for 
any of the reasons outlined in Section 9.7.
9.6
Completion of Study (for Individual Patients)
Patients will be considered to have completed the study if they are discontinued from study drug 
and 1 or more of the following situations occurs:
!
Death.
!
PD.
!
Start of new systemic treatment.
!
Consent withdrawal.
!
Study terminated by the sponsor.
!
Lost to follow-up
!
Transfer of patient to a long-term safety study, named patient program, compassionate use 
program, or similar.
Once a patient completes the study, all study procedures outlined for the EOT visit will be 
completed as specified in the SOE (Appendix A).
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 after the EOT visit 30 days after 
last dose is completed.
9.7
Discontinuation of Treatment With Study Drug and Patient Replacement
Patients will be informed that they have the right to discontinue study treatment at any time for any 
reason, without prejudice to their medical care. 
Treatment with study drug may be discontinued for any of the following reasons: 
!
AE.
!
Major protocol deviation.
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
PD.

Symptomatic deterioration. 

Withdrawal by patient.

Lost to follow-up.

Initiation of another systemic anticancer treatment. 

Treatment completion: the patient completes 1 year of treatment and continuation is not 
approved.

Study terminated by sponsor.

Death. 
Once study drug has been discontinued, all study procedures outlined for the EOT and PFS visits 
will be completed as specified in the SOE (Appendix A). The primary reason for study drug 
discontinuation will be recorded on the eCRF.
Note that some patients may discontinue study drug for reasons other than PD before completing 
the full treatment course; these patients will remain in the study for posttreatment assessments as 
outlined in the SOE until PD occurs. See Section 13.1.1 for patient replacement in the 
PK-evaluable population. 
9.8
Withdrawal of Patients From Study
A patient may be withdrawn from the study for any of the following reasons:

Lost to follow-up.

Withdrawal by patient.

Death. 

Study terminated by sponsor.

Transfer of patient to a long-term safety study, single-patient investigational new drug 
application, or similar program.

Pregnancy.
The consequence of study withdrawal is that no new information will be collected from the 
withdrawn patient and added to the existing data or any database.
9.9
Study Compliance
Study drug will be administered or dispensed only to eligible patients under the supervision of the 
investigator or identified subinvestigator(s). The appropriate study personnel will maintain records 
of study drug receipt and dispensing.
Patients are responsible for taking and storing TAK-931 at home as instructed by site personnel 
and will receive a sufficient quantity of study drug for 1 cycle of treatment. Patients will be given a 
diary to record study drug dosing and associated events (time of intake, doses missed, vomiting, 
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symptoms, etc). The study center staff will check the patient’s drug diary versus the patient’s 
supply of TAK-931 to assess compliance.
Tests and procedures should be performed on schedule; however, unless otherwise specified, 
occasional changes are allowable within a 2-day window for holidays, vacations, and other 
administrative reasons. 
9.10
Posttreatment Follow-up Assessments (PFS)
The EOT visit for all patients will take place 30 to 40 days after the last dose. 
Patients who stop treatment for any reason other than progressive disease (or clinical deterioration) 
will continue to have PFS follow-up visits. PFS follow-up visits should be conducted at the site 
every 12 weeks from the EOT visit until the occurrence of death, PD, start of a new systemic 
anticancer treatment, consent withdraw, or loss to follow up, whichever occurs first.
The end-of-study visit is to be completed when the patient discontinues from the follow-up period. 
See the SOE for appropriate assessments during follow-up.
NOTE: Related SAEs must be reported to the Takeda Global Pharmacovigilance department or 
designee. This includes deaths that the investigator considers related to study drug that occur 
during posttreatment follow-up. Refer to Section 10.0 for details regarding definitions, 
documentation, and reporting of SAEs. 
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10.0
ADVERSE EVENTS
10.1
Definitions
10.1.1 PTE Definition
A PTE is any untoward medical occurrence in a patient or subject who has signed informed 
consent to participate in a study but before administration of any study medication; it does not 
necessarily have to have a causal relationship with study participation.
10.1.2 AE Definition
AE means any untoward medical occurrence in a patient or subject administered a pharmaceutical 
product; the untoward medical occurrence does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product whether or not it is related to the medicinal product. This includes any 
newly occurring event, or a previous condition that has increased in severity or frequency since the 
administration of study drug.
An abnormal laboratory value will not be assessed as an AE unless that value leads to 
discontinuation or delay in treatment, dose modification, therapeutic intervention, or is considered 
by the investigator to be a clinically significant change from baseline.
10.1.3 SAE Definition
SAE means any untoward medical occurrence that at any dose:

Results in death.

Is life-threatening (refers to an AE in which the patient was at risk of death at the time of the 
event. It does not refer to an event which hypothetically might have caused death if it were 
more severe).

Requires inpatient hospitalization or prolongation of an existing hospitalization (see 
clarification in the paragraph in Section 10.2 on planned hospitalizations).

Results in persistent or significant disability or incapacity. (Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions).

Is a congenital anomaly/birth defect.

Is a medically important event. This refers to an AE that may not result in death, be 
immediately life threatening, or require hospitalization, but may be considered serious when, 
based on appropriate medical judgment, may jeopardize the patient, require medical or 
surgical intervention to prevent 1 of the outcomes listed above, or involves suspected 
transmission via a medicinal product of an infectious agent. Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at home, 
blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
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development of drug dependency or drug abuse; any organism, virus, or infectious particle 
(eg, prion protein transmitting transmissible spongiform encephalopathy), pathogenic or 
nonpathogenic, is considered an infectious agent.
In this study, intensity for each AE, including any lab abnormality, will be determined using the 
NCI CTCAE, version 5.0, effective date 27 November 2017 [18]. Clarification should be made 
between an SAE and an AE that is considered severe in intensity (Grade 3 or 4), because the terms 
serious and severe are not synonymous. The general term severe is often used to describe the 
intensity (severity) of a specific event; the event itself, however, may be of relatively minor 
medical significance (such as a Grade 3 headache). This is not the same as serious, which is based 
on patient/event outcome or action criteria described above, and is usually associated with events 
that pose a threat to a patient’s life or ability to function. A severe AE (Grade 3 or 4) does not 
necessarily need to be considered serious. For example, a WBC count of 1000/mm3 to less than 
2000 is considered Grade 3 (severe) but may not be considered serious. Seriousness (not intensity) 
serves as a guide for defining regulatory reporting obligations.
10.2
Procedures for Recording and Reporting AEs and SAEs
All AEs spontaneously reported by the patient or in response to an open question from study 
personnel or revealed by observation, physical examination, or other diagnostic procedures will be 
recorded on the appropriate page of the eCRF (see Section 10.3 for the period of observation). Any 
clinically relevant deterioration in laboratory assessments or other clinical finding is considered an 
AE. When possible, signs and symptoms indicating a common underlying pathology should be 
noted as a single comprehensive event.
Regardless of causality, SAEs must be reported (see Section 10.3 for the period of observation) by 
the investigator to the Takeda Global Pharmacovigilance department or designee within 24 hours 
of becoming aware of the event. This will be done by transmitting an electronic data capture 
(EDC) SAE report. If transmission of an EDC SAE report is not feasible, then a facsimile of the 
completed Takeda paper-based SAE form will be sent. A sample of the paper-based SAE form and 
processing directions are in the study manual. Information in the SAE report or form must be 
consistent with the data provided on the eCRF.
If information not available at the time of the first report becomes available at a later date, then the 
investigator will transmit a follow-up EDC SAE report (or a paper-based SAE form if an EDC 
SAE report is not feasible) or provide other documentation immediately within 24 hours of receipt. 
Copies of any relevant data from the hospital notes (eg, ECGs, laboratory tests, discharge 
summary, postmortem results) should be sent to the addressee, if requested.
All SAEs should be followed up until resolution or permanent outcome of the event. The timelines 
and procedure for follow-up reports are the same as those for the initial report.
Planned hospital admissions or surgical procedures for an illness or disease that existed before the 
patient was enrolled in the study are not to be considered AEs unless the condition deteriorated in 
an unexpected manner during the study; eg, surgery was performed earlier or later than planned.
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For both serious and nonserious AEs, the investigator must determine both the severity (toxicity 
grade) of the event and the relationship of the event to study drug administration. 
Severity (toxicity grade) for each AE, including any laboratory abnormality, will be determined 
using the NCI CTCAE, version 5.0, effective 27 November 2017 [18]. The criteria are provided in 
the study manual.
Relationship of the event to study drug administration (ie, its causality) will be determined by the 
investigator responding yes (related) or no (unrelated) to this question: Is there a reasonable 
possibility that the AE is associated with the study drug?
10.3
Monitoring of AEs and Period of Observation
AEs, both nonserious and serious, will be monitored throughout the study as follows: 

AEs
–
AEs will be reported from the signing of informed consent through 30 days after 
administration of the last dose of study drug and recorded in the eCRFs. 

SAEs
–
Serious PTEs will be reported to the Takeda Global Pharmacovigilance department or 
designee from the time of the signing of the ICF up to first dose of study drug, and will also 
be recorded in the eCRF. 
–
Related and unrelated treatment-emergent SAEs will be reported to the Takeda Global 
Pharmacovigilance department or designee from the first dose of study drug through 
30 days after administration of the last dose of study drug and recorded in the eCRF. After 
this period, only related SAEs must be reported to the Takeda Global Pharmacovigilance 
department or designee. SAEs should be monitored until they are resolved or are clearly 
determined to be due to a patient’s stable or chronic condition or intercurrent illness(es).
10.4
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events
If a woman becomes pregnant or suspects that she is pregnant while participating in this study, she 
must inform the investigator immediately and permanently discontinue study drug. The sponsor 
must also be contacted immediately by faxing a completed Pregnancy Form to the Takeda Global 
Pharmacovigilance department or designee (see Section 10.2). The pregnancy must be followed 
for the final pregnancy outcome.
If a female partner of a male patient becomes pregnant during the male patient’s participation in 
this study, the sponsor must also be contacted immediately by faxing a completed pregnancy form 
to the Takeda Global Pharmacovigilance department or designee (see Section 10.2). Every effort 
should be made to follow the pregnancy for the final pregnancy outcome.
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10.5
Procedures for Reporting Product Complaints or Medication Errors (Including 
Overdose)
A product complaint is a verbal, written, or electronic expression that implies dissatisfaction 
regarding the identity, strength, purity, quality, or stability of a drug product. Individuals who 
identify a potential product complaint situation should immediately report this via the phone 
numbers or e-mail addresses provided below.
A medication error is a preventable event that involves an identifiable patient and that leads to 
inappropriate medication use, which may result in patient harm. Whereas overdoses and 
underdoses constitute medication errors, doses missed inadvertently by a patient do not. 
Individuals who identify a potential medication error (including overdose) situation should 
immediately report this via the phone numbers or e-mail addresses provided below.
Call center
Phone number
E-mail
Fax
Product complaints in and of themselves are not AEs. If a product complaint results in an SAE, an 
SAE form should be completed and sent to Cognizant (refer to Section 10.2). 
10.6
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, including the European 
Medicines Agency, investigators and IRBs or IECs, as applicable, in accordance with national 
regulations in the countries where the study is conducted. Relative to the first awareness of the 
event by/or further provision to the sponsor or sponsor’s designee, SUSARs will be submitted to 
the regulatory authorities as an expedited report within 7 days for fatal and life-threatening events 
and 15 days for other serious events, unless otherwise required by national regulations. The 
sponsor will also prepare an expedited report for other safety issues where these might materially 
alter the current benefit-risk assessment of an investigational medicinal product or that would be 
sufficient to consider changes in the investigational medicinal product’s administration or in the 
overall conduct of the study. The investigational site also will forward a copy of all expedited 
reports to his or her IRB or IEC in accordance with national regulations. 
PPD
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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11.0
STUDY-SPECIFIC COMMITTEES
No steering committee, data safety monitoring committee, or clinical endpoint committee will be 
used in this study. 
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12.0
DATA HANDLING AND RECORDKEEPING 
The full details of procedures for data handling will be documented in the data management plan. 
If selected for coding, AEs, PTEs, medical history, and concurrent conditions will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA). Drugs will be coded using the 
World Health Organization (WHO) Drug Dictionary.
12.1
eCRFs 
Completed eCRFs are required for each subject who signs an ICF.
The sponsor or its designee will supply investigative sites with access to eCRFs and will make 
arrangements to train appropriate site staff in the use of the eCRF. These forms are used to transmit 
the information collected in the performance of this study to the sponsor, CRO partners, and 
regulatory authorities. Investigative sites must complete eCRFs in English.
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site.
Any change of, modification of, or addition to the data on the eCRFs should be made by the 
investigator or appropriate site personnel. Corrections to eCRFs are recorded in an audit trail that 
captures the old information, the new information, identification of the person making the 
correction, the date the correction was made, and the reason for change.
The principal investigator must review the eCRFs for completeness and accuracy and must sign 
and date the appropriate eCRFs as indicated. Furthermore, the principal investigator must retain 
full responsibility for the accuracy and authenticity of all data entered on the eCRFs.
eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The sponsor or its designee will be permitted to review the subject’s medical 
and hospital records pertinent to the study to ensure accuracy of the eCRFs. The completed eCRFs 
are the sole property of the sponsor and should not be made available in any form to third parties, 
except for authorized representatives of appropriate governmental health or regulatory authorities, 
without written permission of the sponsor.
12.2
Record Retention
The investigator agrees to keep the records stipulated in Section 12.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating subjects, medical records, temporary media such as thermal sensitive paper, source 
worksheets, all original signed and dated ICFs, subject authorization forms regarding the use of 
personal health information (if separate from the ICFs), electronic copy of eCRFs, including the 
audit trail, and detailed records of drug disposition to enable evaluations or audits from regulatory 
authorities, the sponsor or its designees. Any source documentation printed on degradable 
thermal-sensitive paper should be photocopied by the site and filed with the original in the 
subject’s chart to ensure long-term legibility. Furthermore, ICH E6 Section 4.9.5 requires the 
investigator to retain essential documents specified in ICH E6 (Section 8) until at least 2 years 
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after the last approval of a marketing application for a specified drug indication being investigated 
or, if an application is not approved, until at least 2 years after the investigation is discontinued and 
regulatory authorities are notified. In addition, ICH E6 Section 4.9.5 states that the study records 
should be retained until an amount of time specified by applicable regulatory requirements or for a 
time specified in the clinical study site agreement between the investigator and sponsor.
Refer to the clinical study site agreement for the sponsor’s requirements on record retention. The 
investigator should contact and receive written approval from the sponsor before disposing of any 
such documents.
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13.0
STATISTICAL METHODS
13.1
Statistical and Analytical Plans
A statistical analysis plan will be prepared and finalized before database lock. This document will 
provide further details regarding the definition of analysis variables and analysis methodology to 
address all study objectives. 
13.1.1 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.

PK population: The PK population is defined as all patients for whom there are sufficient 
dosing and TAK-931 concentration-time data to reliably estimate the PK parameters. This 
population will be used for analyses of PK parameters. Patients who have any of the 
occurrences listed in Section 6.2 during Cycle 0 will not be considered PK-evaluable and may 
be replaced.

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 have at least
1 postbaseline response assessment.
13.1.2 Procedures for Handling Missing, Unused, and Spurious Data
All available safety, tolerability, antitumor activity, 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. 
13.1.3 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.
13.1.4 Antitumor Activity Analysis
Secondary antitumor activity parameters are ORR, PFS, DCR, and DOR. DCR will be assessed 
per RECIST version 1.1 (CR + PR + SD; SD must be ≥1 post baseline CT scan evaluation from 
treatment initiation to qualify for DCR). 
The DCR and ORR will be estimated with 2-sided 95% exact binomial CIs using the 
response-evaluable population (Section 13.1.1). 
PFS is defined as the time from the date of randomization to the date of first documentation of PD 
or death due to any cause, whichever occurs first. The Kaplan-Meier survival curves, 25th, 50th 
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(median), and 75th percentiles (if estimable), along with their 2-sided 95% CIs and percentage of 
censored observations will be provided. PFS will be analyzed using the safety population. 
DOR is defined as the time from the date of first documentation of a response to the date of first 
documentation of PD. Patients without documentation of PD at the time of analysis will be 
censored at the date of their last response assessment that is SD or better. DOR will be analyzed 
using the Kaplan-Meier method. DOR will be analyzed using the responders in the 
response-evaluable population.
13.1.5 PK Analysis
13.1.5.1 Part 1
For the relative bioavailability assessment, the ratio (tablet to PIC) of geometric mean AUClast, 
AUC∞and Cmax and associated 2-sided 90% CIs will be calculated, based on the within-patient 
variance estimated by analysis of variance. The PK population will be used for the analysis.
13.1.5.2 Part 2
For the food effect assessment, the ratio (fed to fasted) of geometric mean AUClast, AUC∞and Cmax
and associated 2-sided 90% CIs will be calculated, based on the within-patient variance estimated 
by analysis of variance. For evaluating the effect of esomeprazole on TAK-931 PK, the ratio 
(presence of esomeprazole to absence of esomeprazole) of geometric mean AUClast, AUC∞, and 
Cmax and associated 2-sided 90% CIs will be calculated based on the within-patient variance 
estimated by analysis of variance. The PK population will be used for these analyses.
TAK-931 PK parameters will be estimated using noncompartmental methods with WinNonlin 
Phoenix version 6.2 or higher (Pharsight Corp, Mountain View, California). Descriptive statistics 
for TAK-931 plasma concentrations and the following PK parameters will be tabulated by 
formulation (part 1), food intake state (fed or fasted, part 2) and the use of esomeprazole (in the 
presence or absence of esomeprazole, part 2):

Cmax.

CL/F.

tmax.

AUClast. 

AUC∞.

t1/2z.
Individual TAK-931 concentration-time data and individual PK parameters will be presented in 
listings and tabulated using summary statistics. Individual and mean plasma concentration-time 
profiles will be plotted. 
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13.1.6
13.1.7 Safety Analysis
Safety will be evaluated by the incidence of TEAEs, defined as any AEs that occur after signing 
the ICF through 30 days after the last dose of study drug, severity, and by changes from baseline in 
the patient’s vital signs and clinical laboratory results using the safety population. Exposure to 
study drug will be summarized, and reasons for discontinuation and modification will be tabulated. 
Safety will be summarized by cohort. 
TEAEs will be tabulated according to the MedDRA by System Organ Class, High Level Term, and 
Preferred Term and will include the following categories:
!
TEAEs.
!
Drug-related TEAEs.
!
Grade ≥3 TEAEs.
!
Grade ≥3 drug-related TEAEs.
!
Most common TEAEs (≥10% of all patients).
!
SAEs.
Listings of TEAEs resulting in study drug discontinuation and dose modification will be provided.
Descriptive statistics for the actual values of clinical laboratory parameters (and/or change from 
baseline in clinical laboratory parameters) will be presented for all scheduled measurements over 
time. Mean laboratory values over time will be plotted for key laboratory parameters.
Descriptive statistics for the actual values (and/or the change from baseline) of vital signs, weight, 
ECHO, or MUGA scans over time will be tabulated by scheduled time point.
Shift tables for laboratory parameters and other safety parameters deemed appropriate will be 
generated to show changes in NCI CTCAE grade from baseline to the worst postbaseline value. 
Graphical displays of key safety parameters, such as scatter plots of baseline versus worst 
postbaseline values, may be used to understand the TAK-931 safety profile.
Concomitant medications collected from ICF signature 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.
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ECG Analysis
ECG intervals (QT, QTc, 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. 
Patients will undergo ECGs as specified in the Schedule of Events (Appendix A, Tables 1, 2, and 
4). 
13.2
Determination of Sample Size
The sample size calculation is based on the expected 2-sided 90% CI for the difference in the 
paired, log transformed AUC (or Cmax) means of TAK-931 administered as tablet and PIC 
formulations. On the basis of the preliminary data obtained from Study TAK-931-1002, the 
within-subject %CV was estimated to be 35.0% for AUC and 36.9% for Cmax. Assuming the 
true/assumed AUC (or Cmax) ratio is 1.0, with a sample size of 14 evaluable patients, the 90% CI of 
the ratio of geometric means is expected to be (0.795-1.257) for AUC and (0.786-1.272) for Cmax
on the basis of the previously discussed variance assumptions. If the ratio is X, the 90% CI of the 
ratio of geometric means is expected to be within (0.795X-1.257X) for AUC and (0.786X-1.272X) 
for Cmax. Patients who are not PK-evaluable may be replaced to ensure the availability of 14 to 16 
PK-evaluable patients for the final analysis of part 1 and part 2. 
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14.0
QUALITY CONTROL AND QUALITY ASSURANCE
14.1
Study-Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and institution guarantee access to source documents by the sponsor or its 
designee (CRO) and by the IRB or IEC.
All aspects of the study and its documentation will be subject to review by the sponsor or designee 
(as long as blinding is not jeopardized), including but not limited to the Investigator’s Binder, 
study medication, subject medical records, informed consent documentation, documentation of 
subject authorization to use personal health information (if separate from the ICFs), and review of 
eCRFs and associated source documents. It is important that the investigator and other study 
personnel are available during the monitoring visits and that sufficient time is devoted to the 
process.
14.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will require 
deviation from protocol-specified procedures, the investigator should consult with the sponsor or 
designee (and IRB or IEC, as required) to determine the appropriate course of action. There will be 
no exemptions (a prospectively approved deviation) from the inclusion or exclusion criteria.
The site should document all protocol deviations in the subject’s source documents. If a significant 
deviation occurs, 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.
14.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, including 
those of foreign governments (eg, the United States [US] Food and Drug Administration [FDA], 
the United Kingdom Medicines and Healthcare products Regulatory Agency [MHRA], and the 
Pharmaceuticals and Medical Devices Agency of Japan [PMDA]). If the study site is contacted for 
an inspection by a regulatory body, the sponsor should be notified immediately. The investigator 
and institution guarantee access for quality assurance auditors to all study documents as described 
in Section 14.1.
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15.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (ie, 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” listed in Appendix B. The 
principles of Helsinki are addressed through the protocol and through appendices containing 
requirements for informed consent and investigator responsibilities.
15.1
IRB and/or IEC Approval
IRBs and IECs must be constituted according to the applicable local requirements of each 
participating region. The sponsor or designee will require documentation noting all names and 
titles of members who make up the respective IRB or IEC. If any member of the IRB or IEC has 
direct participation in this study, written notification regarding his or her abstinence from voting 
must also be obtained. Those US 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 IB, a copy of the ICF, and, if 
applicable, subject recruitment materials and/or advertisements and other documents required by 
all applicable laws and regulations, must be submitted to a central or local IRB or IEC for 
approval. The IRB’s or IEC’s written approval of the protocol and subject informed consent must 
be obtained and submitted to the sponsor or designee before commencement of the study (ie, 
before shipment of the sponsor-supplied drug or study specific screening activity). The IRB or IEC 
approval must refer to the study by exact protocol title, number, and version date; identify versions 
of other documents (eg, ICF) reviewed; and state the approval date. The sponsor will ship drug the
sponsor has confirmed the adequacy of site regulatory documentation and, when applicable, the 
sponsor has received permission from competent authority to begin the study. 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 ICF, recruitment 
materials intended for viewing by subjects, local safety reporting requirements, reports and 
updates regarding the ongoing review of the study at intervals specified by the respective IRB or 
IEC, and submission of the investigator’s final status report to IRB or IEC. All IRB and IEC 
approvals and relevant documentation for these items must be provided to the sponsor or its 
designee.
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and sponsor.
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15.2
Subject Information, Informed Consent, and Subject Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The ICF, subject authorization form (if applicable), and subject 
information sheet (if applicable) describe the planned and permitted uses, transfers, and 
disclosures of the subject’s personal and personal health information for purposes of conducting 
the study. The ICF and the subject information sheet (if applicable) further explain the nature of 
the study, its objectives, and potential risks and benefits, as well as the date informed consent is 
given. The ICF will detail the requirements of the participant and the fact that he or she is free to 
withdraw at any time without giving a reason and without prejudice to his or her further medical 
care.
The investigator is responsible for the preparation, content, and IRB or IEC approval of the ICF 
and if applicable, the subject authorization form. The ICF, subject authorization form (if 
applicable), and subject information sheet (if applicable) must be approved by both the IRB or IEC 
and the sponsor before use.
The ICF, subject authorization form (if applicable), and subject information sheet (if applicable) 
must be written in a language fully comprehensible to the prospective subject. It is the 
responsibility of the investigator to explain the detailed elements of the ICF, subject authorization 
form (if applicable), and subject information sheet (if applicable) to the subject. Information 
should be given in both oral and written form whenever possible and in the manner deemed 
appropriate by the IRB or IEC. In the event the subject is not capable of rendering adequate written 
informed consent, then the subject’s legally acceptable representative may provide such consent 
for the subject in accordance with applicable laws and regulations.
The subject, or the subject’s legally acceptable representative, must be given ample opportunity to: 
(1) inquire about details of the study and (2) decide whether or not to participate in the study. If the 
subject, or the subject’s legally acceptable representative, determines he or she will participate in 
the study, then the ICF and subject authorization form (if applicable) must be signed and dated by 
the subject, or the subject’s legally acceptable representative, at the time of consent and before the 
subject enters into the study. The subject or the subject’s legally acceptable representative should 
be instructed to sign using their legal names, not nicknames, using blue or black ballpoint ink. The 
investigator must also sign and date the ICF and subject authorization (if applicable) at the time of 
consent and before subject entering into the study; however, the sponsor may allow a designee of 
the investigator to sign to the extent permitted by applicable law.
Once signed, the original 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.
All revised ICFs must be reviewed and signed by relevant subjects or the relevant subject’s legally 
acceptable representative in the same manner as the original informed consent. The date the 
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revised consent was obtained should be recorded in the subject’s medical record, and the subject 
should receive a copy of the revised ICF.
15.3
Subject Confidentiality
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or date 
of birth, and subject initials may be used to verify the subject and accuracy of the subject’s unique 
identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the sponsor 
requires the investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (eg, US FDA, MHRA, and PMDA), the sponsor’s designated auditors, and 
the appropriate IRBs and IECs to review the subject’s original medical records (source data or 
documents), including, but not limited to, laboratory test result reports, ECG reports, admission 
and discharge summaries for hospital admissions occurring during a subject’s study participation, 
and autopsy reports. Access to a subject’s original medical records requires the specific 
authorization of the subject as part of the informed consent process (see Section 15.2).
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s CRF).
15.4
Publication, Disclosure, and Clinical Study Registration Policy
15.4.1 Publication 
The investigator is obliged to provide the sponsor with complete test results and all data derived by 
the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the sponsor.
The sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 
this section and the clinical study site agreement. If there is any discrepancy between the protocol 
and the clinical study site agreement, the clinical study site agreement will prevail.
15.4.2 Clinical Study Registration
To ensure that information on clinical studies reaches the public in a timely manner and to comply 
with applicable laws, regulations and guidance, Takeda will, at a minimum register interventional 
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clinical studies it sponsors anywhere in the world on ClinicalTrials.gov or other publicly 
accessible websites on or before start of study, as defined in Takeda Policy/Standard. Takeda 
contact information, along with investigator’s city, state (for Americas investigators), country, and 
recruiting status will be registered and available for public viewing. 
As needed Takeda and investigator/site contact information may be made public to support 
participant access to studies via registries. In certain situations/registries, Takeda may assist 
participants or potential participants to find a clinical study by helping them locate study sites 
closest to their homes by providing the investigator name, address, and phone number via 
email/phone or other methods callers requesting study information. Once subjects receive 
investigator contact information, they may call the site requesting enrollment into the study. The 
investigative sites are encouraged to handle the study inquiries according to their established 
subject screening process. If the caller asks additional questions beyond the topic of study 
enrollment, they should be referred to the sponsor.
Any investigator who objects to Takeda providing this information to callers must provide Takeda 
with a written notice requesting that their information not be listed on the registry site. 
15.4.3 Clinical Study Results Disclosure
Takeda will post the results of clinical studies on ClinicalTrials.gov or other publicly accessible 
websites (including the Takeda corporate site) and registries, as required by Takeda 
Policy/Standard, applicable laws and/or regulations. 
15.5
Insurance and Compensation for Injury
Each subject in the study must be insured in accordance with the regulations applicable to the site 
where the subject is participating. If a local underwriter is required, then the sponsor or sponsor’s 
designee will obtain clinical study insurance against the risk of injury to clinical study subjects. 
Refer to the clinical study site agreement regarding the sponsor’s policy on subject compensation 
and treatment for injury. If the investigator has questions regarding this policy, he or she should 
contact the sponsor or sponsor’s designee.
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16.0
REFERENCES
1.
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.
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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.
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Bousset K, Diffley JF. The Cdc7 protein kinase is required for origin firing during S phase. 
Genes Dev 1998;12(4):480-90.
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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.
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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.
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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.
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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 
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Hou Y, Wang HQ, Ba Y. Effects of CDC7 gene silencing and Rituximab on apoptosis in 
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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.
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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.
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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.
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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.
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Kastan MB, Bartek J. Cell-cycle checkpoints and cancer. Nature 2004;432(7015):316-23.
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Sawa M, Masai H. Drug design with Cdc7 kinase: a potential novel cancer therapy target. 
Drug Design, Development and Therapy 2008;2:255–64.
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Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0. U.S. 
Department of Health and Human Services National Cancer Institute. 27 Nov 2017.
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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.
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Smith TJ, Bohlke K, Lyman GH, Carson KR, Crawford J, Cross SJ, et al. 
Recommendations for the Use of WBC Growth Factors: American Society of Clinical 
Oncology Clinical Practice Guideline Update. Journal of Clinical Oncology 
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21.
Rizzo JD, Brouwers M, Hurley P, Seidenfeld J, Arcasoy MO, Spivak JL, et al. American 
Society of Clinical Oncology/American Society of Hematology clinical practice guideline 
update on the use of epoetin and darbepoetin in adult patients with cancer. Journal of 
Clinical Oncology 2010;28(33):4996-5010.
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NEXIUM® (esomeprazole magnesium) Delayed-Release Capsules [package insert]. 
Wilmington, DE: AstraZeneca Pharmaceuticals LP, 2012.
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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 
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Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. 
Nephron 1976;16(1):31-41.
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CONFIDENTIAL
Appendix A
Schedule of Events
Table 1: Schedule of Events for Treatment Part 1, Cycle 0 (16 Days)
Screening a
Day 1
Day 3
Day 5
Day 6
Day 7
Day 8
Day 9
Day 10
Day 11
Day 12
Day 16
Informed consent a
X
Inclusion/exclusion criteria
X
Demographics
X
Medical history
X
Symptom-directed physical 
examination b
X
X
X
Height
X
Weight
X
Vital signs c
X
  X c
X
ECOG performance status
X
X
Safety ECG d
X
12-Lead ECG (triplicate)
X e
X e
ECHO/MUGA scan (LVEF) f
X
Disease assessment g
X
HBV/HCV testing
X
Monitoring of concomitant 
medications and procedures
Recorded from the signing of ICF through 30 days after the last dose of study drug (EOT visit)
Adverse event reporting
Recorded from the signing of ICF through 30 days after the last dose of study drug (EOT visit)
SAEs h will be reported from signing of the ICF through 30 days after the last 
dose of study drug (EOT visit). Only drug-related SAEs should be reported >30 days from last dose. 
TAK-931 administration i
X
X
Day 5 through Day 16
Samples/Laboratory Assessments
Pregnancy test j
X
X
Hematology/chemistry k
X
X
X n
Plasma sample for TAK-931 PK l
Refer to Table 4, below. 
Footnotes are on last page of schedule of assessments tables.
CCI
Property of Takeda: Fo
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o t
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TAK-931
Study No. TAK-931-1003
Page 79 of 87
Protocol 
21 June 2018
CONFIDENTIAL
Table 2: Schedule of Events for Treatment Part 2, Cycle 0 (22 Days)
Scr a
D1
D3
D5
D6
D7
D8
D9
D10 D11 D12 D13 D14 D15 D16
D17
D18 D19
D20
D21
D22
Informed consent
X
Inclusion/exclusion criteria
X
Demographics
X
Medical history
X
Symptom-directed physical 
examination b
X
X
X
Height
X
Weight
X
Vital signs d
X
  X d
X
X
ECOG performance status
X
X
Safety ECG d
X
ECHO/MUGA scan (LVEF) f
X
Disease assessment g
X
HBV/HCV testing 
X
Monitoring of concomitant medications 
and procedures
Recorded from the signing of ICF through 30 days after the last dose of study drug (EOT visit)
Adverse event reporting
Recorded from the signing of ICF through 30 days after the last dose of study drug (EOT visit)
SAEs h will be reported from signing of the ICF through 30 days after the last 
dose of study drug (EOT visit). Only drug-related SAEs should be reported >30 days from last dose.
TAK-931 administration i
X
X
X
X
X
X
X
X
X
X
X
X
Esomeprazole administration
X
X
X
X
X
X
X
X
X
Samples/Laboratory Assessments
Pregnancy test j
X
X
Hematology/ chemistry k
X
X
  X o
  X n
Plasma sample for TAK-931 PK l
Refer to Table 4, below.
Footnotes are on last page of schedule of assessments tables.
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TAK-931
Study No. TAK-931-1003
Page 80 of 87
Protocol 
21 June 2018
CONFIDENTIAL
Table 3: Schedule of Events for Treatment Cycle 1 (21 Days) Through End of Treatment (Parts 1 and 2)
Day 1
Day 14
Day 15
EOT
Follow-up PFS
Symptom-directed physical examination b
X
X
Vital signs c
X
X
ECOG performance status
X
X
SafetyECG d
X
ECHO/MUGA scan (LVEF) f
X
Disease assessment f
Every third cycle starting at the end of Cycle 3
X
X (Q12wk)
Monitoring of concomitant medications and procedures
Recorded from the signing of ICF 
through 30 days after the last dose of 
study drug (EOT visit)
AE reporting
Recorded from the signing of ICF 
through 30 days after the last dose of 
study drug (EOT visit)
SAEs m will be reported from signing of 
the ICF through 30 days after the last 
dose of study drug (EOT visit). Only 
drug-related SAEs should be reported 
>30 days from last dose.
TAK-931 administration i
Days 1 to 14 of each 21-day cycle
Hematology/chemistry o
X
X
X
Abbreviations: C, cycle; 
 circulating tumor DNA; D, Day; ECG, electrocardiogram; ECHO, echocardiogram; ECOG, Eastern Cooperative Oncology Group; EOT, end of 
treatment; HBV, hepatitis B virus; HCV hepatitis C virus; ICF, informed consent form; LVEF, left ventricular ejection fraction; MUGA, multiple-gated acquisition; PFS, 
progression-free survival; PK, pharmacokinetic(s); Q, every; QD, once daily; SAE, serious adverse event; Scr, screening. 
Note: Tests and procedures should be performed on schedule, but occasional changes are allowable (±2 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.
a Unless otherwise noted, the screening visit must occur within 28 days before the day of the first dose of study drug (C0D1). The ICF may be signed more than 28 days before C0D1.
b The symptom-directed physical examination will be conducted at the screening visit, within 3 days before dosing on Day 1 of each treatment cycle, on Day 16 (part 1) or Day 22 
(part 2) of Cycle 0, and at the EOT/early termination visit. The symptom-directed physical examination may be performed at other visits during the treatment cycle at the discretion 
of the investigator.
c Perform vital signs measurement before dosing. On C0D1 only, perform vital signs measurements at 1, 3, and 8 hours (±10 minutes) postdose. Vital signs outside of C0D1 will be 
collected before dosing of TAK-931 as a single determination. Blood pressure should be determined with the patient in a supine position after the patient has been quietly for 
5 minutes. 
d Safety ECG should be acquired predosing and in the supine position after patients have been resting for 5 minutes.
e Triplicate 12-lead ECGs will be performed as detailed in Table 4 below. The schedule for ECG sampling may be modified on the basis of data from previous cohorts. 
f ECHO estimate of the LVEF can be measured as an alternative to MUGA scan.
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TAK-931
Study No. TAK-931-1003
Page 81 of 87
Protocol 
21 June 2018
CONFIDENTIAL
g Radiological evaluations (computed tomography [CT] scan or magnetic resonance imaging as clinically indicated in areas of known or clinically suspected disease) will be 
employed to assess the status of the patient’s underlying disease. Brain CT scan evaluation at screening is not required in the absence of symptoms. An evaluation of lesions will be 
performed during screening (within 28 days before the first dose of study drug) and every 3rd cycle beginning with Cycle 3. Refer to Section 9.4.15 for details.
h Including serious pretreatment events; see Section 10.1.1. 
i For part 1, Cycle 0 patients will be randomized to Sequence A (1 dose of 80 mg powder-in-capsule [PIC] on Day 1 followed by 1 dose of 80 mg tablet on Day 3) or Sequence B 
(1 dose of 80 mg tablet on Day 1 followed by 1 dose of 80 mg PIC on Day 3). From Day 5 through Day 16 inclusive, all patients regardless of the sequence will receive 1 daily dose 
of TAK-931 50 mg PIC followed by 7 days of rest. For part 2, Cycle 0 patients will be randomized to receive a tablet of TAK-931 on Days 1 either of a fed or a fasted state followed 
by another tablet of TAK-931 on Day 3 in the alternate fasted or fed state. In both sequences, patients will receive 1 dose of TAK-931 on Day 12, followed by 1 tablet QD from 
Days 14 through 22 inclusive. After Day 22 administration, there is a 1-week rest period before Cycle 1 Day 1. In parts 1 and 2 Cycle 1 and after, TAK-931 will be administered on 
Days 1 to 14 inclusive of 21-day cycles. In part 1, the dose for Cycle 1 and after is 50 mg PIC QD. In part 2 TAK-931 will be administered QD in tablets at the dose that produces 
comparable exposure to 50 mg PIC as determined in part 1. The study center staff will cross-check the patient’s diary against the patient’s supply of oral TAK-931 on Days 1 and 14
of each cycle to assess compliance.
j A serum human chorio gonadotropin beta pregnancy test will be performed only for patients of childbearing potential during screening and again at C0D1 (baseline) if the screening 
test was performed more than 4 days before the first dose of any 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 C0D1), or as otherwise required by local regulations. If Cycle 0 Day 1 serum pregnancy results are not 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 independent ethics committee/institutional review board, or 
if required by local regulations. 
k The hematology and chemistry blood samples for C0D1 may be collected within 4 days before dosing to ensure patient eligibility on Day 1. If screening clinical laboratory testing 
was performed within 4 days before the C0D1 dose, it need not be repeated on C0D1. For hematology and chemistry panels, refer to Table 9.a. 
l Time points for blood samples for PK analysis will be collected as specified in Table 4 below. 
m After EOT, only related SAEs must be reported to the sponsor’s Department of Pharmacovigilance or designee. 
n Safety laboratory samples can be collected up to 2 days before the actual visit date. In Cycle 4 and beyond, the hematology and chemistry tests will be conducted on Day 1 of each 
cycle only if, in the opinion of the investigator, it is safe to do so. For hematology and chemistry panels, refer to Table 9.a.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-931
Study No. TAK-931-1003
Page 82 of 87
Protocol 
21 June 2018
CONFIDENTIAL
Table 4: PK and Triplicate ECG Sampling Schedule
Part 1, Cycle 0
Part 2, Cycle 0
D1
D2 b
D3 b
D4 b
D5 b
D1 b
D2 b
D3 b
D4 b
D5 b
D12 b
D13 b
D14 b
Triplicate 
ECG a
PK
PK
Triplicate 
ECG a
PK
PK
PK
PK
PK
PK
PK
PK
PK
PK
PK
Predose (within 1 h before dosing)
X
X
 X c
 X d
 X e
 X f
X
 X c
 X d
 X e
 X f
X
 X g
 X h
30 min postdose (5 min)
X
X
X
X
X
1 h postdose (20 min)
X
X
X
X
X
X
X
2 h postdose (30 min)
X
X
X
X
X
X
X
4 h postdose (30 min)
X
X
X
X
X
X
X
6 h postdose (30 min)
X
X
X
X
X
8 h postdose (30 min)
X
X
X
X
X
X
X
24 h postdose (1 h)
 X c
 X e
 X c
 X e
 X g
48 h postdose (1 h)
 X d
 X f
 X d
 X f
 X h
Abbreviations: Cx, Cycle; Dx, Day; ECG, electrocardiogram; PK, pharmacokinetic(s).
Note: When the timing of a PK or safety laboratory blood sample coincides with the timing of ECG measurements, the ECG will be completed before the collection of the blood 
sample. The triplicate ECG measurements should be completed immediately before the corresponding PK blood draw. 
Note: All PK analyses will be performed using plasma samples. 
a Triplicate 12-lead ECG measurements are to be performed with the patient supine, completed after a 15-minute rest period, and will be recorded within 3 minutes of the previous 
recording over a 10-minute window. 
b Patients should be instructed to come to the clinic in the morning without taking their morning doses of study drug(s). The timing of the morning visits should occur at approximately 
the same time as the morning dosing times on previous days of the cycle.
c 24 hours after Day 1 dose. 
d 48 hours after Day 1 dose. The sample should be collected prior to the Day 3 dosing of TAK-931. 
e 24 hours after Day 3 dose.
f 48 hours after Day 3 dose. The sample should be collected prior to the Day 5 dosing of TAK-931 (part 1). 
g 24 hours after Day 12 dose.
h 48 hours after Day 12 dose. The sample should be collected prior to the Day 14 dosing of TAK-931 (part 2). 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-931
Study No. TAK-931-1003
Page 83 of 87
Protocol 
21 June 2018
Appendix B
Responsibilities of the Investigator
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. The investigator agrees to assume the following responsibilities by 
signing a Form FDA 1572: 
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff who will assist in the protocol. If the 
investigator/institution retains the services of any individual or party to perform study related 
duties and functions, the investigator/institution should ensure that this individual or party is 
qualified to perform those study related duties and functions and should implement procedures 
to ensure the integrity of the study related duties and functions performed and any data 
generated.
3. Ensure that study related procedures, including study specific (non routine/non standard panel) 
screening assessments are NOT performed on potential subjects, before the receipt of written 
approval from relevant governing bodies/authorities.
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 ICF should contain a subject authorization section that 
describes the uses and disclosures of a subject’s personal information (including personal 
health information) that will take place in connection with the study. If an ICF does not include 
such a subject authorization, then the investigator must obtain a separate subject authorization 
form from each subject or the subject’s legally acceptable representative.
9. Prepare and maintain adequate case histories of all persons entered into the study, including 
eCRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
2 years following notification by the sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
contact and receive written approval from the sponsor before disposing of any such 
documents.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-931
Study No. TAK-931-1003
Page 84 of 87
Protocol 
21 June 2018
10. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
11. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor.
12. Report adverse reactions to the sponsor promptly. In an SAE occurs, notify the sponsor within 
24 hours.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-931
Study No. TAK-931-1003
Page 85 of 87
Protocol 
21 June 2018
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, US, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
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 study 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.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-931
Study No. TAK-931-1003
Page 86 of 87
Protocol 
21 June 2018
Appendix D
Eastern Cooperative Oncology Group 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 [23].
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TAK-931
Study No. TAK-931-1003
Page 87 of 87
Protocol 
21 June 2018
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 [24]. 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


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SAP_001.pdf: 


Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: A Phase 1, Open-Label Study to Assess the Relative Bioavailability, Effect of Food, and 
Gastric pH Modification on the Pharmacokinetics of TAK-931 in Patients with Advanced Solid 
Tumors 
NCT Number: NCT03708211
SAP Approve Date: Mar 5, 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 (PPD) information 
or company confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.


TAK931 
Statistical Analysis Plan, Study TAK-931-1003 
 
1
STATISTICAL ANALYSIS PLAN 
TAK-931 
A Phase 1, Open-Label Study to Assess the Relative Bioavailability, Effect of Food, and 
Gastric pH Modification on the Pharmacokinetics of TAK-931 in Patients with Advanced 
Solid Tumors 
Protocol #:  1003 
SAP Version: 
Date of Statistical Analysis Plan: 
Final 
Mar 5, 2020 
Approval Signatures 
 
Date 
Date 
Date 
Date 
31-Mar-2020
Mar 31, 2020
Property of Takeda: For Non-Commer
Co
plicable Terms of Use
erm of
CCI


Property of Takeda: For Non-Commer
plicable Terms of Use
CCI


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TAK931
Statistical Analysis Plan, Study TAK-931-1003
2
TABLE OF CONTENTS
1. LIST OF ABBREVIATIONS...........................................................................................3
2. INTRODUCTION............................................................................................................5
2.1 Study Design..............................................................................................................5
2.2 Study Objectives ........................................................................................................6
2.2.1 Primary Objectives ..............................................................................................6
2.2.2 Secondary Objectives...........................................................................................6
2.2.3 Exploratory Objectives ........................................................................................7
2.3 Endpoint.....................................................................................................................7
2.3.1 Primary endpoints................................................................................................7
2.3.2 Secondary endpoints ............................................................................................8
2.3.3 Safety endpoints...................................................................................................8
2.3.4 Exploratory endpoints..........................................................................................9
3. POPULATIONS FOR ANALYSIS..................................................................................9
3.1 Safety population........................................................................................................9
3.2 Pharmacokinetic population........................................................................................9
3.3 Response-Evaluable Population..................................................................................9
4. HYPOTHESES AND DECISION RULES.......................................................................9
5. INTERIM ANALYSIS...................................................................................................10
6. STATISTICAL METHODOLOGY ...............................................................................10
6.1 Sample Size Justification..........................................................................................10
6.2 Randomization and Stratification..............................................................................11
6.3 Unblinding ...............................................................................................................11
6.4 Data Handling ..........................................................................................................12
6.4.1 Methods for Handling Missing Data...................................................................12
6.4.2 Definition of Baseline Values ............................................................................14
6.4.3 Windowing of Visits..........................................................................................14
6.4.4 Justification of Pooling ......................................................................................14
6.5 Patient Disposition ...................................................................................................14
6.6 Demographics and Baseline Disease Characteristics.................................................14
6.6.1 Demographics....................................................................................................14
6.6.2 Medical History.................................................................................................15
6.6.3 Baseline Disease Status......................................................................................15
6.7 Treatments and Medications.....................................................................................15
6.7.1 Concomitant Medications ..................................................................................15
6.7.2 Study Treatments...............................................................................................15
6.7.3 Pharmacokinetic Analyses .................................................................................16
6.7.4 Efficacy Analysis...............................................................................................18
6.7.5 
...........................................................................................19
6.7.6 Safety Analyses .................................................................................................20
6.7.7 Laboratory Data.................................................................................................21
6.7.8 Electrocardiograms ............................................................................................22
7. PROGRAMMING CONSIDERATIONS .......................................................................22
7.1 Statistical Software...................................................................................................22
7.2 Rules and Definitions ...............................................................................................22
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8. REFERENCES...............................................................................................................22
1. LIST OF ABBREVIATIONS
%CV
coefficient of variation
AE
adverse event
ALT
alanine aminotransferase
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
ATP
adenosine triphosphate
AUC
area under the plasma concentration-time curve
AUC∞
area under the concentration-time curve from time 0 to infinity, calculated using the 
observed value of the last quantifiable concentration
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
CDC7
cell division cycle 7
CL/F
apparent oral clearance
Cmax
maximum observed plasma concentration
CNS
central nervous system
CRO
contract research organization
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CxDx
Cycle x, Day x
CV
cardiovascular
DCR
disease control rate
DDI
drug-drug interaction
DDR
DNA damage response
DOR
duration of response
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EOT
end-of-treatment (visit)
IC50
the concentration producing 50% inhibition
IHC
immunohistochemistry
IRB
institutional review board
MedDRA
Medical Dictionary for Regulatory Activities
MHRA
Medicines and Healthcare products Regulatory Agency
NCI
National Cancer Institute 
ORR
overall response rate
PD
progression of disease
PFS
progression-free survival
PIC
powder-in-capsule (formulation)
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PK
pharmacokinetic(s)
PPI
proton pump inhibitor
PR
partial response
QD
once daily
QTc
QT interval corrected for heart rate
RECIST
Response Evaluation Criteria in Solid Tumors
SAE
serious adverse event
SD
stable disease
TEAE
treatment-emergent adverse event
t1/2z
terminal disposition phase half-life
tmax
time to first occurrence of Cmax
WHO
World Health Organization
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Statistical Analysis Plan, Study TAK-931-1003
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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 an open-label, multicenter, phase 1 study designed to evaluate the relative 
bioavailability of TAK-931 tablet in reference to PIC (Part I), the effect of food and 
esomeprazole, a PPI, on PK of TAK-931 as tablet (Part 2). For the purposes of this study, 
cycle 0 will be defined as the PK cycle. 
Part I: in cycle 0 (PK cycle), approximately 20 patients (to ensure 14 to 16 patients 
evaluable for PK) will be randomized in a crossover fashion to receive a single dose of 
TAK-931 80 mg PIC or tablet on Day 1 and a single dose of TAK-931 80 mg with the 
alternate formulation on Day 3 (PIC to tablet, or tablet to PIC). There will be no TAK-931 
dosing on Day 2 and Day 4. Starting on Day 5, patients will then continue to receive TAK-
931 50 mg PIC once daily for 12 days followed by a 7-day rest period. Starting from cycle 
1, patients will receive 50 mg PIC QD for 14 days followed by 7-day rest period in a 21-day 
treatment cycle until one of the discontinuation criteria is met. 
Part 2: After the preliminary PK data from part 1 have been analyzed to estimate the relative 
bioavailability of the tablet formulation in reference to PIC, the dose of TAK-931 tablet will 
be calculated that provides total exposure (AUC) comparable to the 80-mg dose of PIC. In 
Part 2 cycle 0 (PK cycle), approximately 24 patients (to ensure 14 to 16 patients evaluable 
for PK) will be randomized in a crossover fashion to receive a single dose of TAK-931 
tablet with or without a standard high-fat breakfast on Day 1, with the alternate food intake 
condition and dosing on Day 3 (fasted fed or fed fasted). Starting from Day 5, patients 
will receive esomeprazole 40 mg once daily through Day 13. On Day 12, each patient will 
receive a single dose of TAK-931 tablet (with a dose producing an equivalent exposure to 80 
mg PIC), and PK samples will be collected up to 48 hours postdose (Day 14 predose). 
Starting on Day 14, patients will then continue to receive TAK-931 tablet at a dose expected 
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Statistical Analysis Plan, Study TAK-931-1003
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to achieve exposures comparable to 50 mg PIC once daily for 11 days followed by a 7-day 
rest period until a discontinuation criterion is met. Starting from Cycle 1, patients will 
receive TAK-931 tablet at a dose expected to achieve exposures comparable to 50 mg PIC 
QD for 14 days followed by 7-day rest period in a 21-day treatment cycle. 
2.2    Study Objectives
2.2.1 Primary Objectives
The primary objectives are:
Part 1

Estimate the relative bioavailability of a tablet formulation of TAK-931 in 
reference to a PIC formulation.
     Part 2

Assess the effect of high-fat meal on the single dose PK of TAK-931 administered 
as a tablet formulation.

Assess the effect of esomeprazole, a PPI on the single dose PK of TAK-931 
administered as a tablet formulation.
2.2.2 Secondary Objectives
The secondary objectives are:
Part 1

To further characterize PK of TAK-931 administered as PIC or tablet 
formulations.

To assess the safety and tolerability of TAK-931 administered as tablet and PIC 
formulations.

To assess the antitumor activity of TAK-931 in patients with locally advanced or 
metastatic solid tumors.
     Part 2

To further characterize PK of TAK-931 as a tablet formulation under the fasting 
or fed conditions.

To further characterize PK of TAK-931 administered as a tablet formulation in the 
presence or absence of esomeprazole, or PPI.
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Statistical Analysis Plan, Study TAK-931-1003
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!
To assess the safety and tolerability of TAK-931 administered as tablet under fed 
and fasted conditions.
!
To assess the antitumor activity of TAK-931 in patients with locally advanced or 
metastatic solid tumors. 
2.2.3 Exploratory Objectives
2.3    Endpoint
2.3.1   Primary endpoints
The primary endpoints are:
Part 1
!
Ratio of geometric mean of following pharmacokinetic parameters for TAK-931 
tablet in  reference to PIC and associated 90% confidence intervals (Cis): 
Cmax. 
AUClast.
           AUCinf.
Part 2
!
Ratio of geometric mean of following pharmacokinetic parameters for TAK-931 
tablet under fed in reference to fasting conditions and associated 90% CIs: 
Cmax. 
AUClast.
AUCinf. 
!
Ratio of geometric mean of following pharmacokinetic parameters for TAK-931 
tablet in the presence versus in the absence of esomeprazole and associated 90% CIs: 
Cmax. 
AUClast. 
AUCinf. 
!
Summary statistics of the following PK parameters for TAK-931: 
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Cmax. 
AUClast.
AUCinf. 
2.3.2    Secondary endpoints
The secondary endpoints are:
Part 1

PK parameters: 
tmax, CL/F, and t1/2z of TAK-931 following a single dose administration as PIC and 
tablet at 80 mg, respectively. 
Safety: Percent of TEAEs, Grade ≥3 TEAEs, TEAEs producing discontinuation or 
dose modification, percent of laboratory abnormalities. 

Antitumor activity: 
ORR. 
PFS.
DCR.
DOR. 
Part 2

PK parameters: 
tmax, CL/F, and t1/2z of TAK-931 tablet following a single dose administration under 
fasting and fed conditions, respectively. 
tmax, CL/F, and t1/2z of TAK-931 tablet following a single dose administration in the 
absence and in the presence of esomeprazole, respectively. 

Antitumor activity:
ORR. 
PFS.
DCR.
DOR. 
2.3.3   Safety endpoints
The safety endpoints for parts 1 and 2 are:

Frequency of TEAEs per National Cancer Institute Common Terminology Criteria for 
Adverse Events version 5.0: 

SAEs. 

TEAEs leading to dose modifications. 

TEAEs leading to treatment discontinuation. 

Percentage of patients with TEAEs: 

Grade ≥3 TEAEs.
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
SAEs. 

TEAEs leading to treatment discontinuation or dose modifications, and 

Clinically significant changes in laboratory values and vital sign measurements.
2.3.4   Exploratory endpoints
3.    POPULATIONS FOR ANALYSIS
3.1
Safety population
The safety population is defined as all patients who receive at least one dose of study drug.
All safety analyses will be based on the safety population.
3.2 Pharmacokinetic population
The PK population is defined as all patients who completed the protocol-specified dosing 
and PK sampling requirement to have sufficient plasma TAK-931 concentration-time data to 
reliably estimate the PK parameter(s). 
PK analyses will be performed using the PK population.
3.3 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. 
4.    HYPOTHESES AND DECISION RULES
No formal hypothesis testing will be performed.
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5.    INTERIM ANALYSIS
An interim analysis will be conducted after completion of Part 1. The preliminary PK data 
from Part 1 will be analyzed to estimate the relative bioavailability of the tablet formulation 
in reference to PIC, the dose of TAK-931 tablet will be calculated that provides total 
exposure (area under the concentration-time curve [AUC]) comparable to the 80-mg dose of 
PIC. If for the purposes of clinical study report (CSR) writing the analysis is performed 
immediately after Part 1 completion, the interim analysis is not needed. 
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. 
6.1   Sample Size Justification
The study is designed to assess the bioavailability of TAK-931 tablet formulation in 
reference to PIC and the effect of food and esomeprazole on PK of TAK-931 as tablet in 
patients with advanced solid tumors. It is anticipated that as many as 44 patients will be 
enrolled in this study.
The relative bioavailability study (Part 1) will use a crossover design to compare 2 
formulations of TAK-931 (tablet and PIC). Approximately 20 patients will be randomized in 
a 1:1 ratio to 1 of 2 treatment sequences: single dose of 80 mg PIC or tablet TAK-931on 
Cycle 0 Day 1 and a single dose of TAK-931 80 mg with the alternate formulation on Day 3 
(PIC to tablet or tablet to PIC). Approximately 14-16 PK-evaluable patients will be needed 
for this part. The sample size calculation is based on the expected 2-sided 90% confidence 
interval (CI) for difference in the paired, log transformed AUC (or Cmax) means on Day 1 
and Day 3. According to preliminary data obtained from study TAK-931-1002, the within-
subject CV was estimated to be 35% for AUC and 36.9% for Cmax respectively. Assuming 
the AUC ratio of the two formulations (tablet versus PIC) is 1, with a sample size of 14, the 
90% CI for the AUC ratio is expected to be (0.795, 1.257) for AUC and (0.786, 1.272) for 
Cmax based on the previously discussed variance assumptions. Patients who are not PK-
evaluable may be replaced to ensure the availability of 14 to 16 PK-evaluable patients in the 
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Statistical Analysis Plan, Study TAK-931-1003
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final analysis of part 1. Assuming that up to 4-6 patients will be replaced, approximately 20 
patients will be needed in Part 1.
The food and Esomeprazole effect study (Part 2) will use a crossover design to assess the 
effects of food on a single dose PK of TAk-931. Approximately 14-16 PK-evaluable 
patients will be randomized into 1 of 2 treatment sequences: single dose of TAK-931 tablet 
formulation with or without a standard high-fat breakfast on Cycle 0 Day 1, with the 
alternate food intake and dosing on Day 3 (fasted to fed or fed to fasted). The planed sample 
size for the food effects assessment is similar to that discussed for the relative BA study 
design. Patients who are not PK-evaluable may be replaced to ensure the availability of 14 
to 16 PK-evaluable patients in the final analysis of part 2. Assuming that up to 8-10 patients 
will be replaced, approximately 24 patients will be needed in Part 2.
If the ratio is X, the 90% CI of the ratio of geometric means is expected to be within 
(0.795X, 1.257X) for AUC and (0.786X, 1.272X) for Cmax. 
6.2    Randomization and Stratification 
In the relative BA study (Part 1), patients will be randomized in a 1:1 ratio to receive 
TAK-931 in the tablet or PIC on Cycle 0 Day 1, and receive alternate formulation on Day 3. 
Patients will be replaced if they are considered not PK evaluable. Approximately 20 patients 
will be enrolled in Part 1 to ensure 14-16 PK-evaluable patients in the final analysis in 
Part 1.
In the food effect study (Part 2), patients will be randomly assigned in a 1:1 ratio to receive a 
single dose of TAK-931 in either the fasted state of the fed state on Cycle 0 Day 1. On Day 
15, a single dose will be administered in the respective alternate food intake state. Patients 
may be replaced if they are considered not PK evaluable. Approximately 24 patients will be 
enrolled in Part 2 to ensure 14-16 PK-evaluable patients in the final analysis in Part 2.     
6.3 Unblinding
Not applicable. 
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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).

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.  

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.  

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.  
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.  
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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, 

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.  

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, 

If the resolution date is available, the earlier of the resolution date (possibly 
imputed) and the date of first treatment will be used.  

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.  

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.
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.  
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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 based on the number of patients in the safety 
population.  
A listing will present data concerning patient disposition.
6.6 Demographics and Baseline Disease Characteristics
6.6.1    
Demographics
Demographics and baseline characteristics will be summarized by treatment group
(randomization arm) in a descriptive fashion for the safety 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. 
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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 treatment group and total if there is sufficient data for analysis. 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. 
6.7 Treatments and Medications
6.7.1
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 medications will also be presented in a by-patient listing.
Concomitant procedures will not be coded, but will be presented in a by-patient listing.
6.7.2
Study Treatments
In Part 1 relative BA study, patients will be randomized in a crossover fashion to receive a 
single dose of TAK-931 80 mg PIC or tablet on Day 1 and a single dose of TAK-931 80 mg 
with the alternate formulation on Day 3 of Cycle 0. There will be no TAK-931 dosing on 
Day 2 and Day 4. Patients will then continue to receive TAK-931 50 mg PIC once daily for 
12 days followed by a 7-day rest period. Starting from Cycle 1, patients will take 50 mg PIC 
QD for 14 days followed by 7-day rest period in a 21-day treatment cycle until one of the 
discontinuation criteria is met.
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In Part 2 for the effect of food and esomeprazole study, patients will be randomized to 
receive a single dose of TAK-931 tablet with or without a standard high-fat breakfast on 
Day 1, with the alternate food intake condition and dosing on Day 3. Starting from Day 5, 
patients will receive esomeprazole 40 mg once daily through Day 13. On Day 12, each 
patient will receive a single dose TAK-931 tablet and continue to receive TAK-931 tablet at 
dose expected to achieve exposures comparable to 50 mg PIC once daily for 11 days 
followed by a 7-day rest period until a discontinuation criterion is met. Starting from cycle 
1, patients will receive TAK-931 tablet at a dose expected to achieve exposures comparable 
to 50 mg PIC QD for 14 days followed by 7-day rest period in a 7-day treatment cycle. 
6.7.2.1 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 by arms. 
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). 
Dosing data will also be presented in a by-patient listing.
6.7.2.2 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 by randomization arms.
Reasons for dose modification may also be tabulated similarly. 
6.7.3 Pharmacokinetic Analyses 
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 
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Statistical Analysis Plan, Study TAK-931-1003
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occurring after two or more BQLs, will be set to missing at the discretion of the 
pharmacokineticist. Actual sampling timeswill be used in deriving TAK-931 PK parameters.
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.
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 TAK-931 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.
Part 1
For the relative bioavailability estimation of tablet vs. PIC, at least the ratios of geometric 
mean AUClast, AUCinf and Cmax (tablet vs. PIC) associated 2-sided 90% CIs will be 
calculated, based on the within-patient variance calculated via analysis of Variance
(ANOVA). Following log-transformation, AUClast, AUCinf and Cmax will be separately will 
be analyzed by ANOVA fitting terms for treatment (formulation) group (TAK-931 tablet 
and PIC), sequence and period. Subject within sequence will be treated as a random effect in 
the model. Point estimates and adjusted 90% confidence intervals for the difference in 
treatment (tablet or PIC) will be constructed. The point estimate and adjusted 90% 
confidence intervals will then be exponentially back transformed to provide point and 
confidence interval estimates for the ratios of interest appropriately (eg, AUC0-last of the 
TAK-931 in PIC vs. AUC0-last of the TAK-931 in Tablet).
Part 2
For the estimation of food effect, the ratios of geometric mean AUC0-last, AUCinf and Cmax 
(TAK-931 administered with and without food intake) and associated 2-sided 90% CIs will 
be calculated, based on the within-patient variance calculated via ANOVA. Following log-
transformation, AUClast, AUCinf and Cmax will be separately analyzed by ANOVA fitting 
terms for treatment groups (fed: fasted). Subject will be treated as a random effect in the 
model. Point estimates and adjusted 90% confidence intervals for the difference in treatment 
will be constructed. The point estimate and adjusted 90% confidence intervals will then be 
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Statistical Analysis Plan, Study TAK-931-1003
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exponentially back transformed to provide point and confidence interval estimates for the 
ratios of interest appropriately (eg, AUClast of fed vs. AUClast of fasted). For evaluating the 
effect of esomeprazole on TAK-931 PK, the ratio of geometric mean AUC0-last, AUCinf and 
Cmax (presence of esomeprazole:absence of esomeprazole) and associated 2-sided 90% CIs 
will be calculated, based on the within-patient variance estimated by analysis of variance. 
The PK population will be used for these analyses.
Descriptive statistics for TAK-931 plasma concentrations and PK parameters will be 
tabulated by formulation (part 1), food intake state (fed or fasted, part 2) and the use of 
esomeprazole (in the presence or absence of esomeprazole, part 2):
Individual comparison of AUClast, AUCinf and Cmax will be plotted by formulation, food 
intake and the use of esomeprazole, respectively. Individual and mean plasma concentration-
time profiles will be plotted by formulation, food intake state, and the use of esomeprazole, 
respectively. 
TAK-931 plasma concentration-time data will be listed using the PK-Evaluable population.  
6.7.4 Efficacy Analysis
The secondary efficacy parameters include ORR (CR + PR), PFS, DCR 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 by 
treatment groups. 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 treatment group 
if there is sufficient data. PFS will be analyzed using safety population. The details 
regarding the handling of missing assessments and censoring for the PFS analysis are 
presented in the table below.
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Statistical Analysis Plan, Study TAK-931-1003
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Handling of Missing Assessments and Censoring for PFS 
Primary Analysis Based on FDA guidance
Situation
Date of Progression or Censoring
Outcome
No baseline and/or no post baseline assessment, no 
subsequent anticancer therapy after study 
treatment, no death
Date of Randomization 
Censored
Disease progression documented between 
scheduled visits 
Date of next scheduled visit
Progressed
No documented death or disease progression 
Date of last adequate assessmenta
Censored
Lost to follow-up, withdraw consent before any 
documented death or disease progression  
Date of last adequate assessmenta
Censored 
Death or progression after more than 1 missed 
visitb
Date of last adequate assessmenta
Censored
Alternate antineoplastic therapy started prior to 
disease progression 
Date of last adequate assessment prior 
to starting alternate antineoplastic 
therapy
Censored
Death before first assessment
Date of death
Progressed
Death between adequate assessment visits
Date of death
Progressed
a Adequate disease assessment is defined as there is sufficient data to evaluate a patient’s disease status.
b Death or progression occur more than 90 days from previous adequate assessment.
DCR will be assessed by investigator per RECIST version 1.1 [1] (CR + PR + SD; SD must 
be ≥1 post baseline CT scan evaluation from treatment initiation to qualify for DCR).
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 based on the responders in the response-evaluable 
population if there is sufficient data (at least 3 responders).
If there are less than 3 responders in the Response-Evaluable population, only the secondary 
efficacy analysis for disease control rate and PFS will be conducted if applicable and disease 
response will be presented in listings only.
6.7.5
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Statistical Analysis Plan, Study TAK-931-1003
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6.7.6   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. Reasons for discontinuation and modification will be 
tabulated. Safety will be summarized by different dose sequence of different formulation,
food intake state, and the use of esomeprazole by randomization arms. 
These analyses will be performed using the safety population. 
6.7.6.1 Adverse Events
AEs will be coded using the MedDRA dictionary, version 21.0.  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.   
!
Treatment-emergent AEs
!
Drug-related treatment-emergent AEs
!
Grade 3 or higher treatment-emergent AEs
!
Grade 3 or higher drug-related treatment-emergent AEs
The most commonly reported treatment-emergent AEs (ie, those events reported by ∀10% 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.
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 TAK-931-1003
21
6.7.6.2    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.
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).
6.7.6.3    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.
6.7.6.4    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. 
Additional safety analyses may be performed to more clearly enumerate rates of toxicities 
and to further define the safety profile of TAK-931.
6.7.7    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.
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 by treatment groups. 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.
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TAK931
Statistical Analysis Plan, Study TAK-931-1003
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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:

Hematology: hemoglobin, hematocrit, platelets, absolute neutrophil counts (ANC), 
lymphocytes, eosinophils, and WBC

Clinical chemistry: ALT/SGPT, AST/SGOT, alkaline phosphatase, bilirubin (total), 
calcium, creatinine, glucose, hemoglobin A1c, magnesium, phosphate, potassium, 
and sodium
By-patient listings to be presented include hematology and clinical chemistry.
6.7.8    Electrocardiograms
A summary of ECG abnormalities will be presented by visit and treatment groups.  ECG
intervals (QT, QTc and PR) will be summarized by treatment groups at each scheduled time 
point, along with mean change from baseline at each scheduled time point.  The number and 
percentage of patients with ECG abnormalities will be summarized at each time point.
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 6.4.2.
8. REFERENCES
1. 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.
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