Clinical trial NCT03482453
Conditions: Healthy Volunteers
Keywords: Drug Therapy
Sponsor: Millennium Pharmaceuticals, Inc.
Start date: 2018-03-28; Completion date: 2019-01-18
Enrollment: 69 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The purpose of this study is to assess the safety, tolerability of TAK-788 and to identify a tolerable single oral dose of TAK-788 administered as a drug-in-capsule (DiC) formulation, to characterize the effects of a low-fat meal on the PK of the TAK-788 administered as DiC formulation and to evaluate the bioavailability of a test (Process B) DiC of TAK-788 relative to a reference (Process A) DiC of TAK-788 in healthy participants.

Detailed description:
The drug being tested in this study is called TAK-788. The study will assess the safety and tolerability of single oral dose of TAK-788, evaluate the effect of a low-fat meal on PK of TAK-788 and will assess the relative bioavailability of two DiCs of TAK-788.

The study will enroll approximately 69 participants. The study is designed to consist of 3 parts: Part 1- dose escalation phase, Part 2- low fat meal effect and Part 3 - relative bioavailability. The study population of Part 1 will consist of 40 participants enrolled into 5 cohorts. Each cohort will have 8 randomized participants with 6 receiving a single dose of TAK-788, and 2 receiving matching placebo under fasted conditions. In Cohorts 1 to 5, safety of single-dose TAK-788 will be evaluated. For Part 2, the effect of a low-fat meal on a single tolerable dose of TAK-788 will be determined following review of safety and tolerability data from the previous cohorts in Part 1. The study population of Part 2 will consist of 16 participants enrolled into 2 cohorts of different doses, where participants will be randomized to a cross-over sequence of:

* TAK-788 Fed + TAK-788 Fasted
* TAK-788 Fasted + TAK-788 Fed

The study population of Part 3 will consist of 13 participants enrolled into 1 cohort, where participants will be randomized to a cross-over sequence of:

* TAK-788 DiC (reference) + TAK-788 DiC (test)
* TAK-788 DiC (test) + TAK-788 DiC (reference) This single-center trial will be conducted in the United States. The overall time to participate in this study is approximately 7 months. Participants will be contacted by telephone 30 days after the last dose of study drug for a follow-up assessment.

Arms: arm 1: TAK-788, capsule, orally or TAK-788 matching placebo capsule, orally, once under fasted conditions on Day 1. arm 2: TAK-788, capsule, orally or TAK-788 matching placebo capsule, orally, once under fasted conditions on Day 1 following review of safety data from Cohort 1. arm 3: TAK-788, capsule, orally or TAK-788 matching placebo capsule, orally, once under fasted conditions on Day 1 following review of safety data from Cohort 2. arm 4: TAK-788, capsule, orally or TAK-788 matching placebo capsule, orally, once under fasted conditions on Day 1 following review of safety data from Cohort 3. arm 5: TAK-788, capsule, orally or TAK-788 matching placebo capsule, orally, once under fasted conditions on Day 1 following review of safety data from Cohort 4. arm 6: TAK-788, capsule, orally, once on Day 1 of Intervention Period 1 under fed conditions with low-fat meal (Treatment A), followed by at least 7 days washout period, further followed by TAK-788, capsule, orally, once on Day 1 of Intervention Period 2 under fasted conditions (Treatment B). TAK-788 dose will be determined based on review of safety and tolerability data from cohorts of Part 1. arm 7: TAK-788, capsule, orally, once on Day 1 of Intervention Period 1 under fasted conditions (Treatment B), followed by at least 7 days washout period, further followed by TAK-788, capsule, orally, once on Day 1 of Intervention Period 2 under fed conditions with low-fat meal (Treatment A). TAK-788 dose will be determined based on review of safety and tolerability data from cohorts of Part 1. arm 8: TAK-788 160 mg, DiC A (reference), orally, under fasted condition, once on Day 1 of Intervention Period 1, followed by at least 7 days washout period, further followed by TAK-788 160 mg, DiC B (test), orally, under fasted condition, once on Day 1 of Intervention Period 2. arm 9: TAK-788 160 mg, DiC B (test), orally, under fasted condition, once, on Day 1 of Intervention Period 1, followed by at least 7 days washout period, further followed by TAK-788 160 mg, DiC A (reference), orally, under fasted condition, once on Day 1 of Intervention Period 2.
Interventions: intervention 1: TAK-788 intervention 2: Placebo intervention 3: TAK-788
Intervention descriptions: intervention 1: TAK-788 capsules. intervention 2: TAK-788 placebo-matching capsules. intervention 3: TAK-788 DiC.

Protocol documents:
Prot_000.pdf: 



Title: Phase 1, Randomized, Double-blind, Placebo-Controlled, Single Rising Dose Study to 
Evaluate Pharmacokinetics, Safety, and Tolerability of TAK-788 Followed by Open-Label, 
Crossover Evaluation of the Effects of a Low-Fat Meal on TAK-788 Pharmacokinetics and 
Evaluation of Relative Bioavailability of TAK-788 Capsules in Healthy Subjects
NCT Number: NCT03482453
Protocol Approve Date: 13 November 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
Phase 1, Randomized, Double-blind, Placebo-Controlled, Single Rising Dose Study to 
Evaluate Pharmacokinetics, Safety, and Tolerability of TAK-788 Followed by Open-Label, 
Crossover Evaluation of the Effects of a Low-Fat Meal on TAK-788 Pharmacokinetics and 
Evaluation of Relative Bioavailability of TAK-788 Capsules in Healthy Subjects
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-788-1001
IND Number:
126,721
EudraCT Number:
Not applicable
Compound:
TAK-788 (formerly AP32788)
Date:
13 November 2018
Amendment Number:
03
Amendment History:
Date
Amendment Number
Amendment Type
Region
08 February 2018
Initial Protocol
Not applicable
Global
13 June 2018
01
Substantial
Global
02 November 2018
02
Substantial
Not applicable a
13 November 2018
03
Substantial 
Global
a Protocol Amendment 02 was not activated.
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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 10.0, as 
is information on reporting product complaints.
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site. Information on service providers is given in Section 3.1 and relevant guidelines 
provided to the site.
Contact Type/Role
United States Contact
Serious adverse event and pregnancy reporting
See Section 10.0.
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1.2
Approval 
REPRESENTATIVES OF TAKEDA 
This study will be conducted with the highest respect for the individual participants in accordance 
with the requirements of this clinical study protocol and also in accordance with the following:
!
The ethical principles that have their origin in the Declaration of Helsinki.
!
International Conference on Harmonisation (ICH) E6 Good Clinical Practice (GCP): 
Consolidated Guideline.
!
All applicable laws and regulations, including, without limitation, data privacy laws, clinical 
trial disclosure laws, and regulations.
SIGNATURES
The signature of the responsible Takeda medical officer (and other signatories, as applicable) can 
be found on the signature page.
Electronic signatures may be found on the last page of this document.
PPD
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
dance
dance
wing:
wing:
e (GCP):
(GCP
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other sig
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For non-commercial use only an


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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 10.0 of this 
protocol.

Terms outlined in the clinical study site agreement.

Responsibilities of the Investigator (Appendix B).
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix C of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Provence)
Location of Facility (Country)
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1.3
Protocol Amendment 03 Summary of Changes
Rationale for Amendment 03
This document describes the changes in reference to the protocol incorporating Amendment 03. 
As Protocol Amendment 02 was not activated, the changes described below are based on a 
comparison with Amendment 01. The primary reason for this amendment is to add Part 3 to assess 
the relative bioavailability of the single dose of TAK-788 160 mg administered as Process B 
drug-in-capsule (DiC) (test) versus a single dose of TAK-788 160 mg administered as Process A 
DiC (reference) in healthy subjects.
Minor grammatical, editorial, formatting, and administrative changes not affecting the conduct of 
the study are included for clarification and administrative purposes only.
For specific descriptions of text changes and where the changes are located, see Appendix E.
Changes in Amendment 03 (Compared with Amendment 01)
1. Addition of Part 3 to assess the relative bioavailability of TAK-788 capsules in healthy 
subjects.
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TABLE OF CONTENTS
1.0
ADMINISTRATIVE.......................................................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
1.3
Protocol Amendment 03 Summary of Changes ..........................................................5
2.0
STUDY SUMMARY ....................................................................................................11
3.0
STUDY REFERENCE INFORMATION ......................................................................19
3.1
Study-Related Responsibilities.................................................................................19
3.2
Principal Investigator/Coordinating Investigator ......................................................19
3.3
List of Abbreviations ...............................................................................................20
3.4
Corporate Identification...........................................................................................21
4.0
INTRODUCTION.........................................................................................................22
4.1
Scientific Background..............................................................................................22
4.2
Nonclinical Experience............................................................................................23
4.3
Clinical Experience..................................................................................................23
4.4
Rationale for the Proposed Study.............................................................................24
4.4.1
Risk-Benefit Assessment....................................................................................24
4.4.2
Rationale for Single Dose Escalation (Part 1).....................................................24
4.4.3
Rationale for Food Interaction (Part 2)...............................................................25
4.4.4
Rationale for Relative Bioavailability Assessment (Part 3).................................26
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................27
5.1
Objectives................................................................................................................27
5.1.1
Primary Objectives.............................................................................................27
5.1.2
Secondary Objectives.........................................................................................27
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 .......................................................................................28
6.0
STUDY DESIGN..........................................................................................................30
6.1
Overview of Study Design.......................................................................................30
6.1.1
Part 1 – Dose Escalation.....................................................................................30
6.1.2
Part 2 – Food Effect ...........................................................................................31
6.1.3
Part 3 – Relative Bioavailability.........................................................................32
6.2
Number of Subjects .................................................................................................33
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6.3
Duration of Study ....................................................................................................34
6.3.1
Duration of an Individual Subject’s Study Participation .....................................34
6.3.2
End of Study/Study Completion Definition and Planned Reporting....................34
6.3.3
Time Frames for Primary and Secondary Endpoints to Support Disclosures.......34
6.3.4
Total Study Duration..........................................................................................36
7.0
STUDY POPULATION................................................................................................37
7.1
Inclusion Criteria .....................................................................................................37
7.2
Exclusion Criteria ....................................................................................................37
8.0
STUDY DRUG .............................................................................................................40
8.1
Study Drug Administration......................................................................................40
8.1.1
Dose Escalation Phase (Part 1)...........................................................................40
8.1.2
Food Effects Study Phase (Part 2)......................................................................40
8.1.3
Relative Bioavailability (Part 3).........................................................................41
8.2
Definitions of DLT ..................................................................................................42
8.3
Dose Escalation Rules..............................................................................................42
8.4
Criteria for Tolerable Dose ......................................................................................42
8.5
Excluded Concomitant Medications and Procedures ................................................42
8.6
Permitted Concomitant Medications and Procedures................................................43
8.7
Precautions and Restrictions ....................................................................................43
8.8
Management of Selected EGFR TKI Class AEs.......................................................44
8.8.1
Pneumonitis .......................................................................................................44
8.8.2
Nausea and Vomiting.........................................................................................45
8.8.3
Diarrhea.............................................................................................................45
8.9
Blinding and Unblinding..........................................................................................45
8.10
Description of Investigational Agents ......................................................................45
8.11
Preparation, Reconstitution, and Dispensation..........................................................46
8.12
Packaging and Labeling...........................................................................................46
8.13
Storage, Handling, and Accountability.....................................................................46
8.13.1 Disposition of Used Supplies .............................................................................47
8.13.2 Inventory of Unused Supplies ............................................................................47
8.14
Other Protocol-Specified Materials ..........................................................................47
9.0
STUDY CONDUCT......................................................................................................48
9.1
Study Personnel and Organizations..........................................................................48
9.2
Arrangements for Recruitment of Subjects...............................................................48
9.3
Treatment Group Assignments.................................................................................48
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9.4
Study Procedures.....................................................................................................48
9.4.1
Informed Consent...............................................................................................49
9.4.2
Subject Demographics .......................................................................................49
9.4.3
Medical History .................................................................................................49
9.4.4
Physical Examination.........................................................................................49
9.4.5
Subject Height ...................................................................................................49
9.4.6
Vital Signs .........................................................................................................49
9.4.7
Pulmonary Function Tests..................................................................................49
9.4.8
Drug, Alcohol, and Tobacco Testing..................................................................49
9.4.9
Pregnancy Test...................................................................................................50
9.4.10 Concomitant Medications and Procedures..........................................................50
9.4.11 AEs....................................................................................................................50
9.4.12 Enrollment .........................................................................................................50
9.4.13 ECG...................................................................................................................50
9.4.14 Chest CT Scan ...................................................................................................51
9.4.15 Clinical Laboratory Evaluations .........................................................................51
9.4.16 PK Measurements..............................................................................................52
9.5
Completion of Study Treatment for Individual Subjects...........................................53
9.6
Discontinuation of Treatment With Study Drug and Subject Replacement ...............53
9.7
Study Compliance....................................................................................................54
10.0
ADVERSE EVENTS ....................................................................................................55
10.1
Definitions...............................................................................................................55
10.1.1 PTE....................................................................................................................55
10.1.2 AE Definition ....................................................................................................55
10.1.3 SAE Definition ..................................................................................................55
10.2
Procedures for Recording and Reporting AEs and SAEs..........................................56
10.3
Monitoring of AEs and Period of Observation .........................................................57
10.4
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events.........57
10.5
Procedures for Reporting Product Complaints or Medication Errors (Including 
Overdose) ................................................................................................................57
10.6
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities...........58
11.0
STUDY COMMITTEES...............................................................................................59
12.0
DATA HANDLING AND RECORDKEEPING............................................................60
12.1
eCRFs......................................................................................................................60
12.2
Record Retention .....................................................................................................60
13.0
STATISTICAL METHODS..........................................................................................62
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13.1
Statistical and Analytical Plans ................................................................................62
13.1.1 Analysis Sets......................................................................................................62
13.1.2 Analysis of Demographics and Other Baseline Characteristics ...........................62
13.1.3 PK Analysis .......................................................................................................62
13.1.4 Safety Analysis ..................................................................................................63
13.2
Determination of Sample Size..................................................................................64
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................65
14.1
Study-Site Monitoring Visits ...................................................................................65
14.2
Protocol Deviations..................................................................................................65
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................65
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................66
15.1
IRB and/or IEC Approval ........................................................................................66
15.2
Subject Information, Informed Consent, and Subject Authorization .........................67
15.3
Subject Confidentiality ............................................................................................68
15.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................68
15.4.1 Publication.........................................................................................................68
15.4.2 Clinical Trial Registration..................................................................................69
15.4.3 Clinical Trial Results Disclosure ........................................................................69
15.4.4 Data Sharing ......................................................................................................69
15.5
Insurance and Compensation for Injury....................................................................69
16.0
REFERENCES..............................................................................................................70
LIST OF IN-TEXT TABLES
Table 6.a
Primary and Secondary Endpoints for Disclosures .............................................35
Table 8.a
Low-fat Meal Content........................................................................................41
Table 8.b
Contraceptive Methods ......................................................................................44
Table 9.a
Clinical Chemistry and Hematology Tests..........................................................51
Table 9.b
Clinical Urinalysis Tests ....................................................................................52
LIST OF IN-TEXT FIGURES
Figure 6.a
Dose Escalation Schema (Part 1)........................................................................31
Figure 6.b
Food Effect Schema (Part 2) ..............................................................................32
Figure 6.c
Relative Bioavailability Schema (Part 3)............................................................33
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LIST OF APPENDICES
Appendix A
Schedule of Events.............................................................................................72
Appendix B
Responsibilities of the Investigator.....................................................................81
Appendix C
Investigator Consent to Use of Personal Information..........................................83
Appendix D
List of Strong Inhibitors and Inducers of CYP3A...............................................84
Appendix E
Detailed Description of Amendments to Text.....................................................85
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2.0
STUDY SUMMARY
Name of Sponsor:
Millennium Pharmaceuticals, Inc 
Compound:
TAK-788 (formerly AP32788)
Title of Protocol: Phase 1, Randomized, Double-blind, 
Placebo-Controlled, Single Rising Dose Study to Evaluate 
Pharmacokinetics, Safety, and Tolerability of TAK-788 
Followed by Open-Label, Crossover Evaluation of the 
Effects of a Low-Fat Meal on TAK-788 Pharmacokinetics 
and Evaluation of Relative Bioavailability of TAK-788 
Capsules in Healthy Subjects 
IND No.: 
126,721
EudraCT No.: 
Not applicable 
Study Number: TAK-788-1001
Phase: 1
Study Design:
This is a randomized, double-blind, placebo-controlled single rising dose study, followed by an open-label, crossover 
evaluation of the effects of a low-fat meal on the pharmacokinetics (PK) of TAK-788 and its 2 active metabolites in 
healthy subjects, and a crossover evaluation of the relative bioavailability of TAK-788 Process B DiC (test) versus 
Process A DiC (reference) in healthy subjects under fasting conditions. Following the completion of Part 1 (dose 
escalation phase) where a safe and tolerable dose in healthy subjects will be identified, Part 2 (food effect phase) and 
Part 3 (relative bioavailability of TAK-788 capsules) will be initiated where the effects of a low-fat meal on TAK-788 
and the relative bioavailability of TAK-788 in test versus reference will be studied. 
Part 1 – Dose Escalation:
In the double-blind, randomized, placebo-controlled dose escalation phase, cohorts of 8 healthy subjects will be 
randomized: Under fasting conditions, 6 subjects will receive a single dose of TAK-788 and 2 subjects will receive 
placebo. The starting dose will be 20 mg then with each subsequent 8-subject cohort the dose will escalate to a single 
dose of 40, 80, 120, up to 160 mg. Dose escalation can occur if there are no dose-limiting toxicities following 
administration of TAK-788 and all Grade ≥2 treatment-related adverse events (AEs) resolve to Grade ≤1 or return to 
baseline by Day 5. If all treatment-related Grade ≥2 AEs have not resolved to Grade 1 or returned to baseline by Day 5, 
the assessment will be repeated on Day 8 and Day 15, if necessary, before proceeding to the next planned higher dose. 
The subjects will remain at the clinical study site for at least 48 hours postdose for close safety monitoring. The 
subjects will be furloughed from the site 48 hours postdose if there are no Grade ≥2 AEs. Subjects will return to the 
site for the PK sample collection on Days 4, 5, and 8. A final safety phone conference will occur 30 days after the last 
dose (window of up to 2 days after Day 30).
Additional cohorts may also be enrolled in Part 1 to assess the safety, tolerability, and PK of single-dose TAK-788 
DiC containing TAK-788 active pharmaceutical ingredient from a different synthetic process (such as Process A). The 
dose(s) in the additional cohort(s) will be determined by the safety, tolerability, and PK exposure data from the 
completed cohorts in this study and the experience in the ongoing phase 1/2 study in patients with non–small-cell lung 
cancer (Study AP32788-15-101). The highest dose tested in Part 1 of the study will not exceed the unit dose of the 
maximum tolerated dose identified in Study AP32788-15-101. 
To mitigate the risk of treatment, pulmonary function tests (PFTs) (spirometry, lung volumes, and diffusion capacity 
[DLco]) and a chest computed tomography (CT) scan are required to be performed and assessed to be normal (PFTs 
≥80% of predicted normal) at screening; baseline PFTs to be performed no more than 7 days before Day 1. At 
48 hours postdose before furlough, PFTs will be performed and pulmonary symptoms assessed. If the DLco has 
decreased by >20% of baseline or the subject reports pulmonary symptoms on Day 3, a chest CT scan will be 
performed. Any DLco abnormalities or chest CT scan abnormalities will be followed weekly until resolution. An 
appropriate treatment will be initiated by the investigator or attending pulmonologist in the event of clinically 
significant pulmonary symptoms, abnormal DLco, and/or abnormal chest CT scan.
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Study Schema for Single Rising Dose Phase (Part 1)
DiC, drug-in-capsule. 
Part 2 – Food Effect:
In the food effect part of the study, all subjects will receive TAK-788 only. Subjects will be randomized to a crossover 
sequence at a 1:1 ratio and administered the dose of TAK-788 identified in Part 1 on Day 1 in Period 1 and on Day 8 
in Period 2 with a low-fat meal (Treatment A) or under fasting conditions (Treatment B) with a washout period of ≥7 
days between each dose of TAK-788. The duration of the washout period may be updated pending the PK results from 
Part 1. The duration of washout will be adjusted to ensure that the Ctrough (observed plasma trough concentration at the 
end of a dosing interval) of TAK-788 at 168 hours postdose in Part 1 is <5% of the Cmax (maximum observed 
concentration) of TAK-788 at the dose used in the food effect evaluation. The planned washout period for Part 2 is 7 
days. PFTs and chest CT scan are required to be performed and assessed as normal at screening; PFTs must be 
performed no more than 7 days before Day 1. If pulmonary symptoms are reported, PFTs and a chest CT will be 
repeated 48 hours postdose before furlough. Other clinical study procedures are the same as those in the dose 
escalation phase. 
Cohort 4, 120 mg
n=8 (6 active, 2 placebo)
Cohort 1, 20 mg
n=8 (6 active, 2 placebo)
Cohort 2, 40 mg
n=8 (6 active, 2 placebo)
Cohort 3, 80 mg
n=8 (6 active, 2 placebo)
Cohort 5, 160 mg
n=8 (6 active, 2 placebo)
Food effect with DiC (Part 2)
n= up to 16 crossover
Bioavailability DiC (Part 3)
n= up to 12 crossover
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Part 3 – Bioavailability Study
Subjects will be randomly assigned to a crossover sequence at a 1:1 ratio and administered a single dose of 160 mg 
TAK-788 capsule A DiC (reference) or 160 mg TAK-788 capsule B DiC (test) on Day 1 in Period 1 and on Day 8 in 
Period 2 under fasting conditions, with a planned washout period of 7 days. PFTs (spirometry, lung volumes, and 
DLco) are required to be performed and assessed as normal at screening. PFTs will be performed on Day 3, Day 10, 
and/or Early Termination visit in Part 3 only if indicated on the basis of pulmonary symptoms; no chest CT scans will 
be done. Other clinical study procedures are the same as those in the dose escalation phase. Subjects will have PK 
collection samples collected during confinement, and the last PK sample will be collected at 72 hours postdose in each 
period. Subjects will be furloughed after the last PK sample collection in Period 1. Subjects will return to the clinical 
study site on Day 7 for Period 2 study. Subjects will be released from the clinical study site after the last PK sample 
collection in Period 2. Safety phone conferences will occur on Day 15 and 30 days after the last dose (window of up to 
2 days after Day 38).
Study Schema for Food Effect Phase (Part 2)
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Study Schema for Relative Bioavailability Phase (Part 3)
Primary Objectives:
!
Part 1: To assess safety and tolerability of TAK-788 and to identify a tolerable single oral dose of TAK-788 
administered as a drug-in-capsule (DiC) formulation in healthy subjects. 
!
Part 2: To characterize the effect of a low-fat meal on the PK of TAK-788 administered as a DiC formulation in 
healthy subjects.
!
Part 3: To evaluate the bioavailability of a test (Process B) DiC of TAK-788 relative to a reference (Process A) 
DiC of TAK-788 in healthy subjects.
Secondary Objectives:.
!
Part 1: To characterize the PK of TAK-788 and its active metabolites, AP32960 and AP32914, administered as a 
DiC formulation in healthy subjects. 
!
Part 2/Part 3: To assess the safety of TAK-788 following a single dose of TAK-788 in healthy subjects.
Exploratory Objectives:
!
!
Subject Population: Healthy subjects aged 18-55 years.
Number of Subjects:
Up to approximately 84 (approximately 56 in Part 1, up to 
16 in Part 2, and up to 12 in Part 3)
Number of Sites: 
1
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Dose Levels:
Part 1:
Single rising dose starting at 20 mg, escalating to 
40, 80, 120, up to 160 mg. 
Part 2: A tolerable single dose identified in Part 1. 
Part 3: A 160 mg single dose DiC.
Route of Administration:
Oral
Duration of Treatment:
One day (single dose) for Part 1, 2 days (2 single doses 
separated by ≥7-day washout) for each of Parts 2 and 3.
Period of Evaluation:
Part 1: 30 days 
Part 2: 38 days
Part 3: 38 days
Main Criteria for Inclusion:

Aged 18-55 years of age at the time of informed consent. 

Healthy subjects defined as the absence of acute or chronic clinically significant deviations from normal in 
medical history, physical examination, electrocardiogram (ECG), and clinical laboratory determinations at 
screening. 

Body weight of ≥45 kg (women) or ≥55 kg (men) and a body mass index of 18.0-30.0 kg/m2 at screening. 

Normal baseline PFTs (≥80% of predicted normal for spirometry, lung volumes, and DLco) for Parts 1, 2 and 3; 
and chest CT scan at screening for Parts 1 and 2. 

Nonsmoker (never smoked or >20 years from last occurrence of smoking).

Normal organ function including hepatic, renal, and bone marrow function (please refer to study reference manual 
or site manual for normal ranges). 
Main Criteria for Exclusion:

Medical History and Concurrent Diseases
–
Ongoing or prior pulmonary disease including asthma, chronic obstructive pulmonary disease, interstitial 
lung disease, and pneumonitis including but not limited to drug-related pneumonitis. 
–
Any history of cardiovascular disease including a history of congenital prolonged QT syndrome or 
unexplained cardiac arrest.
–
Manifestations of malabsorption due to prior gastrointestinal (GI) surgery, GI disease, or for an unknown 
other reason that may alter the PK of TAK-788.
–
Pulmonary infection ongoing or within 30 days of informed consent.
–
Current or recent (within 3 months) GI disease.
–
Any major surgery within 4 weeks before study drug administration.
–
Blood transfusion within 4 weeks before study drug administration. 
–
History of bleeding disorder.
–
Inability to tolerate oral medication. 
–
Inability to undergo venipuncture and/or tolerate venous access. 
–
Inability to tolerate multiple blood sampling. 
–
Ongoing or active infection, including but not limited to, the requirement for intravenous antibiotics. 
–
Positive serology or a known history of hepatitis B virus, hepatitis C virus, and HIV. 

Physical and Laboratory Test Findings
–
Any clinically significant abnormality at screening of cardiac, hepatic, renal, respiratory, GI, endocrine, 
immunologic, dermatologic, hematologic, neurologic, or psychiatric disease.
–
Resting blood pressure >140/90 mmHg at screening (a single repeat measurement is allowed if the initial 
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TAK-788 (formerly AP32788)
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measurement is outside these limits).
–
Resting pulse rate <45 beats per minute.

Allergies and Adverse Drug Reactions
–
History of severe allergy/hypersensitivity reaction or ongoing allergy/hypersensitivity reaction, as judged by 
the investigator, or history of hypersensitivity to epidermal growth factor receptor/human epidermal growth 
factor receptor 2 inhibitors. 

Prohibited Treatments and Therapies 
–
Prior exposure to TAK-788.
–
Exposure to any small molecular drug treatment, including investigational small molecular drugs, within 
4 weeks or biologic drug treatment, including investigational biologics, within 16 weeks before study drug 
administration. 
–
Use of any prescription or over-the-counter (OTC) stomach acid controllers within 2 weeks before study drug 
administration.
–
Use of any other drugs, including OTC medications, nutritional supplements, and herbal preparations 
(including St. John’s wort) within 1 week before study drug administration (except occasional use of 
acetaminophen and ibuprofen which are allowed up to 24 hours before dosing). 
–
Consumption of any food or beverages containing grapefruit, Seville oranges, blood oranges, or 
pomegranates within 1 week before study drug administration.
Endpoints:

Primary: 
–
Part 1: safety profile of orally administered TAK-788. 
–
Number and percentage of subjects with 1 or more AE.
–
Number and percentage of subjects with 1 or more serious AE.
–
Number and percentage of subjects with clinically defined abnormal laboratory values.
–
Number and percentage of subjects with clinically defined abnormal vital signs.
–
Part 2: summary statistics of the PK parameters for TAK-788 under fasted conditions or following a low-fat 
meal. 
–
Cmax.
–
tmax (time of first occurrence of Cmax).
–
AUCt (area under the concentration-time curve [AUC] from time 0 to time t).
–
AUC∞(AUC from time 0 to infinity calculated using the last quantifiable concentration.
–
t1/2z: terminal disposition phase half-life.
–
Part 3: summary statistics of the PK parameters for TAK-788 in different DiC under fasted conditions. 
–
Cmax.
–
tmax.
–
AUCt.
–
AUC∞ (if data permitted).
–
t1/2z.

Secondary: 
–
Part 1: summary statistics of the PK parameters for TAK-788 and its 2 active metabolites, AP32960 and 
AP32914 under fasted conditions. 
–
Cmax.
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TAK-788 (formerly AP32788)
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–
tmax.
–
AUCt.
–
AUC∞.
–
t1/2z.
–
Part 2: safety profile of TAK-788 under fasted conditions or following a low-fat meal. 
–
Part 3: safety profile of TAK-788 under fasted conditions.
!
Exploratory: 
Statistical Considerations:
Pharmacokinetic Analyses
Descriptive statistics, including mean, SD, coefficient of variation (%CV), minimum, median, and maximum, will be 
calculated and presented by dose level in Part 1,for each treatment under fasted versus fed conditions in Part 2, and for 
the test versus reference treatments in Part 3 for plasma concentrations of TAK-788 and its 2 active metabolites.
Analysis of PK parameters will be performed for TAK-788 and its 2 active metabolites. The concentration versus time 
profiles will be analyzed via non-compartmental methods to estimate PK parameters in plasma. Descriptive statistics 
(number of observations, arithmetic mean, geometric mean, SD, %CV, median, minimum, and maximum values) will 
be presented for the PK parameters (Cmax, tmax, AUCt, AUC∞, t1/2z, AUCextrap% (area under the curve from the last 
quantifiable concentration to infinity calculated using the observed value of the last quantifiable concentration, 
expressed as a percentage of AUC∞), CL/F (apparent clearance after extravascular administration, calculated using the 
observed value of the last quantifiable concentration), Vz/F (apparent volume of distribution during the terminal 
disposition phase after extravascular administration, calculated using the observed value of the last quantifiable 
concentration), 
. 
In Part 2, PK parameters (natural log-transformed [ln]) of TAK-788 will be compared under fasted versus fed 
conditions using an analysis of variance (ANOVA) model. The ANOVA model will include fasted versus fed 
condition, period, and sequence as fixed effects and subject nested within sequence as a random effect. Each ANOVA 
will calculate the least-squares mean (LSM), the difference between treatment LSMs, and the SE associated with the 
difference. Residual, subject nested within sequence, and intersubject variance, along with the intrasubject and 
intersubject CV, will be reported. Ratios of LSM will be calculated using the exponential function of the difference 
between treatment LSMs from the analyses on the ln-transformed Cmax, AUCt, and AUC∞.
In Part 3, PK parameters (ln-transformed) of TAK-788 for the test formulation (Process B DiC) and the reference 
formulation (Process A DiC) will be compared using an ANOVA model. The ANOVA model will include treatment 
CCI
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TAK-788 (formerly AP32788)
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(test versus reference), period, and sequence as fixed effects and subject nested within sequence as a random effect. 
Each ANOVA will calculate the LSM, the difference between treatment LSMs, and the SE associated with the 
difference. Residual, subject nested within sequence, and intersubject variance, along with the intrasubject and 
intersubject CV, will be reported. Ratios of LSM will be calculated using the exponential function of the difference 
between treatment LSMs from the analyses on the ln-transformed Cmax, AUCt, and AUC∞(if data permitted).
Safety Analyses
Safety assessments will include AEs, vital signs, ECGs, physical examinations, clinical laboratory tests, PFTs, from 
Parts 1, 2, and 3; and chest CT scan for Parts 1 and 2. The incidence of AEs will be tabulated and reviewed for clinical 
significance. 
Safety and tolerability parameters will be listed by subject, study group, and treatment group, and displayed in 
summary tables using descriptive statistics. All subjects receiving placebo in Part 1 will be pooled and analyzed as one 
placebo group. Original terms used in the electronic case report forms by the investigator or designees to identify AEs 
will be coded using Medical Dictionary for Regulatory Activities (version 20.0 or higher) terminology. 
Sample Size Justification: 

Part 1: The sample size is determined based on clinical rather than statistical considerations. The number of 
subjects in this part of study is consistent with phase 1 dose-finding studies.

Part 2: With a sample size of 14 healthy subjects, the 90% confidence interval for the AUC ratio is expected to be 
in the range of 84% to 119%, using an intrasubject AUC variability of 27% in cancer patients and assuming a 
TAK-788 AUC ratio of 1 in the fed versus fasted comparison. After accounting for 2 potential dropouts in Part 2, 
the final sample size is up to 16 healthy subjects. This sample size assumes no replacement of subjects who may 
drop out of the study before the completing the PK sample collections in Part 2.

Part 3: With a sample size of 10 healthy subjects, the 90% confidence interval for the Cmax ratio is expected to be 
in the range of 87% to 115%, using an intrasubject Cmax variability of 17% estimated in healthy subjects. After 
accounting for 2 potential dropouts in Part 3, the final sample size is up to 12 healthy subjects. This sample size 
assumes no replacement of subjects who may drop out of the study before the completing the PK sample 
collections in Parts 3
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3.0
STUDY REFERENCE INFORMATION
3.1
Study-Related Responsibilities 
The sponsor will perform all study-related activities with the exception of those identified in the 
clinical study supplier list or equivalent. The identified vendors 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 and 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
-hCG
-human chorionic gonadotropin
AE
adverse event
ANOVA
analysis of variance
API
active pharmaceutical ingredient
AUC
area under the plasma concentration-time curve
AUC24
area under the plasma concentration-time curve from time 0 to 24 hours
AUCextrap%
area under the curve from the last quantifiable concentration to infinity calculated using 
the observed value of the last quantifiable concentration, expressed as a percentage of 
AUC∞
AUCt
area under the concentration-time curve from time 0 to time t
AUC∞
area under the concentration-time curve from time 0 to infinity, calculated using the 
observed value of the last quantifiable concentration
Cav
average plasma concentration
CFR
Code of Federal Regulations
Cmax
maximum observed plasma concentration
CNS
central nervous system
CRO
contract research organization
CT
computed tomography
Ctrough
observed plasma concentration at the end of a dosing interval
CV
coefficient of variation
DiC
drug-in-capsule (formulation)
DLco
diffusion capacity
DLT
dose-limiting toxicity
ECG
electrocardiogram
eCRF
electronic case report form
EGFR
epidermal growth factor receptor
FDA
Food and Drug Administration
FIH
first-in-human
GCP
Good Clinical Practice
GI
gastrointestinal
GLP
Good Laboratory Practice
HBV
hepatitis B virus
HCV
hepatitis C virus
HER2
human epidermal growth factor 2
IB
investigator’s brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IRB
institutional review board
IV
intravenous
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TAK-788 (formerly AP32788)
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ln
natural log-transformed
LSM
least-squares mean
MedDRA
Medical Dictionary for Regulatory Activities
MTD
maximum tolerated dose
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NSCLC
non–small-cell lung cancer
NOAEL
no-observed-adverse-effect level
OTC
over-the-counter
PFT
pulmonary function test
PK
pharmacokinetic(s)
PO
per os (oral)
PTE
pretreatment event
QD
quaque die (once daily)
RP2D
recommended phase 2 dose
SAE
serious adverse event
SOP
standard operating procedure
SUSAR
suspected unexpected serious adverse reaction
t1/2z
terminal disposition phase half-life
TEAE
treatment-emergent adverse event
TKI
tyrosine kinase inhibitor
tmax
time to first occurrence of Cmax
UK
United Kingdom
US
United States
WHO
World Health Organization
WT
wild type
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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TAK-788 (formerly AP32788)
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4.0
INTRODUCTION
4.1
Scientific Background
Specific genetic lesions that drive the proliferation of cancer cells, such as those resulting in 
activation of certain tyrosine kinases, render many cancers highly sensitive to therapeutic agents 
that inhibit the affected kinase (eg, tyrosine kinase inhibitors [TKIs]). These include activating 
mutations in the epidermal growth factor receptor (EGFR), which have been identified in 21% to 
40% of patients with non–small-cell lung cancer (NSCLC) [1,2]. There are multiple classes of 
activating mutations in EGFR that vary widely in their degree of sensitivity to available TKIs. 
Because inhibition of wild-type (WT) EGFR in normal tissues is associated with dose limiting 
toxicities (DLTs), substantial clinical benefit has generally been associated with TKIs that inhibit 
specific, activated variants of EGFR more potently than they inhibit WT EGFR.
The most common activating mutations in EGFR are in-frame deletions in exon 19 and a 
Leu858Arg (L858R) substitution in exon 21, together accounting for approximately 90% of all 
EGFR activating mutations [3]. Erlotinib and gefitinib (“first generation” EGFR TKIs), and 
afatinib (a second-generation EGFR TKI), potently inhibit these mutants in vitro and induce high 
response rates of approximately 60% to 70% in patients with these mutations [4]. Although these 
TKIs are approved for use in patients with these specific mutations, their clinical efficacy is 
ultimately limited by the development of resistance, such as by mutation of the EGFR kinase 
domain gatekeeper residue (T790M), which occurs in 50% of patients [5,6]. Recently, osimertinib 
was approved for treatment of patients with metastatic EGFR T790M mutation-positive NSCLC, 
whose disease has progressed on or after EGFR TKI therapy. 
For erlotinib and gefitinib, high response rates have largely been restricted to patients with the 
most common activating mutants; however, preliminary results with afatinib suggest that 
relatively high response rates are also achieved in patients with a second class of activating 
mutants, so-called “uncommon” mutants, such as those occurring at other amino acids in 
exons 19 and 21 (eg, G719 and L861) [7]. 
The final class of EGFR activating mutations, known as exon 20 insertions, accounts for 
approximately 9% of EGFR mutant NSCLC [8]. Unlike mutations in exons 19 or 21, almost all 
EGFR exon 20 insertions confer in vitro and primary clinical resistance to the 3 approved EGFR 
TKIs [7,9,10]. Patients with NSCLC containing EGFR exon 20 insertions exhibit clinical 
characteristics similar to those carrying common EGFR mutations [11] (eg, young, nonsmoker, 
with adenocarcinoma subtype), consistent with potential roles as driver mutations that could 
confer benefit to targeted therapy. In summary, while erlotinib, gefitinib, and afatinib are approved 
for use in NSCLC patients with common activating mutations in EGFR (ie, exon 19 deletions and 
L858R substitutions), no therapies are approved for patients with EGFR exon 20 insertions. 
Human epidermal growth factor 2 (HER2) mutations, typically consisting of in-frame insertions in 
exon 20, have also been identified as potential oncogenic drivers in 2% to 4% of patients with 
NSCLC. These patients exhibit clinical characteristics similar to patients with EGFR mutations 
[12-14]. Currently, no therapies are approved for use in NSCLC patients with HER2 activating 
mutations.
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TAK-788 is an orally administered small molecule TKI and was specifically designed to address 
the unmet medical need in the subset of NSCLC patients for whom no target therapy is available. 
This patient population includes, but is not limited to, patients whose tumors harbor EGFR exon 
20 insertion mutations, HER2 exon 20 insertion mutations. In nonclinical studies, TAK-788 
potently inhibited all activated forms of EGFR tested, including those containing exon 20 
activating insertions, other uncommon activating mutations, and the common activating mutations 
(exon 19 deletions and L858R) with or without the T790M resistance mutation. TAK-788 also 
potently inhibits HER2 activated by exon 20 insertions and point mutations, and by amplification. 
TAK-788 inhibits all of these variants more potently than it inhibits WT EGFR, suggesting it may 
have the selectivity necessary to achieve levels of exposure required to inhibit all activated forms 
of these kinases [8,9,11-14]. A first-in-human (FIH) phase 1/2 study of TAK-788 
(AP32788-15-101) is ongoing with the main objectives of determining the safety profile, 
identifying recommended phase 2 dose (RP2D) and dose-limiting toxicities (DLTs) of TAK-788, 
characterizing the pharmacokinetic (PK) of TAK-788, and evaluating the antitumor activity of 
TAK-788 in NSCLC patients with EGFR or HER2 mutations. 
4.2
Nonclinical Experience
Refer to the IB. 
4.3
Clinical Experience
An FIH phase 1/2 study in patients with NSCLC (AP32788-15-101) is ongoing. As of the 
08 September 2017 data cut-off, a total of 34 patients have been treated with 6 different once-daily 
(QD) doses evaluated. Two DLTs were observed and reported in the current dose escalation 
cohorts, 1 each at 80 mg (Grade 3 pneumonitis) and 120 mg (Grade 5 pneumonitis). Of the 
33 patients included in the clinical database reports, 21 patients (63.6%) had EGFR exon 20 
insertion mutations, and 4 patients (12.1%) had HER2 exon 20 insertions or point mutations. 
Preliminary PK data suggest that TAK-788 was absorbed into systemic circulation with tmax
(median time to first occurrence of the maximum observed plasma concentration [Cmax]) ranging 
from 4-6 hours following oral (PO) administration of repeated daily doses of TAK-788. The 
steady-state PK of TAK-788 was achieved within 1 week of TAK-788 treatment. Steady-state area 
under the plasma concentration-time curve (AUC) from time 0 to 24 hours (AUC24) of TAK-788 
increased in approximately dose-proportionally at doses ranging from 5-180 mg. Administration 
of TAK-788 PO QD resulted in approximately 50% accumulation in AUC24. The effective 
half-life based on accumulation was approximately 16 hours (range, 6-28 hours). 
The clinical safety data available indicated no particular safety findings that are unique compared 
with other EGFR TKIs. Diarrhea (33.3%) was the most common treatment-related adverse event 
(AE) and was the only Medical Dictionary for Regulatory Activities (MedDRA) Preferred Term 
occurring in ≥20% of patients treated with TAK-788. Rash, which is commonly observed with 
other EGFR TKIs, was also observed with TAK-788 (12.1% of all patients).
Preliminary efficacy data showed 2 confirmed PRs and 1 PR awaiting confirmation in a total of 
8 patients who had at least 1 disease assessment following treatment with TAK 788 at 80 mg QD 
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and 120 mg QD, respectively. All patients who responded to treatment with TAK-788 had EGFR 
exon 20 insertion mutations.
In mid-January 2018, 160 mg QD was identified as the maximum tolerated dose (MTD) and was 
the RP2D for the phase 2 expansion cohorts which include 4 histologically and molecularly 
defined cohorts targeting patients with NSCLC containing: (1) EGFR exon 20 insertions without 
active, measurable central nervous system (CNS) metastases, (2) HER2 exon 20 insertions or point 
mutations without active, measurable CNS metastases, (3) EGFR exon 20 insertions or HER2 
exon 20 insertions or point mutations with active, measurable CNS metastases, and (4) other 
targets against which TAK-788 is active, with or without CNS metastases. 
In summary, TAK-788 was generally well-tolerated, and preliminary anticancer activity was 
observed in EGFR exon 20 insertion-positive NSCLC patients who had been previously treated. 
4.4
Rationale for the Proposed Study
This study is proposed to characterize safety and tolerability of a single oral dose of TAK-788, to 
identify a safe and tolerable dose of TAK-788 administered as a drug-in-capsule (DiC) 
formulation in healthy subjects, to evaluate the effects of a low-fat meal on the PK of TAK-788 
and its active metabolites AP32960 and AP32916, and to assess the relative bioavailability of 
2 DiCs of TAK-788. Part 1 of the study will use a randomized, double-blind, placebo-controlled, 
single rising dose escalation design to determine the safety and tolerability of TAK-788 and 
characterize the PK of TAK-788 and its active metabolites, and to identify a tolerable single dose 
in healthy subjects. Part 2 of the study will assess the effects of a low-fat meal on the PK of 
TAK-788 administered as a DiC formulation. Part 3 of the study will evaluate the relative 
bioavailability of a single dose of TAK-788 160 mg Process B DiC (test) versus a single dose of 
TAK-788 160 mg Process A DiC (reference).
4.4.1
Risk-Benefit Assessment
The available information suggests that the present clinical study has an acceptable benefit-risk 
profile. 
The inclusion and exclusion criteria and safety monitoring practices employed by this protocol are 
adequate to protect the subjects’ safety and should detect all expected treatment-emergent adverse 
events (TEAEs).
There will be no direct health benefit for trial participants from receipt of study drug. An indirect 
health benefit to the subjects enrolled in this trial is the free medical tests received at screening and 
during the study.
4.4.2
Rationale for Single Dose Escalation (Part 1)
This is the first single-dose experience with TAK-788 in healthy subjects. In this double-blind, 
randomized, placebo-controlled study, the safety, tolerability, and PK of TAK-788 and its 2 active 
metabolites, AP32940 and AP32916, will be evaluated. Additionally, a tolerable single dose will 
be identified for future clinical pharmacology studies in healthy subjects.
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The starting dose of 20 mg for healthy subjects is based on clinical safety/tolerability data from 
phase 1 study (AP32788-15-101) in cancer patients and is supported by nonclinical safety data. 
The phase 1 clinical study (AP32788-15-101) investigating the safety and PK of repeated doses of 
TAK-788 in patients with NSCLC started at 5 mg QD. At the time of first data cut-off in 
September 2017, the 120-mg QD dose was being tested. No Grade ≥2 treatment-related AEs were 
reported within 3 days of the repeated treatment in any patient. 
In a 28-day Good Laboratory Practice (GLP)-compliant repeat-dose study in dogs (Report 
WIL-69513), a single dose of 1 mg/kg is considered to be the no-observed-adverse-effect level 
(NOAEL). The Cav (mean total average plasma concentration) of TAK-788 and its metabolites 
was 44.7 nM, which was ~4 fold the mean total Cav (12.6 nM) following a single dose 20 mg 
TAK-788 in cancer patients (data on file). Additionally, there were no TAK-788–related effects on 
the cardiovascular, respiratory and CNS (on the basis of monitoring in repeat-dose GLP toxicity 
studies), TAK-788 was neither a potent hERG inhibitor, and TAK-788 was neither mutagenic nor 
clastogenic in GLP-compliant bacterial reverse mutation assays (Report 9601435) and in in vitro
mammalian chromosome aberration assays (Report 9601436). Therefore, the nonclinical safety 
data supports a single clinical starting dose of 20 mg. 
The starting dose of TAK-788 in this study will be a single dose of 20 mg and the dose escalation 
steps will be similar to those in study AP32788-15-101. The highest dose tested in the dose 
escalation phase will not exceed the unit dose of MTD identified in Study AP32788-15-101.
The aim of Part 1 of this protocol is to determine the single-dose safety and tolerability of 
TAK-788 administered as DiC in healthy subjects. The dose in Part 1 of this study may be 
escalated up to 160 mg. The dose escalation decisions in Part 1 of the study will be guided by 
safety/tolerability data in previous cohorts as outlined in Section 8.3.
4.4.3
Rationale for Food Interaction (Part 2)
Typically, a clinical study in healthy subjects may provide a more accurate estimate of food effect 
on drug PK than a study in patients. 
Information on the effects of food ingestion on TAK-788 PK will provide meal intake instructions 
when TAK-788 is administered to patients in future clinical studies. Food can affect oral
bioavailability via various mechanisms, including altering gastric emptying rate, stimulating bile 
flow, altering gastrointestinal (GI) pH, increasing splanchnic blood flow, changing the luminal
metabolism of drug substances, and physically or chemically interacting with drug substance or 
dosage form.
Food interaction is generally greatest when drug is administered shortly after food has been
ingested. In addition, the nutritional and caloric content of food, volume of food, and temperature
may also play a role in food-drug interactions and it is generally accepted that food that is high in 
calories and fat represents a worst-case scenario for this assessment. However, several recently 
approved oral EGFR TKIs and ALK+ inhibitors were also studied with a standard meal or a 
low-fat and low-calorie meal for patients with cancer who are receiving routine oral
administration of these drugs [15,16]. If possible, food effects assessments are preferably 
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conducted on the to-be-marketed formulation of a drug to avoid having to reassess food-drug 
interactions because of formulation changes. However, timely evaluation of food-drug interactions 
will provide important information on dosing conditions in future clinical trials. 
In vitro, neither high-fat nor low-fat meals appear to increase or decrease TAK-788 absorption in a 
perfusion chamber study at 2 relevant clinical doses of 120 and 180 mg (data on file). Therefore, a 
low-fat meal is not expected to increase bioavailability. 
Because TAK-788 is a Biopharmaceutics Classification System class 2 compound, there is a 
possibility that the magnitude of the food effect can be dose-dependent. Accordingly, it is 
important to conduct the food effect evaluation at or near the unit dose of the RP2D regimen. The 
dose used in the food effect study will be the unit doses determined in Part 1 of this study in 
healthy subjects to be safe and tolerable. 
Since the DiC formulation will be used in the planned phase 2 pivotal clinical study, this portion of 
the study will be conducted with DiC of TAK-788. This part of the study will evaluate the effects
of low-fat and low-calorie meal on the PK of TAK-788 administered as DiC. 
4.4.4
Rationale for Relative Bioavailability Assessment (Part 3)
Process A and Process B TAK-788 drug substance (succinate salt) are chemically identical but are 
synthesized by different synthetic routes. The physiochemical properties of Process A and Process 
B TAK-788 drug substance are, however, different. The API powder prepared via Process B has 
larger primary particles, lower specific surface area, and a higher bulk density than the API powder 
prepared via Process A. The rationale for Part 3 of the study is to perform relative bioavailability 
assessment of Process B versus Process A DiC to enable PK bridging across the patients who are 
using or will be using these 2 DiCs in the TAK-788 clinical development program.
 
CCI
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objectives
The primary objectives are: 
Part 1: To assess safety and tolerability of TAK-788 and to identify a tolerable single oral dose of
TAK-788 administered as a drug-in-capsule (DiC) formulation in healthy subjects. 
Part 2: To characterize the effect of a low-fat meal on the PK of TAK-788 administered as a DiC 
formulation in healthy subjects.
Part 3: To evaluate the bioavailability of a test (Process B) DiC of TAK-788 relative to a 
reference (Process A) DiC of TAK-788 in healthy subjects.
5.1.2
Secondary Objectives
The secondary objectives are: 
Part 1: To characterize the PK of TAK-788 and its active metabolites, AP32960 and AP32914, 
administered as a DiC formulation in healthy subjects. 
Part 2/ Part 3: To assess the safety of TAK-788 following a single dose of TAK-788 in healthy 
subjects.
5.1.3
Exploratory Objectives
The exploratory objective is: 
5.2
Endpoints
5.2.1
Primary Endpoints
The primary endpoints are: 
Part 1: safety profile of orally administered TAK-788. 
!
number and percentage of subjects with 1 or more AEs.
!
number and percentage of subjects with 1 or more SAEs.
!
number and percentage of subjects with clinically defined abnormal laboratory values.
!
number and percentage of subjects with clinically defined abnormal vital signs.
CCI
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Part 2: summary statistics of the PK parameters for TAK-788 under fasted conditions or following 
a low-fat meal.
!
Cmax.
!
tmax.
!
AUCt (area under the concentration-time curve from time 0 to time t).
!
AUC∞(area under the first moment concentration-time curve from time 0 to infinity calculated 
using the last quantifiable concentration.
!
t1/2z (terminal disposition phase half-life).
Part 3: summary statistics of the PK parameters for TAK-788 with different DiC under fasted 
conditions. 
!
Cmax.
!
tmax.
!
AUCt.
!
AUC∞(if data permitted).
!
t1/2z.
5.2.2
Secondary Endpoints
The secondary endpoints are: 
Part 1: summary statistics of the PK parameters for TAK-788 and its 2 active metabolites,
AP32960 and AP32914 under fasted conditions. 
!
Cmax.
!
tmax.
!
AUCt.
!
AUC∞.
!
t1/2z.
Part 2: safety profile of TAK-788 under fasted conditions or following a low-fat meal.
Part 3: safety profile of TAK-788 under fasted conditions.
5.2.3
Exploratory Endpoints
The exploratory endpoint is: 
CCI
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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6.0
STUDY DESIGN
This is a randomized, double-blind, placebo-controlled single rising dose study, followed by an 
open-label, crossover evaluation of the effects of a low-fat meal on the PK of TAK-788 and its 
2 active metabolites in healthy subjects, and a crossover evaluation of the relative bioavailability 
of TAK-788 Process B DiC (test) versus Process A DiC (reference) in healthy subjects under 
fasting conditions. Following the completion of Part 1 (dose escalation phase) where a safe and 
tolerable dose in healthy subjects will be identified, Part 2 (food effect phase) and Part 3 (relative 
bioavailability of TAK-788 capsules) will be initiated where the effects of a low-fat meal on 
TAK-788 and the relative bioavailability of TAK-788 in test versus reference will be studied.
6.1
Overview of Study Design
6.1.1
Part 1 – Dose Escalation
The purpose of Part 1 of the study is to assess the safety and tolerability of TAK-788 and to 
identify a tolerable single dose. A single dose escalation design will be used, as detailed in 
Section 8.3. 
In the double-blind, randomized, placebo-controlled dose escalation phase, cohorts of 8 healthy 
subjects will be randomized: Under fasting conditions, 6 subjects will receive a single dose of 
TAK-788 and 2 subjects will receive placebo. The starting dose will be 20 mg, then with each 
subsequent 8-subject cohort the dose will escalate to a single dose of 40, 80, 120, up to 160 mg. 
Dose escalation can occur if there are no DLTs following the administration of TAK-788 and all 
Grade ≥2 treatment-related AEs resolve to Grade ≤1 or return to baseline by Day 5. If all 
treatment-related Grade ≥2 AEs have not resolved to Grade ≤1 or returned to baseline by Day 5, 
the assessment will be repeated on Day 8 and Day 15, if necessary, before proceeding to the next 
planned higher dose. The subjects will remain at the clinical study site for at least 48 hours 
postdose for close safety monitoring. The subjects will be furloughed from the site 48 hours 
postdose if there are no Grade ≥2 AEs. Subjects will return to the site for PK sample collection on 
Days 4, 5, and 8. A final safety phone conference will occur 30 days after the last dose (window of 
up to 2 days after Day 30). 
Additional cohorts may also be enrolled in Part 1 to assess the safety, tolerability, and PK of 
single-dose TAK-788 DiC containing TAK-788 active pharmaceutical ingredient (API) from a 
different synthetic process (such as Process A). The dose(s) of TAK-788 in the additional
cohort(s) will be determined by the safety, tolerability, and PK exposure data from the completed 
cohorts in this study and the experience in the ongoing phase 1/2 study in patients with NSCLC 
(Study AP32788-15-101). The highest dose tested in Part 1 of the study will not exceed the unit 
dose of the MTD identified in Study AP32788-15-101.
To mitigate the risk of treatment, pulmonary function tests (PFTs: spirometry, lung volumes, and 
diffusion capacity [DLco]) and chest computed tomography (CT) scan are required to be 
performed and assessed to be normal (PFTs ≥80% of predicted normal) at screening no more than 
7 days before Day 1. At 48 hours postdose before furlough, PFTs will be performed and 
pulmonary symptoms assessed. If the DLco has decreased by >20% from baseline or the subject 
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reports pulmonary symptoms on Day 3, a chest CT scan will be performed. Any DLco 
abnormalities or chest CT scan abnormalities will be followed weekly until resolution. An 
appropriate treatment will be initiated by the investigator or attending pulmonologist in the event 
of clinically significant pulmonary symptoms, abnormal DLco, or abnormal chest CT scan.
Figure 6.a
Dose Escalation Schema (Part 1)
Abbreviations: DiC, drug-in-capsule. 
6.1.2
Part 2 – Food Effect
The purpose of Part 2 is to evaluate the effect of a low-fat meal on TAK-788 PK using a 2-way 
crossover design. The dose used will be a tolerable single dose identified in Part 1. 
In the food effects part of the study, subjects will be randomized to a crossover sequence at a 
1:1 ratio and administered the tolerable single dose on Day 1 in Period 1 and Day 8 in Period 2 
with a low-fat meal (Treatment A) or under fasting conditions (Treatment B) with a planned 
washout period of at least 7 days which may be updated pending the PK results from Part 1. The 
content of a low-fat meal is shown in Table 8.a. The duration of washout will be adjusted to ensure 
that the Ctrough (observed plasma trough concentration) of TAK-788 at 168 hours postdose in Part 1 
is <5% of the observed Cmax of TAK-788 at the dose of the food effect evaluation. The planned 
washout period used in Part 2 is 7 days. PFTs (spirometry, lung volumes, and DLco) and chest CT 
scan are required to be performed and be assessed as normal at screening. PFTs and chest CT scan 
will be done on Day 3, Day 10, and/or Early Termination visit in Part 2 only if indicated on the 
basis of pulmonary symptoms. Other clinical study procedures are the same as those in the dose 
escalation phase. Subjects will return to the site for the PK sample collection on Days 4, 5, 8, 11, 
12, and 15. A final safety phone conference will occur 30 days after the last dose (window of up to 
2 days after Day 38). 
Cohort 4, 120 mg
n=8 (6 active, 2 placebo)
Cohort 1, 20 mg
n=8 (6 active, 2 placebo)
Cohort 2, 40 mg
n=8 (6 active, 2 placebo)
Cohort 3, 80 mg
n=8 (6 active, 2 placebo)
Cohort 5, 160 mg
n=8 (6 active, 2 placebo)
Food effect with DiC (Part 2)
n= up to 16 crossover
Bioavailability DiC (Part 3)
n= up to 12 crossover
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Figure 6.b
Food Effect Schema (Part 2)
6.1.3
Part 3 – Relative Bioavailability
The purpose of Part 3 is to evaluate the bioavailability of a test DiC of TAK-788 relative to a 
reference DiC of TAK-788. Part 3 of the study will be open-label. 
Subjects will be randomly assigned to a crossover sequence at a 1:1 ratio and administered a single 
dose of 160 mg TAK-788 capsule A DiC (reference) or 160 mg TAK-788 capsule B DiC (test) on 
Day 1 in Period 1 and on Day 8 in Period 2 under fasting conditions, with a planned washout 
period of 7 days. PFTs (spirometry, lung volumes, and DLco) are required to be performed and 
assessed as normal at screening. PFTs will be performed on Day 3, Day 10, and Early Termination 
visit in Part 3 only if indicated on the basis of pulmonary symptoms; no chest CT scans will be 
done. Other clinical study procedures are the same as those in the dose escalation phase. Subjects 
will have PK collection samples collected during confinement, and the last PK sample will be 
collected at 72 hours postdose in each period. Subjects will be furloughed after the last PK sample 
collection in Period 1. Subjects will return to the clinical study site on Day 7 for Period 2 study. 
Subjects will be released from the clinical study site after the last PK sample collection in Period 2. 
Safety phone conferences will occur on Day 15 and 30 days after the last dose (window of up to 2 
days after Day 38).
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Figure 6.c
Relative Bioavailability Schema (Part 3)
6.2
Number of Subjects
Part 1: The estimated sample size of approximately 56 subjects is determined on the basis of 
clinical rather than statistical considerations. The number of subjects in this part of study is 
consistent with phase 1 dose-finding studies. 
Part 2: With a sample size of 14 healthy subjects, the 90% CI for the AUC ratio is expected to be in 
the range of 84% to 119%, using an intrasubject AUC variability of 27% in patients with cancer 
and assuming a TAK-788 AUC ratio of 1 in the fed versus fasted comparison. After accounting for 
2 potential dropouts in Part 2, the final sample size is up to 16 healthy subjects. Subjects who vomit 
within 8 hours after dosing will be considered nonevaluable for PK assessments. Subjects who are 
withdrawn from treatment before completing study-required PK assessments and subjects who are 
not non–PK-evaluable will not be replaced. 
Part 3: With a sample size of 10 healthy subjects, the 90% CI for the Cmax ratio is expected to be in 
the range of 87% to 115%, using an intrasubject Cmax variability of 17% estimated in healthy 
subjects. After accounting for 2 potential dropouts in Part 3, the final sample size is up to 
12 healthy subjects. This sample size assumes no replacement of subjects who may drop out of the 
study before the completing the PK sample collections in Part 3. 
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6.3
Duration of Study
6.3.1
Duration of an Individual Subject’s Study Participation
Subjects in the single rising dose part of the study (Part 1) will be treated for 1 day (single dose). 
Subjects in the food-effect part of the study (Part 2) and the relative bioavailability part of the 
study (Part 3) will receive 2 single doses separated by a ≥7-day washout. 
Subjects will be followed for 30 days (window of up to 2 days after the Day 30 [Part 1] or Day 38 
[Parts 2 and 3] visits) after the last dose of TAK-788. For Part 3, safety phone conferences will 
occur on Day 15 and 30 days after the last dose (window of up to 2 days after Day 38).
6.3.2
End of Study/Study Completion Definition and Planned Reporting
6.3.2.1
Definition of Trial Discontinuation
The trial may be discontinued for nonsafety reasons, such as:

A finding (eg, PK, pharmacodynamic, efficacy, biologic targets) from another nonclinical or 
clinical trial using the trial treatment(s) results in the trial being stopped for a non–
safety-related reason.

Data from comparator(s), drug(s) of the same class, or methodology(ies) used in this trial 
become available and results in the trial being stopped for a non–safety-related reason.

The trial is stopped because of nonscientific and nonsafety reasons, such as slow enrollment.
The trial may be discontinued for safety reasons:

Early trial termination because of unanticipated concerns of safety to the trial subjects arising 
from nonclinical studies or clinical trials with the trial treatment(s), drug(s) of the same class, 
or methodology(ies) used in this trial.
6.3.2.2
Criteria for Premature Termination or Suspension of Trial Sites
A trial site may be terminated prematurely or suspended if the site (including the investigator) is 
found in significant violation of GCP, protocol, or contractual agreement, is unable to ensure 
adequate performance of the trial, or as otherwise permitted by the contractual agreement. 
6.3.2.3
Procedures for Premature Termination or Suspension of the Trial or the Participation of 
Trial Site
If the sponsor, an institutional review board (IRB), or regulatory authority elects to terminate or 
suspend the trial or the participation of an investigational site, a trial-specific procedure for early 
termination or suspension will be provided by the sponsor; the procedure will be followed by 
applicable investigational sites during the course of termination or trial suspension.
6.3.3
Time Frames for Primary and Secondary Endpoints to Support Disclosures
Please refer to Table 6.a for disclosures information for all primary and secondary endpoints. 
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Table 6.a
Primary and Secondary Endpoints for Disclosures
Endpoint
Maximum Time Frame
Primary
Part 1: safety profile of orally administered TAK-788.

Number and percentage of subjects with 1 or more adverse events.

Number and percentage of subjects with 1 or more serious adverse events.

Number and percentage of subjects with clinically defined abnormal laboratory 
values.

Number and percentage of subjects with clinically defined abnormal vital signs. 
Up to 30 days after last dose
Part 2: summary statistics of the PK parameters for TAK-788 under fasted 
conditions or following a low-fat meal.

Cmax.

tmax.

AUCt.

AUC∞.

t1/2z.
Up to 7 days following each 
dose
Part 3: summary statistics of the PK parameters for TAK-788 with different DiC 
under fasted conditions.

Cmax.

tmax.

AUCt.

AUC∞(if data permitted).

t1/2z.
Up to 7 days following each 
dose
Secondary
Part 1: summary statistics of the PK parameters for TAK-788 and its 2 active 
metabolites, AP32960 and AP32914 under fasted conditions.

Cmax.

tmax.

AUCt.

AUC∞.

t1/2z.
Up to 7 days
Part 2: assess the safety profile of TAK-788 under fasted conditions or following a 
low-fat meal.
Up to 30 days after last dose
Part 3: assess the safety profile of TAK-788 under fasted.
Up to 30 days after last dose
Footnotes are on last table page.
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Table 6.a
Primary and Secondary Endpoints for Disclosures (continued)
Endpoint
Maximum Time Frame
Exploratory
AUC#, area under the concentration-time curve from time 0 to infinity, calculated using the observed value of the last 
quantifiable concentration; AUCt, area under the concentration-time curve from time 0 to time t; Cmax, maximum 
observed plasma concentration; PK, pharmacokinetic; t1/2z, terminal disposition phase half-life; tmax, time to first 
occurrence of Cmax. 
6.3.4
Total Study Duration
It is anticipated that this study will last for approximately 10 months.
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Property of Takeda: For non-commercial use 
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7.0
STUDY POPULATION
Healthy subjects who meet all of the inclusion criteria and none of the exclusion criteria will be 
enrolled in this study.
7.1
Inclusion Criteria
Each subject must meet all the following inclusion criteria to be enrolled in the study. 
1. Aged 18-55 years at the time of informed consent. 
2. Healthy subjects defined as the absence of acute or chronic clinically significant deviations 
from normal in medical history, physical examination, electrocardiogram (ECG), and clinical 
laboratory determinations at screening. 
3. Body weight of ≥45 kg (women) or ≥55 kg (men) and a body mass index of 18.0-30.0 kg/m2 at 
screening. 
4. Normal baseline PFTs (≥80% of predicted normal for spirometry, lung volumes, and DLco) 
Parts 1, 2, and 3; and chest CT scan at screening for Parts 1 and 2. 
5. Nonsmoker (never smoked or >20 years from last occurrence of smoking). 
6. Normal organ function including hepatic, renal, and bone marrow function. 
7. Agree to practice effective contraception (see Section 8.7 for details). 
8. 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 subject at any time without prejudice to future medical care.
9. The subject must be able to understand the requirements of the study and be willing to comply 
with the study requirements and provide their written informed consent to participate in the 
study. 
7.2
Exclusion Criteria
Subjects meeting any of the following exclusion criteria are not to be enrolled in the study.

Medical History and Concurrent Diseases
1. Ongoing or prior pulmonary disease including asthma, chronic obstructive pulmonary disease, 
interstitial lung disease, and pneumonitis including but not limited to drug-related 
pneumonitis. 
2. Any history of cardiovascular disease including a history of congenital prolonged QT 
syndrome or unexplained cardiac arrest.
3. Manifestations of malabsorption due to prior GI surgery, GI disease, or for an unknown other 
reason that may alter the PK of TAK-788.
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4. Pulmonary infection ongoing or within 30 days of informed consent.
5. Current or recent (within 3 months) GI disease.
6. Any major surgery within 4 weeks before study drug administration.
7. Blood transfusion within 4 weeks before study drug administration. 
8. History of bleeding disorder.
9. Inability to tolerate oral medication. 
10. Inability to undergo venipuncture and/or tolerate venous access. 
11. Inability to tolerate multiple blood sampling. 
12. Ongoing or active infection, including but not limited to, the requirement for intravenous (IV) 
antibiotics. 
13. Positive serology or a known history of hepatitis B virus (HBV), hepatitis C virus (HCV), or 
HIV. 
14. Pregnancy or breastfeeding (see Section 8.7 for details). 

Physical and Laboratory Test Findings
15. Any clinically significant abnormality at screening of cardiac, hepatic, renal, respiratory, GI, 
endocrine, immunologic, dermatologic, hematologic, neurologic, or psychiatric disease.
16. Resting blood pressure >140/90 mmHg at screening (a single repeat measurement is allowed if 
the initial measurement is outside these limits).
17. Resting pulse rate <45 beats per minute.

Allergies and Adverse Drug Reactions
18. History of severe allergy/hypersensitivity reaction or ongoing allergy/hypersensitivity 
reaction, as judged by the investigator, or history of hypersensitivity to EGFR/HER2 
inhibitors.

Prohibited Treatments and Therapies 
19. Prior exposure to TAK-788.
20. Exposure to any small molecule drug treatment, including investigational small molecule 
drugs, within 4 weeks or biologic drug treatment, including investigational biologics, within 
16 weeks before study drug administration. 
21. Use of any prescription or over-the-counter (OTC) stomach acid controllers within 2 weeks 
before study drug administration.
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22. Use of any other drugs, including OTC medications, nutritional supplements, or herbal 
preparations (including St. John’s wort) within 1 week before study drug administration 
(except occasional use of acetaminophen and ibuprofen, which are allowed up to 24 hours 
before dosing). 
23. Consumption of any food or beverages containing grapefruit, Seville oranges, blood oranges, 
or pomegranates within 1 week before study drug administration.
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8.0
STUDY DRUG
8.1
Study Drug Administration
8.1.1
Dose Escalation Phase (Part 1)
TAK-788 will be supplied as 20-mg and/or 40-mg capsules (DiC), if the 40-mg capsules are 
available at the time of the study. 
In each cohort of 8 subjects, 6 subjects will receive a single dose of TAK-788 and 2 subjects will 
receive a single dose of placebo during the dose escalation phase (Part 1) under fasting conditions 
(see Section 8.1.2). TAK-788 dosing will begin at 20 mg (Cohort 1) and escalate to 40 mg 
(Cohort 2), 80 mg (Cohort 3), 120 mg (Cohort 4), up to 160 mg (Cohort 5). 
All protocol-specific criteria for administering study drug must be met and documented before 
drug administration. Study drug will be administered only to eligible subjects under the 
supervision of the investigator or identified subinvestigator(s). The investigator(s) will remain 
blinded to the treatment in Part 1. 
Subjects in Part 1 will receive a single dose of TAK-788 on Day 1 following an overnight fast 
(nothing to eat for at least 10 hours before and 4 hours after the TAK-788 dose). The drug product 
should be administered with 240 mL (8 fluid ounces) of water. No food should be allowed for at 
least 4 hours postdose.
Water can be allowed as desired except for 1 hour before and after drug administration. Subjects 
should receive standardized meals scheduled at the same time in each period of the study.
Before each dose escalation in Part 1, the investigator and sponsor will review the safety data from 
the previous dose cohort and will consider new safety data from nonclinical sources and the 
ongoing study in patients with NSCLC (AP32788-15-101). 
8.1.2
Food Effects Study Phase (Part 2)
Before starting Part 2, the sponsor will evaluate the safety and tolerability of the dose identified in 
Part 1 and will include all available data, nonclinical and clinical, from both healthy subjects and 
patients in the ongoing clinical trial. 
Subjects in Part 2 will receive a single dose of TAK-788 DiC formulation identified in Part 1 on 
Day 1, with or without a low-fat meal, followed by administration under the alternate treatment 
condition (fastedfed or fedfasted) on Day 8 (at least 7 days apart). 
For fasted treatment: 

Following an overnight fast of at least 10 hours, subjects should be administered the drug 
product with 240 mL (8 fluid ounces) of water. 

No food should be allowed for at least 4 hours postdose. 
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
Water can be allowed as desired except for 1 hour before and after drug administration. 
Subjects should receive standardized meals scheduled at the same time in each period of the 
study.
For fed treatment:

Following an overnight fast of at least 10 hours, subjects should start the recommended low-fat 
meal 30 minutes before administration of the drug product. 

Study subjects should eat this meal in 30 minutes or less; however, the drug product should be 
administered 30 minutes after the start of the meal. 

The drug product should be administered with 240 mL (8 fluid ounces) of water. No food 
should be allowed for at least 4 hours postdose. 

Water can be allowed as desired except for 1 hour before and after drug administration. 
Subjects should receive standardized meals scheduled at the same time in each period of the 
study.
The standard low-fat meal will be provided and served in the clinic by site personnel before dosing 
on Day 1 or Day 8 (or extended if the Ctrough/Cmax ratio is >5% at the same dose from Part 1). This 
meal will have the approximate composition described in Table 8.a. 
Table 8.a
Low-fat Meal Content
Food Item
Calories (kcal) (a)
Fat (a)
Carbohydrates (a)
Protein (a)
2 Slices of white bread, 
toasted
129
1.8 g
24.0 g
4.0 g
1 Teaspoon low-fat 
margarine
24
2.8 g
trace
Trace
1 Tablespoon jam
56
0.3 g
13.8 g
Trace
5 Ounces of apple juice 
73
0.2 g
18.1 g
0.1 g
Total grams 
—
5.1 g
63.3 g
9.3 g
Total calories (kcal)
336
46
253
37
% Of total calories 
100
14
75
11
(a) Source; US Department of Agriculture Nutrient Database for Standard Reference, Release 18 (August 2005). 
8.1.3
Relative Bioavailability (Part 3)
Subjects in Part 3 will receive a single dose of TAK-788 160 mg test DiC (Process B) or a single 
dose of TAK-788 160 mg reference DiC (Process A) under fasted conditions on Day 1 or Day 8 
following an overnight fast of at least 10 hours. The drug product should be administered with 
240 mL (8 fluid ounces) of water. No food should be allowed for at least 4 hours postdose.
Water can be allowed as desired except for 1 hour before and after drug administration. Subjects 
should receive standardized meals scheduled at the same time in each period of the study.
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8.2
Definitions of DLT
DLTs will be summarized by category (hematologic and nonhematologic) and by MedDRA 
preferred term. Toxicity grade will be evaluated according to the National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE), version 5.0 [17]. These criteria 
are provided in the study manual. A DLT is any Grade ≥3 nonhematologic toxicity, hematologic 
toxicity, or laboratory abnormality that occurred within 5 days following the administration of 
study drug and is considered by the investigator to be at least possibly related to therapy with 
TAK-788. 
8.3
Dose Escalation Rules
For each cohort, the investigator and sponsor will confirm the safety and tolerability of the 
administered dose on Day 5 before proceeding to the next planned higher dose. This assessment 
will be based on all clinical findings such as AEs, vital signs, ECGs, PFTs, clinical laboratory 
tests, and physical examination. Once adequate subject safety and tolerability are confirmed, 
enrollment in the next dose level will proceed. The following criteria will be applied to subjects 
dosed with TAK-788 and must be met to proceed to next dose level:

No DLTs have occurred at the current dose level.

All Grade ≥2 treatment-related AEs resolve to Grade ≤1 or return to baseline by Day 5. If a 
Grade ≥2 treatment-related AE has not resolved to Grade ≤1 or returned to baseline by Day 5, 
the assessment will be repeated on Day 8 and Day 15, if necessary, to ensure all Grade ≤2 
treatment-related AEs have resolved to Grade ≤1 or returned to baseline before escalation to 
the next dose. 

If any clinically significant serious adverse reaction or other findings are observed at any dose, 
the investigator and sponsor may terminate dose escalation in this study. 
8.4
Criteria for Tolerable Dose
The dose is considered tolerable if ≤1 of 6 subjects experiences a study drug–related DLT at the 
given dose within 5 days of dosing.
8.5
Excluded Concomitant Medications and Procedures
The following medications and procedures are prohibited during the study:

Other investigational medicinal products or devices.

Blood products or blood donation. 

Prescription medications, except as noted in Section 8.6.

Nutraceuticals, including St. John’s wort, ginseng, kava, ginkgo biloba, and melatonin.

Immunizations.
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
Intake of known inhibitors/inducers of cytochrome P450 3A4 (excluding study drugs) (see 
Appendix D).

OTC medications, except as noted in Section 8.6.

Vitamin supplements. 

Proton pump inhibitors (eg, omeprazole, esomeprazole, and pantoprazole). 

H2-receptor antagonists (eg, ranitidine, famotidine, cimetidine, and nizatidine). 

Medications that are known to be associated with development of torsades de pointes. 
8.6
Permitted Concomitant Medications and Procedures
Occasional use of acetaminophen ≤1 g/day is permitted. Other OTC medication must be approved 
by the sponsor on a case-by-case basis.
Treatment with neutralizing antacids is not permitted less than 4 hours before and within 8 hours 
after receiving a dose of TAK-788.
Oral contraceptive pills and any other type of hormonal contraception is permitted.
Use of antiemetics is permitted per standard institutional practice, if needed to control nausea and 
vomiting. 
Other concomitant medications will be assessed on a case-by-case basis.
All concomitant medication use must be recorded on the appropriate eCRF. 
8.7
Precautions and Restrictions
It is not known what effects TAK-788 has on human pregnancy or development of the embryo or 
fetus. Women who are pregnant or breastfeeding will not be allowed to take part in this study. 
Women participating in this study should avoid becoming pregnant or nursing a baby, and men 
subjects should avoid impregnating a female partner for 16 weeks (4 months) after the last dose of 
TAK-788. Nonsterilized women of reproductive age and male subjects should use effective 
methods of contraception through defined periods during and after study treatment as specified 
below.
Women must meet 1 of the following criteria:

Postmenopausal for at least 1 year before the screening visit, OR

Surgically sterile, OR

If they are of childbearing potential, agree to practice 2 effective methods of contraception 
from the time of signing of the informed consent form (ICF) through 16 weeks (4 months) 
after the last dose of study drug, OR
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
Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of 
the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 
methods] and withdrawal are not acceptable methods of contraception.)

Agree to not donate eggs (ova) and male subjects must agree not to donate sperm during the 
course of this study and for 16 weeks (4 months) after receiving their last dose of study drug. 
Men, even if surgically sterilized (ie, status postvasectomy) must agree to 1 of the following:

Agree to practice effective barrier contraception during the entire study treatment period and 
through 16 weeks (4 months) after the last dose of study drug, OR

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of 
the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 
methods for the female partner] and withdrawal are not acceptable methods of contraception.)

Agree not to donate sperm during this study and for 120 days after receiving their last dose of 
study drug. 
Contraception methods meeting the criteria defined above are provided in Table 8.b. If male 
condoms are used as a barrier method by male subjects, their partners must use an intrauterine 
device (Copper T, or Progesteron T) or hormonal contraceptives (combined pills) instead of 
spermicide. 
Table 8.b
Contraceptive Methods
Barrier Methods (Each Time the 
Subject Has Intercourse)
Intrauterine Devices
Hormonal Contraceptives

Male condom PLUS spermicide.

Cap (plus spermicidal cream or 
jelly) PLUS male condom and 
spermicide.

Diaphragm (plus spermicidal 
cream or jelly) PLUS male 
condom and spermicide.

Copper T PLUS condom or 
spermicide.

Progesterone T PLUS condom 
or spermicide.

Implants.

Hormone injections.

Combined pills.

Minipills.

Patches.

Vaginal ring PLUS male 
condom and spermicide.
8.8
Management of Selected EGFR TKI Class AEs
8.8.1
Pneumonitis
Investigators must evaluate subjects who demonstrate potential signs/symptoms of pneumonitis, 
abnormal DLco (decrease of >20% from baseline), and/or abnormal chest CT scan. If clinically 
indicated, high-dose corticosteroid treatment should be initiated. Any DLco abnormalities and/or 
chest CT scan abnormalities will be followed weekly until resolution.
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8.8.2
Nausea and Vomiting
Standard antiemetics may be used for the treatment of nausea and vomiting.
8.8.3
Diarrhea
Diarrhea may be treated at the investigator’s discretion.
8.9
Blinding and Unblinding
Part 1 of this study will be performed in a double-blind manner. 
Because TAK-788 and the placebo formulations may be different in appearance, all subjects will 
be blindfolded during dosing. An unblinded site pharmacist will dispense study drugs. These 
personnel will not be involved in any other study procedures (data collection, assessments, or 
documentation activities). 
One person in the bioanalytical laboratory will be unblinded to exclude the PK samples collected 
from subjects who were dosed with placebo from the bioanalysis. 
If needed, 1 or 2 PK scientists may also be unblinded to conduct the preliminary PK data analysis 
during the study. 
After the subjects’ furlough begins on Day 3 of Part 1, the double-blind will become single-blind. 
The site staff, investigator(s), and sponsor will be unblinded on Day 3 but study subjects will 
remain blinded until after the follow-up phone call 30 days after their last dose (window of up to 
2 days after Day 30). After furlough on Day 3, the overall randomization code will be broken for 
safety evaluation and reporting purposes only. 
The study blind should not be broken before Day 3 of Part 1 except in a medical emergency where 
knowledge of the treatment administered would affect the treatment of the emergency. The 
decision to break the blind will be made on a case-by-case basis, at the discretion of the 
investigator in collaboration with the sponsor/medical monitor. The applicable site standard 
operating procedure (SOP) will be followed for blind-breaking procedures.
8.10
Description of Investigational Agents
TAK-788 drug product is a nonsterile oral DiC formulation. The active study drug is available as 
20 or 40 mg dosage strength capsules. The API has been synthesized using 2 different processes 
(Process A and Process B). Before Amendment 1, all subjects in Part 1 of this study received 
TAK-788 from Process B unmilled only with the capsule strength of 20 mg, and subjects in Part 2 
received TAK-788 from Process A with capsule strength of 20 mg. After Amendment 1, some 
additional cohorts in Part 1 may receive TAK-788 from Process A.
Process A and Process B are the same succinate salt in chemical structure but synthesized with 
different processes. The API from Process B has larger particle size and higher bulk density than 
that from Process A.
Placebo will be commercially available empty size 2 capsules. 
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8.11
Preparation, Reconstitution, and Dispensation
TAK-788 study drug will be provided in appropriately labeled 30-count, 60-cc high-density 
polyethylene bottles, with child-resistant caps and induction seals.
Study drug bottles are considered to be bulk supplies, and are to be dispensed according to the site 
procedures, and according to instruction and guidelines provided in the study pharmacy manual.
TAK-788 is an anticancer drug and caution should be exercised when handling TAK-788 
capsules.
8.12
Packaging and Labeling
TAK-788 study drug will be provided by Takeda and will be handled at the investigative sites as 
blinded material in Part 1. TAK-788 study drug is packaged in accordance with all applicable 
regulations. 
The investigator will be notified of any expiry date or retest date extension of clinical study 
material during the study conduct. On expiry date notification from the sponsor or designee, the 
site must complete all instructions outlined in the notification, including segregation of expired 
clinical study material for return to the sponsor or its designee. 
8.13
Storage, Handling, and Accountability
The recommended storage condition for TAK-788 is at a temperature thermostatically maintained 
at the usual customary working environment of 15°C-30°C, as experienced in pharmacies, 
hospitals, and warehouses (United States [US] Pharmacopeia 659 Packaging and Storage 
Requirements).
The study pharmacist or designee at the site will be responsible for handling and dispensing study 
drug and placebo, and for completing associated documentation. Supplies are shipped to the 
investigative site at appropriate intervals, depending on subject accrual. The site must use an 
appropriate dispensing log/accountability form provided by the sponsor, or an acceptable 
substitute approved by the sponsor. An unblinded site pharmacist will dispense study drug to the 
subjects on the day of administration. The site SOP should be followed. 
All clinical trial material must be kept in an appropriate, limited-access, secure location until used 
or returned to the sponsor or designee. All study medication must be stored under the conditions 
specified on the label, and must remain in the original container until dispensed. A daily 
temperature log of the drug storage area must be maintained.
The investigator or designee must confirm that appropriate temperature conditions have been 
maintained for all TAK-788 received and that any discrepancies are reported and resolved before 
use of TAK-788.
The investigator is responsible for ensuring that deliveries of TAK-788 and other study materials 
from the sponsor are correctly received, recorded, and handled, and stored safely and properly in 
accordance with the Code of Federal Regulations (CFR) or national and local regulations.
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The investigator or designee must ensure that the study medication is used in accordance with the 
approved protocol and is dispensed only to subjects enrolled in the study. To document appropriate 
use of study medication (TAK-788), the investigator must maintain records of all study medication 
delivery to the site, site inventory, use by each subject, and return to the sponsor or designee.
8.13.1 Disposition of Used Supplies
All used bottles of study drug must be destroyed in an appropriate manner according to the 
standard practice at each study center. Destruction of such supplies will be documented, and a 
representative of the sponsor will verify disposition records.
No other use of TAK-788 intended for use in this study is authorized by the sponsor. The principal 
investigator or designee will be responsible for the appropriate handling and disposition of residual 
study drug. 
8.13.2 Inventory of Unused Supplies
At the completion of the trial, a final study drug accountability review will be conducted. Any 
discrepancies must be investigated and all unused study drug must be destroyed on site per the 
SOP of the investigative site.
8.14
Other Protocol-Specified Materials
Not applicable 
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9.0
STUDY CONDUCT
This trial will be conducted in compliance with the protocol, GCP, applicable regulatory 
requirements, and ICH guidelines.
9.1
Study Personnel and Organizations
The contact information for the sponsor clinician for this study, the central laboratory and any 
additional clinical laboratories, the coordinating investigator, and any other vendor may be found 
in the study manual.
9.2
Arrangements for Recruitment of Subjects
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 IRB/independent ethics committee (IEC). It 
is not envisioned that prisoners (or other populations that might be subject to coercion or 
exploitation) will be enrolled into this study.
9.3
Treatment Group Assignments
Subjects in Part 1 will receive a single dose of TAK-788 or placebo under fasted conditions. 
In Part 2, subjects will receive TAK-788 under fed or fasted conditions then crossover to receive 
TAK-788 under the alternate condition (fed versus fasted) after a washout of at least 7 days 
between doses of TAK-788.
In Part 3, subjects will receive TAK-788 Process B DiC (test) or Process A DiC (reference), then 
crossover to receive the alternate TAK-788 (test or reference) formulation after a washout of at 
least 7 days between doses of TAK-788.
Before dosing on Day 1, subjects will be assigned a randomization number in accordance with the 
randomization code generated by the sponsor, the sponsor’s designee, or the clinical site. The 
randomization code will be maintained in a room with access restricted to pharmacy personnel 
only. 
Once a randomization number has been allocated to one subject, it may not be assigned to another 
subject. Subjects withdrawn prematurely from the study will not be replaced.
9.4
Study Procedures
Refer to the schedule of events (Appendix A) for the timing of assessments. Subjects will be 
admitted to the clinical site on the day before dosing days. Study drug administration will be 
considered time zero (starting of Day 1). Additional details are provided as necessary in the 
sections that follow.
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9.4.1
Informed Consent
Each subject must provide written informed consent before any study-required procedures are 
conducted.
9.4.2
Subject Demographics
The date of birth, race, ethnicity, and sex of the subject are to be recorded during screening.
9.4.3
Medical History
During the screening period, a complete medical history will be compiled for each subject. 
9.4.4
Physical Examination
A physical examination will be completed per standard of care at the times specified in the 
schedule of events (Appendix A). A complete physical examination must be performed at 
screening, the extent of which should be consistent with medical history. Subsequent physical 
examinations as described in the schedule of events may be directed to relevant findings.
9.4.5
Subject Height
Height will be measured during screening only (within 21 days before the first dose of TAK-788).
9.4.6
Vital Signs
Vital sign measurements including measurements of diastolic and systolic blood pressure, pulse 
rate, and oral temperature will be obtained at the times specified in the Schedules of Events 
(Appendix A). Subjects should sit quietly for at least 5 minutes before blood pressure is measured. 
When the timing of vital sign measurements coincides with the collection of blood samples, the 
vital sign measurements should be completed first. When vital sign measurements are scheduled at 
the same time as an ECG and a blood draw, the vital sign measurements will be obtained 
immediately before the ECG and the blood draw, and the blood draw will be collected at the 
scheduled time. If vital sign measurement results are abnormal, a repeat measure may be taken 
within 30 minutes. 
9.4.7
Pulmonary Function Tests
PFTs include spirometry, lung volumes, and DLco. In Part 1, PFTs will be performed at screening 
but no more than 7 days before Day 1, and at Day 3 before furlough. In Parts 2 and 3, PFTs will be 
performed at screening and at Day 3, Day 10, and/or Early Termination visit if indicated on the 
basis of pulmonary symptoms. 
9.4.8
Drug, Alcohol, and Tobacco Testing
Urine drug testing and breath alcohol testing will be performed during screening using the site’s 
standard test panel. In addition to negative test results during screening, subjects also must have 
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negative urine and alcohol test results following confinement on Day -1 before the first dose of 
TAK-788.
To test for use of nicotine products, a urine cotinine test will be performed during screening. In 
addition to a negative test result during screening, subjects also must have a negative urine cotinine 
test result following confinement on Day -1 before the first dose of TAK-788.
In Parts 2 and 3 of the study, subjects must also have negative urine drug, breath alcohol, and urine 
cotinine test results the day before the second dose of TAK-788 on Day 8. 
9.4.9
Pregnancy Test
In Part 1 of the study, a serum -human chorionic gonadotropin (-hCG) pregnancy test will be 
performed for women of childbearing potential during screening. In addition to a negative serum 
hCG pregnancy test at screening, female subjects also must have a negative serum hCG pregnancy 
test following confinement on Day -1 before the first dose of TAK-788 on Day 1.
In Parts 2 and 3 of the study, female subjects must have a negative serum hCG pregnancy test at 
screening, Day -1 (before first dose), and Day 7 (before the second dose of TAK-788 on Day 8). 
9.4.10 Concomitant Medications and Procedures
Medications used by the subject and therapeutic procedures completed by the subject will recorded 
in the electronic case report form (eCRF) from signing of the ICF through 30 days after the last 
dose. See Section 8.5 and Section 8.6 for a list of medications and therapies that are prohibited and 
allowed, respectively, during the study. 
9.4.11 AEs
AEs, serious and nonserious, will be recorded from the signing of ICF through 30 days after the 
last dose of study drug, with a follow-up phone call on Day 30 (window of up to 2 days after 
Day 30) for Part 1 subjects or on Day 38 (window of up to 2 days after Day 38) for subjects in 
Parts 2 and 3. Refer to Section 10.1 for details regarding definitions, documentation, and reporting 
of pretreatment events (PTEs), AEs, and SAEs. 
9.4.12
Enrollment
A subject is considered to be enrolled in the study when the subject has met all eligibility criteria 
and is randomized to a study group (TAK-788 versus placebo in Part 1; fed versus fasted in Part 2; 
test versus reference formulation in Part 3). Procedures for completing the enrollment information 
are described in the study manual. 
9.4.13
ECG
Triplicate 12-lead ECG will be administered at the time points specified in the Schedules of Events 
(Appendix A). ECG measurements must be taken at screening; on Days -1, 1, and 3 in Parts 1, 2, 
and 3; and on Days 7, 8, and 10 in Parts 2 and 3. On Days 1 and 8, ECG measurements will be 
obtained between 4 and 6 hours postdose. The clinical site’s ECG machine may be used to obtain 
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the ECG. When the timing of an ECG coincides with the collection of blood samples, the ECG 
should be completed first. When an ECG is scheduled at the same time as vital signs and a blood 
draw, the ECG will be obtained after the vital signs and before the blood draw, and the blood draw 
will be collected at the scheduled time.
9.4.14
Chest CT Scan
A chest CT scan will be performed at screening (within 28 days before dosing) for Parts 1 and 2; 
this scan can be a low-dose scan. The follow-up chest CT scan, if needed on the basis of 
symptoms, should be a high-resolution chest CT scan with the appropriate dose of radiation. No IV 
contrast agent should be used. 
9.4.15
Clinical Laboratory Evaluations
Clinical laboratory evaluations will be performed locally. Additional laboratory samples may be 
taken at the discretion of the investigator (eg, if the results of any tests fall outside reference ranges 
or if clinical symptoms necessitate testing). Handling and shipment of clinical laboratory samples 
will be outlined in the study manual. Clinical laboratory evaluations will be performed as outlined 
below: 
9.4.15.1 Clinical Chemistry, Hematology, and Urinalysis
Blood samples for analysis of the clinical chemistry and hematology parameters shown in 
Table 9.a and urine samples for analysis of the parameters shown in Table 9.b will be obtained as 
specified in the schedule of events. 
Table 9.a
Clinical Chemistry and Hematology Tests
Hematology
Serum Chemistry (a)
Hemoglobin
CBC with 5-part differential
Platelet count
RBC count
Reticulocyte count
Albumin
Alkaline phosphatase
Alanine aminotransferase
Amylase
Aspartate aminotransferase
Bilirubin, direct
Bilirubin, total
Blood urea nitrogen
Calcium
Carbon dioxide
Chloride
Creatinine
Creatine phosphokinase
γ-Glutamyl transferase
Glucose
Lactate dehydrogenase
Lipase
Magnesium
Phosphate, inorganic
Potassium
Protein, total
Sodium
Urate
CBC, complete blood count; RBC, red blood cell. 
(a) For screening serum chemistry, subjects must be fasting (nothing except water) for 8 hours before the 
measurement. 
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Fasting serum glucose will be measured at screening only. Subjects are required to fast overnight 
(nothing except water and/or protocol allowed medications [see Section 8.6] after midnight or for a 
minimum of 8 hours) for each of these measurements. 
In addition to fast serum glucose, serum glucose will also be measured at the time points specified 
in the Schedules of Events (Appendix A). Subjects are not required to fast for these measurements.
The Cockcroft-Gault formula will be used to estimate creatinine clearance as follows: 
	
 
	
 
		
 
= [(140 −
) • 	() ] / [72 • 
! 
	
(/")] 
For female subjects, the result of the formula above should be multiplied by 0.85. 
Table 9.b
Clinical Urinalysis Tests
Bilirubin
Glucose
Ketones
Leukocytes
Nitrite
Occult blood 
pH
Protein
Specific gravity
Urobilinogen
9.4.15.2 Serology
Serology tests performed at screening will include anti-HIV antibodies, HBV surface antigen, and 
anti-HCV antibody. 
9.4.15.3 Coagulation
Prothrombin international normalized ratio will be measured only if alanine aminotransferase or 
aspartate aminotransferase is >3 times the upper limit of normal (ULN). 
9.4.16
PK Measurements
Blood samples for PK analysis of TAK-788 will be collected over a 7-day period (0-168 hours) for 
Parts 1 and 2 and over a 3-day period (0-72 hours) for Part 3 following the dose of TAK-788. Time 
points are specified in the PK blood sampling schedules (Appendix A). While the primary purpose 
of collecting PK samples is for measuring plasma concentrations of TAK-788 and its active 
metabolites, AP32960 and AP32914, if deemed necessary and pending technical feasibility, the 
samples collected may also be used for future performance of exploratory measurements of 
TAK-788 metabolite levels to further understand TAK-788 metabolism in humans. The dates and 
exact times of administration of TAK-788 before collection of the blood sample for PK analysis 
and the dates and exact times of the postdose PK sample collection will be recorded on the eCRF. 
Urine samples for PK analysis of the renal clearance of TAK-788 will be obtained at the time 
points specified in the PK plasma and urine sampling schedules (Appendix A). While the primary 
purpose of collecting urine PK samples is for measuring urine concentrations of TAK-788, if 
deemed necessary and pending technical feasibility, the urine samples collected may also be used 
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for future performance of exploratory measurements of TAK-788 metabolite levels to further 
understand TAK-788 metabolism in humans. The date and exact time of the predose voids; the 
dates and exact times of administration of TAK-788 before the start of urine sample collection for 
PK analysis; and the total volume of each voided sample following administration of TAK-788 
will be recorded on the eCRF. 
For subjects in Parts 2 and 3, the morning dose on Day 8 should occur at approximately the same 
time as the morning dosing time on Day 1. 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 
blood sample collection. 
9.5
Completion of Study Treatment for Individual Subjects
Subjects will be enrolled into Part 1, Part 2, or Part 3 of the study and will be considered to have 
completed study treatment after they have received the prescribed study drug treatments in Part 1, 
Part 2, or Part 3 of this study (single dose for Part 1 and two separated doses for Parts 2 and 3).
9.6
Discontinuation of Treatment With Study Drug and Subject Replacement
Any subject who voluntarily withdraws consent or is discontinued (eg, because of an AE) from the 
study before completion will be considered withdrawn from the study. Treatment with study drug 
may also be discontinued for any of the following reasons:

Occurrence of intolerable AE, as assessed by the investigator or designee. 

Clinically significantly abnormal vital signs, ECG, clinical laboratory, or physical examination 
assessments, as assessed by the investigator. 

Pregnancy.

Withdrawal of consent. 

Lost to follow-up.

Administrative reasons (eg, sponsor decision). 

Major protocol violation. 

If, in the opinion of the investigator, it is in the best interest of the subject.

Non-compliance with study requirements and restrictions.

Use of a concomitant medication that, in the opinion of the investigator, could interfere with
the study procedures or data integrity or compromise the safety of the subject.

Positive urine drug screen, CO breath test, or breath alcohol test at admission to any study visit.

Emesis within 8 hours of drug ingestion (to be evaluated by the investigator or designee on a 
case-by-case basis).

Termination of the study.
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When an event such as a family emergency, a transient intercurrent illness (such as a cold) 
unrelated to study drug, or a remediable act of non-compliance prevents a subject from 
participating in a scheduled visit but the subject wishes to continue in the study, with the 
agreement of the investigator, the research site staff may attempt to reschedule the visit and retain 
the subject in the study. 
If a subject is prematurely discontinued from participation in the study for any reason after drug 
administration, the investigator or designee must make every effort to perform the assessments 
scheduled for the follow-up visit. The reason for withdrawal will be recorded in the eCRF and the 
subject’s source medical record.
Subjects in Parts 2 and 3 who discontinue their participation in the study before receiving the 
Day 8 dose will undergo the safety follow-up as specified in the Schedules of Events. 
Replacement of subjects is not planned but may occur under special circumstances at the sponsor’s 
discretion, in agreement with the investigator.
9.7
Study Compliance
Study drug will be administered or dispensed only to eligible subjects by an unblinded site 
pharmacist and will be under the supervision of the investigator or identified subinvestigator(s). 
The pharmacist will be unblinded in Part 1. The appropriate study personnel will maintain records 
of study drug receipt and dispensing. Subject compliance with study drug administration will be 
confirmed according to standard procedures at the clinical site. 
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10.0
ADVERSE EVENTS
10.1
Definitions
10.1.1 PTE
A PTE is any untoward medical occurrence in a 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 subject 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 a clinically 
significant 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 is considered by the 
investigator to be a clinically significant change from baseline.
10.1.3 SAE Definition
An SAE is any untoward medical occurrence that, at any dose:

Results in death.

Is life-threatening (refers to an AE in which the subject was at risk of death at the time of the 
event. It does not refer to an event that hypothetically might have caused death if it were more 
severe).

Requires in-patient 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, 
on the basis of appropriate medical judgment, may jeopardize the subject, require medical or 
surgical intervention to prevent one of the outcomes listed above, or involves suspected 
transmission via a medicinal product of an infectious agent. Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency department or at 
home, blood dyscrasias or convulsions that do not result in in-patient hospitalization, or the 
development of drug dependency or drug abuse; any organism, virus, or infectious particle 
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(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 [17]. 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 subject/event outcome or action criteria described above, and is usually associated with events 
that pose a threat to a subject’s life or ability to function. A severe AE (Grade 3 or 4) does not 
necessarily need to be considered serious. For example, a white blood cell count of 1000/mm3 to 
less than 2000/mm3 is considered Grade 3 (severe) but may not be considered serious. Seriousness 
(not intensity) serves as a guide for defining regulatory reporting obligations.
10.2
Procedures for Recording and Reporting AEs and SAEs
All AEs spontaneously reported by the subject and/or in response to an open question from study 
personnel or revealed by observation, physical examination, or other diagnostic procedures will be 
recorded on the appropriate page of the eCRF (see Section 10.3 for the period of observation). Any 
clinically relevant deterioration in laboratory assessments or other clinical finding is considered an 
AE. When possible, signs and symptoms indicating a common underlying pathology should be 
noted as 1 comprehensive event.
Regardless of causality, SAEs and serious PTEs (as defined in Section 10.1) must be reported (see 
Section 10.3 for the period of observation) by the investigator to the Takeda Global 
Pharmacovigilance department or designee (contact information provided below). This should be 
done by faxing the SAE form within 24 hours after becoming aware of the event. The SAE Form, 
created specifically by Takeda, will be provided to each clinical study site. A sample of the SAE 
Form may be found in the study manual. Follow-up information on the SAE or serious 
pretreatment event may be requested by Takeda. SAE report information must be consistent with 
the data provided on the eCRF.
SAE Reporting Contact Information
Planned hospital admissions or surgical procedures for an illness or disease that existed before 
study drug was given are not to be considered AEs unless the condition deteriorated in an 
unexpected manner during the trial (eg, surgery was performed earlier or later than planned). For 
both serious and nonserious AEs, the investigator must determine both the severity (toxicity grade) 
of the event and the relationship of the event to study drug administration. For serious PTEs, the 
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investigator must determine both the severity (toxicity grade) of the event and the causality of the 
event in relation to study procedures.
Severity (toxicity grade) for each AE, including any lab abnormality, will be determined using the 
NCI CTCAE, version 5.0, effective date 27 November 2017 [17]. The criteria are provided in the 
study manual. Selected asymptomatic laboratory values may also constitute AEs as defined by the 
NCI CTCAE.
10.3
Monitoring of AEs and Period of Observation
AEs, both nonserious and serious, will be monitored throughout the study as follows: 

AEs will be reported from the signing of informed consent through 30 days after 
administration of the last dose of study drug and recorded in the eCRFs. 

SAEs will be monitored throughout the study as follows:
–
Serious PTEs will be reported to the Takeda Global Pharmacovigilance department or 
designee from the time of the signing of the ICF up to first dose of study drug, and will also 
be recorded in the eCRF. 
–
Related and unrelated treatment-emergent SAEs 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 subject’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 subject becomes pregnant during the male subject’s participation in 
this study, the sponsor must also be contacted immediately by faxing a completed pregnancy form 
to the Takeda Global Pharmacovigilance department or designee (see Section 10.2). Every effort 
should be made to follow the pregnancy for the final pregnancy outcome.
10.5
Procedures for Reporting Product Complaints or Medication Errors (Including 
Overdose)
A product complaint is a verbal, written, or electronic expression that implies dissatisfaction 
regarding the identity, strength, purity, quality, or stability of a drug product. Individuals who 
identify a potential product complaint situation should immediately report this via the phone 
numbers or e-mail addresses provided below.
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A medication error is a preventable event that involves an identifiable subject and that leads to 
inappropriate medication use, which may result in subject harm. While overdoses and underdoses 
constitute medication errors, doses missed inadvertently by a subject do not. Individuals who 
identify a potential medication error (including overdose) situation should immediately report this 
via the phone numbers or e-mail addresses provided below. 
Call center
Phone number
E-mail
Fax
Product complaints in and of themselves are not AEs. If a product complaint results in an SAE, an 
SAE form should be completed and sent to 
 (refer to Section 10.2). 
10.6
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, investigators, and IRBs or 
IECs, as applicable, in accordance with national regulations in the countries where the study is 
conducted. Relative to the first awareness of the event by/or further provision to the sponsor or 
sponsor’s designee, SUSARs will be submitted to the regulatory authorities as an expedited report 
within 7 days for fatal and life-threatening events and 15 days for other serious events, unless 
otherwise required by national regulations. The sponsor will also prepare an expedited report for 
other safety issues where these might materially alter the current benefit-risk assessment of an 
investigational medicinal product or that would be sufficient to consider changes in the 
investigational medicinal product’s administration or in the overall conduct of the trial. The 
investigational site also will forward a copy of all expedited reports to its IRB or IEC in 
accordance with national regulations. 
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11.0
STUDY COMMITTEES
Not applicable. 
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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 
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, contract research 
organization (CRO) partners, and regulatory authorities. Investigative sites must complete eCRFs 
in English.
After completion of the entry process, computer logic checks will be run to identify 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 investigator must review the eCRFs for completeness and accuracy and must sign and date the 
appropriate eCRFs as indicated. Furthermore, the 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 trails, 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.
Refer to the clinical study site agreement for the sponsor’s requirements on record retention. The 
investigator and the head of the institution should contact and receive written approval from the 
sponsor before disposing of any such documents.
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13.0
STATISTICAL METHODS
13.1
Statistical and Analytical Plans
A statistical analysis plan will be prepared and finalized before database lock. This document will 
provide further details regarding the definition of analysis variables and analysis methodology to 
address all study objectives. 
13.1.1 Analysis Sets
The study analysis populations will consist of the following:

Randomized population: All subjects who are randomized to receive study treatment in Part 1, 
Part 2, or Part 3.

Safety population: All enrolled subjects who receive any study treatment in the treatment 
period.

PK population: All subjects in the safety population who have no major protocol deviations 
that would affect the PK analysis and who have sufficient data to calculate PK parameters. 
This population will be used for the PK analyses. Data from subjects who experience emesis 
within the first 8 hours following dosing may be excluded from the final analysis (to be 
evaluated on a case-by-case basis).
13.1.2 Analysis of Demographics and Other Baseline Characteristics
Demographic and baseline characteristics will be summarized descriptively. Mean, SD, minimum, 
median, and maximum will be calculated for continuous variables. Frequency and percentages 
will be calculated for categorical variables.
13.1.3 PK Analysis
Descriptive statistics, including arithmetic mean, geometric mean, SD, coefficient of variation 
(%CV), minimum, median, and maximum, will be calculated and presented by dose level in Part 1, 
for each treatment under fasted versus fed conditions in Part 2, and for each treatment (test vs 
reference drug formulation) under fasted conditions in Part 3 for plasma concentrations of 
TAK-788 and its 2 active metabolites, AP32960 and AP32914. 
Analysis of PK parameters will be performed for TAK-788, AP32960, and AP32914. The 
concentration-time profiles will be analyzed using noncompartmental methods to estimate PK 
parameters in plasma. The number of observations, arithmetic mean, geometric mean, SD, %CV, 
median, minimum, and maximum values will be calculated for the PK parameters Cmax, tmax, 
AUCt, AUC∞, t1/2z, AUCextrap% (area under the curve from the last quantifiable concentration to 
infinity calculated using the observed value of the last quantifiable concentration, expressed as a 
percentage of AUC∞), CL/F (apparent clearance after extravascular administration, calculated 
using the observed value of the last quantifiable concentration), Vz/F (apparent volume of 
distribution during the terminal disposition phase after extravascular administration, calculated 
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using the observed value of the last quantifiable concentration), 
 
In Part 2, PK parameters (natural log-transformed [ln]) of TAK-788, AP32960, and AP32914 will 
be compared under fasted versus fed conditions using an analysis of variance (ANOVA) model. 
The ANOVA model will include fasted versus fed condition, period, and sequence as fixed effects 
and subject nested within sequence as a random effect. Each ANOVA will calculate the 
least-squares mean (LSM), the difference between treatment LSMs, and the standard error 
associated with the difference. Residual, subject nested within sequence, and intersubject variance, 
along with the intrasubject and intersubject CV, will be reported. Ratios of LSM will be calculated 
using the exponential function of the difference between treatment LSMs from the analyses on the 
ln-transformed Cmax, AUCt, and AUC∞. 
In Part 3, PK parameters (ln-transformed) of TAK-788 for the test formulation (Process B DiC) 
and the reference formulation (Process A DiC) will be compared using an ANOVA model. The 
ANOVA model will include treatment (test versus reference), period, and sequence as fixed 
effects and subject nested within sequence as a random effect. Each ANOVA will calculate the 
LSM, the difference between treatment LSMs, and the SE associated with the difference. Residual, 
subject nested within sequence, and intersubject variance, along with the intrasubject and 
intersubject CV, will be reported. Ratios of LSM will be calculated using the exponential function 
of the difference between treatment LSMs from the analyses on the ln-transformed Cmax, AUCt, 
and AUC∞ (if data permitted).
13.1.4 Safety Analysis
Safety and tolerability parameters will be listed by subject, study group, and treatment group, and 
displayed in summary tables using descriptive statistics. All subjects receiving placebo in Part 1 
will be pooled and analyzed as one placebo group. Original terms used in the eCRFs by the 
investigator or designees to identify AEs will be coded using MedDRA (version 20.0 or higher) 
terminology.
The number and percentage of subjects with TEAEs will be summarized by MedDRA System 
Organ Class and Preferred Term and study group and by study group by maximum severity and 
relationship to study treatment. A TEAE is any AE that is new in onset or was aggravated in 
severity or frequency following the first dose of study drug, up to and including the last visit of the 
study.
Descriptive statistics will be calculated for vital signs (blood pressure, pulse rate, and respiratory 
rate) and PFTs (spirometry, lung volumes, and DLco), and will be presented for each time point by 
study group (absolute values and change from baseline). Vital sign abnormalities and PFTs will be 
listed with a flag for clinical significance based on investigator judgment. Oral temperature data 
will be listed.
Chest CT scan results will be described narratively if abnormalities are reported during the study.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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ECG results (absolute values and change from baseline) will be summarized using descriptive 
statistics; frequencies (numbers and percentages) will be calculated for the overall evaluation by 
scheduled time and study group.
Laboratory data will be summarized by the type of laboratory test and chronological time point. 
Descriptive statistics and the number of subjects with laboratory test results below, within, and 
above normal ranges will be tabulated by scheduled time. Abnormal findings in laboratory data 
will be listed with a flag for clinical significance based on investigator judgment.
Medical history abnormalities will be coded to MedDRA terms (version 20.0 or higher). Physical 
examination abnormalities will also be listed.
The original verbatim terms collected in the eCRF for concomitant medications will be coded 
using the WHO Drug Dictionary into drug class (Anatomical Therapeutic Chemical classification 
level 2) and preferred term. These data will be listed. 
Safety analyses will be conducted separately for subjects who received TAK-788 and placebo. 
13.2
Determination of Sample Size
Part 1: The sample size of approximately 56 subjects is determined on the basis of clinical rather 
than statistical considerations. The number of subjects in this part of study is consistent with phase 
1 dose-finding studies.
Part 2: With a sample size of 14 healthy subjects, the 90% CI for the AUC ratio is expected to be in 
the range of 84% to 119%, using an intrasubject AUC variability of 27% in patients with cancer 
and assuming a TAK-788 AUC ratio of 1 in the fed versus fasted comparison. After accounting for 
2 potential dropouts in Part 2, the final sample size is up to 16 healthy subjects. This sample size 
assumes no replacement of subjects who may drop out of the study before the completing the PK 
sample collections in Part 2.
Part 3 With a sample size of 10 healthy subjects, the 90% CI for the Cmax ratio is expected to be in 
the range of 87% to 115%, using an intrasubject Cmax variability of 17% estimated in healthy 
subjects. After accounting for 2 potential dropouts in Part 3, the final sample size allows for up to 
12 healthy subjects. This sample size assumes no replacement of subjects who may drop out of the 
study before the completing the PK sample collections in Part 3.
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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 (eg, CRO) and by the IRB or IEC.
All aspects of the study and its documentation will be subject to review by the sponsor or designee 
(as long as blinding is not jeopardized), including but not limited to the investigator’s binder, study 
medication, subject medical records, informed consent documentation, documentation of subject 
authorization to use personal health information (if separate from the ICFs), and review of eCRFs 
and associated source documents. It is important that the investigator and other study personnel are 
available during the monitoring visits and that sufficient time is devoted to the process.
14.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will require 
deviation from protocol-specified procedures, the investigator should consult with the sponsor or 
designee (and IRB or IEC, as required) to determine the appropriate course of action. There will be 
no exemptions (a prospectively approved deviation) from the inclusion or exclusion criteria.
The site should document all protocol deviations in the subject’s source documents. In the event of 
a significant deviation, the site should notify the sponsor or its designee (and IRB or IEC, as 
required). Significant deviations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the subject, or confound interpretation of primary study 
assessment. 
14.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, including 
those of foreign governments (eg, the US Food and Drug Administration [FDA], the United 
Kingdom [UK] Medicines and Healthcare products Regulatory Agency, the Pharmaceuticals and 
Medical Devices Agency of Japan). If the study site is contacted for an inspection by a regulatory 
body, the sponsor should be notified immediately. The investigator and institution guarantee 
access for quality assurance auditors to all study documents as described in Section 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 state and federal 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. US sites that are 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 US Department of Health and Human 
Services.
The sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the investigator’s brochure, a copy of 
the ICF, and, if applicable, subject recruitment materials and/or advertisements and other 
documents required by all applicable laws and regulations, must be submitted to a central or local 
IRB or IEC for approval. The IRB’s or IEC’s written approval of the protocol and subject 
informed consent must be obtained and submitted to the sponsor or designee before 
commencement of the study (ie, before shipment of the sponsor-supplied drug or study specific 
screening activity). The IRB or IEC approval must refer to the study by exact protocol title, 
number, and version date; identify versions of other documents (eg, ICF) reviewed; and state the 
approval date. The sponsor will notify site once the sponsor has confirmed the adequacy of site 
regulatory documentation and, when applicable, the sponsor has received permission from 
competent authority to begin the trial. Until the site receives notification, no protocol activities 
including screening may occur.
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the 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 that is 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 that he or she will participate 
in the study, then the ICF and subject authorization form (if applicable) must be signed and dated 
by the subject, or the subject’s legally acceptable representative, at the time of consent and before 
the subject enters into the study. The subject or the subject’s legally acceptable representative 
should be instructed to sign using their legal names, not nicknames, using blue or black ballpoint 
ink pen. The investigator must also sign and date the ICF and subject authorization (if applicable) 
at the time of consent and before subject entering into the study; however, the sponsor may allow a 
designee of the investigator to sign to the extent permitted by applicable law.
Once signed, the original ICF, subject authorization form (if applicable), and subject information 
sheet (if applicable) will be stored in the investigator’s site file. The investigator must document 
the date the subject signs the ICF in the subject’s medical record. Copies of the signed ICF, the 
signed subject authorization form (if applicable), and subject information sheet (if applicable) 
shall be given to the subject.
All revised informed consent forms must be reviewed and signed by relevant subjects or the 
relevant subject’s legally acceptable representative in the same manner as the original informed 
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consent. The date the revised consent was obtained should be recorded in the subject’s medical 
record, and the subject should receive a copy of the revised ICF.
15.3
Subject Confidentiality
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will be linked to the 
sponsor’s clinical study database or documentation only via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or date 
of birth, and subject initials may be used to verify the subject and accuracy of the subject’s unique 
identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the sponsor 
requires the investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (eg, US FDA, UK Medicines and Healthcare products Regulatory Agency, 
Japan Pharmaceuticals and Medical Devices Agency), the sponsor’s designated auditors, and the 
appropriate IRBs and IECs to review the subject’s original medical records (source data or 
documents) including, but not limited to, laboratory test result reports, ECG reports, admission and 
discharge summaries for hospital admissions occurring during a subject’s study participation, and 
autopsy reports. Access to a subject’s original medical records requires the specific authorization 
by the subject as part of the informed consent process (see Section 15.2).
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s eCRF).
15.4
Publication, Disclosure, and Clinical Trial Registration Policy
15.4.1 Publication 
The investigator is obliged to provide the sponsor with complete test results and all data derived by 
the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and advertisements, is the sole responsibility of the sponsor.
The sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 
this section and the clinical study site agreement. In the event of any discrepancy between the 
protocol and the clinical study site agreement, the clinical study site agreement will prevail. 
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15.4.2 Clinical Trial Registration
To ensure that information on clinical trials reaches the public in a timely manner and to comply 
with applicable laws, regulations and guidance, Takeda will, at a minimum register interventional 
clinical trials it sponsors anywhere in the world on ClinicalTrials.gov or other publicly accessible 
websites on or before start of study, as defined in Takeda Policy/Standard. Takeda contact 
information, along with investigator’s city, state (for Americas investigators), country, and 
recruiting status will be registered and available for public viewing. 
As needed Takeda and investigator/site contact information may be made public to support 
participant access to trials via registries. In certain situations/registries, Takeda may assist 
participants or potential participants with finding a clinical trial by helping them locate trial sites 
closest to their homes by providing the investigator name, address, and phone number via 
email/phone or other methods to those requesting trial information. Once subjects receive 
investigator contact information, they may call the site to request enrollment into the trial. The 
investigative sites are encouraged to handle the trial inquiries according to their established subject 
screening process. If the caller asks additional questions beyond the topic of trial enrollment, they 
should be referred to the sponsor.
Any investigator who objects to Takeda providing this information to callers must provide Takeda 
with a written notice requesting that their information not be listed on the registry site. 
15.4.3 Clinical Trial Results Disclosure
Takeda will post the results of clinical trials on ClinicalTrials.gov or other publicly accessible 
websites (including the Takeda corporate site) and registries, as required by Takeda Policy/
Standard, applicable laws and/or regulations. 
15.4.4 Data Sharing
The sponsor is committed to responsible sharing of clinical data with the goal of advancing 
medical science and improving subject care. Qualified independent researchers will be permitted 
to use data collected from subjects during the study to conduct additional scientific research, which 
may be unrelated to the study drug or the subject’s disease. The data provided to external 
researchers will not include information that identifies subjects personally. 
15.5
Insurance and Compensation for Injury
Each subject in the study must be insured in accordance with the regulations applicable to the site 
where the subject is participating. If a local underwriter is required, then the sponsor or sponsor’s 
designee will obtain clinical study insurance against the risk of injury to clinical study subjects. 
Refer to the clinical study site agreement for 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.
Kris M, Johnson B, Berry L, Kwiatkowski D, Iafrate A, Wistuba I, et al. Using multiplexed 
assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA 
2014;311(19):1998-2006.
2.
Yatabe Y, Kerr KM, Utomo A, Rajadurai P, Tran VK, Du X, et al. EGFR mutation testing 
practices within the Asia Pacific region: results of a multicenter diagnostic survey. J Thorac 
Oncol 2015;10(3):438-45.
3.
Murray S, Dahabreh I, Linardou H, Manoloukos M, Bafaloukos D, Kosmidis P. Somatic 
mutations of the tyrosine kinase domain of epidermal growth factor receptor and tyrosine 
kinase inhibitor response to TKIs in non-small cell lung cancer: an analytical database. J 
Thorac Oncol 2008;3(8):832-9.
4.
Hirsh V. Next-Generation Covalent Irreversible Kinase Inhibitors in NSCLC: Focus on 
Afatinib. BioDrugs 2015;29(3):167-83.
5.
Yun CH, Mengwasser KE, Toms AV, Woo MS, Greulich H, Wong KK, et al. The T790M 
mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc 
Natl Acad Sci U S A 2008;105(6):2070-5.
6.
Suda K, Murakami I, Katayama T, Tomizawa K, Osada H, Sekido Y, et al. Reciprocal and 
complementary role of MET amplification and EGFR T790M mutation in acquired 
resistance to kinase inhibitors in lung cancer. Clin Cancer Res 2010;16(22):5489-98.
7.
Yang JC, Sequist LV, Geater SL, Tsai CM, Mok TS, Schuler M, et al. Clinical activity of 
afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR 
mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6. 
Lancet Oncol 2015;16(7):830-8.
8.
Oxnard GR, Lo PC, Nishino M, Dahlberg SE, Lindeman NI, Butaney M, et al. Natural 
history and molecular characteristics of lung cancers harboring EGFR exon 20 insertions. J 
Thorac Oncol 2013;8(2):179-84.
9.
Wu JY, Wu SG, Yang CH, Gow CH, Chang YL, Yu CJ, et al. Lung cancer with epidermal 
growth factor receptor exon 20 mutations is associated with poor gefitinib treatment 
response. Clin Cancer Res 2008;14(15):4877-82.
10.
Naidoo J, Sima CS, Rodriguez K, Busby N, Nafa K, Ladanyi M, et al. Epidermal growth 
factor receptor exon 20 insertions in advanced lung adenocarcinomas: Clinical outcomes and 
response to erlotinib. Cancer 2015;121(18):3212-20.
11.
Arcila ME, Nafa K, Chaft JE, Rekhtman N, Lau C, Reva BA, et al. EGFR exon 20 insertion 
mutations in lung adenocarcinomas: prevalence, molecular heterogeneity, and 
clinicopathologic characteristics. Mol Cancer Ther 2013;12(2):220-9.
12.
Arcila ME, Chaft JE, Nafa K, Roy-Chowdhuri S, Lau C, Zaidinski M, et al. Prevalence, 
clinicopathologic associations, and molecular spectrum of ERBB2 (HER2) tyrosine kinase 
mutations in lung adenocarcinomas. Clin Cancer Res 2012;18(18):4910-8.
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13.
Shigematsu H, Takahashi T, Nomura M, Majmudar K, Suzuki M, Lee H, et al. Somatic 
mutations of the HER2 kinase domain in lung adenocarcinomas. Cancer Res 
2005;65(5):1642-6.
14.
Tomizawa K, Suda K, Onozato R, Kosaka T, Endoh H, Sekido Y, et al. Prognostic and 
predictive implications of HER2/ERBB2/neu gene mutations in lung cancers. Lung Cancer 
2011;74(1):139-44.
15.
ZYTIGA (abiraterone acetate) Tablets [package insert]. Horsham, PA: Janssen Biotech, Inc., 
2013.
16.
Zykadia. Ceritinib EU Product Information. Nuremberg, Germany: Novartis Pharma GmbH.
17.
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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Appendix A
Schedule of Events
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CONFIDENTIAL
Table 1 – Single Rising Dose Study (Part 1)
Screening a
Day -1
Day 1
Day 2
Day 3
Day 8
Follow-up b
Informed consent
X
Inclusion/exclusion criteria
X
X
Demographics
X
Medical history
X
Physical examination c
X
X
X
Height
X
Weight c
X
X
Vital signs d
X
X
X
X
X
Chest CT scan e
X
(X)
Pulmonary function tests f
X
X
Concomitant medications and procedures g
X
Adverse event reporting h
X
Electrocardiogram i
X
X
X
X
Admission to clinical site j
X
TAK-788 administration 
X
Pregnancy test k
X
X
Hematology/chemistry/coagulation l
X
X
X
X
Urinalysis l
X
X
X
X
Pharmacokinetic sampling m
X
X
X
X
Drug, alcohol, and tobacco testing n
X
X
Serology l
X
Follow-up questionnaire
X
X
Footnotes are on last table page.
continuous
continuous
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CONFIDENTIAL
Abbreviations: CT, computed tomography; ICF, informed consent form.
An “X” in parentheses indicates that a procedure or test may be done under certain conditions. If extenuating circumstances prevent a subject from beginning treatment or completing 
a scheduled procedure or assessment within this time, the subject may continue the study only with the permission of the medical monitor. 
a Unless otherwise noted, the screening visit must occur within 21 days before the day of the first dose of study drug (Day 1). The ICF may be signed 2-28 days before Day 1, and the 
chest CT scan may be within 28 days from Day 1 dosing.
b Follow-up phone call to query subject about possible adverse events. This contact should take place 30 days after the last dose (window of up to 2 days after Day 30). 
c The Day -1 physical examination and weight assessment are not required if the screening physical examination and weight assessment were conducted within 4-7 days before 
administration of the first dose of study drug (Day 1) and in the opinion of the investigator, there is no reason to believe they have substantially changed.
d Perform vital sign measurement before dosing. On Day 1 only, perform vital signs measurements between 4 and 6 hours postdose. Blood pressure should be determined with the 
subject in a seated position after sitting quietly for 5 minutes. See Section 9.4.6 for timing in relation to other tests and procedures. If vital sign measurement results are abnormal, a 
repeat measure may be taken within 30 minutes. 
e The screening chest CT scan can be a low-dose CT scan within 28 days from Day 1 dosing. The follow-up chest scan, if needed based on symptoms, should be a high-resolution chest 
CT scan with the appropriate dose of radiation. No IV contrast agent should be used. CT is to be performed on Day 3 if indicated based on pulmonary symptoms. 
f See Section 9.4.7. Part 1: Spirometry, lung volumes, and diffusion capacity at screening but no more than 7 days before Day 1 and on Day 3.
g See Section 9.4.10. 
h See Section 9.4.11. 
i See Section 9.4.13. Triplicate 12-lead ECG measurements must be taken at screening and on Day -1, Day 1, and Day 3. On Day 1 only, perform ECG measurements between 4 and 
6 hours postdose. 
j Subjects should be admitted to the clinical site on the day before each dosing day. 
k A serum -human chorionic gonadotropin pregnancy test will be performed only for subjects of childbearing potential during screening and again at Day -1 (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-788 is administered (ie, 
within the 4 days before Day 1), or as otherwise required by local regulations. Additional pregnancy testing may be performed during the study at the discretion of the investigator, 
upon request from an independent ethics committee/institutional review board, or if required by local regulations. See Section 9.4.9. 
l Evaluations to be performed are listed in Table 9.a. On Day 1 only, perform these laboratory tests between 4 and 6 hours postdose unless the timing of test is specified in 
Section 9.4.15. 
m Time points for blood samples for PK analysis will be collected as specified in Appendix A, Table 3. 
n See Sections 9.4.8. 
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CONFIDENTIAL
Table 2 – Food Effect Study (Part 2) 
Screening a
Period 1 
Day -1
Day 1
Day 2
Day 3
Day 8
Follow-up b
Period 2 
Day 7
Day 8
Day 9
Day 10
Day 15
Informed consent
X
Inclusion/exclusion criteria
X
X
Demographics
X
Medical history
X
Physical examination c
X
X
X
Height
X
Weight c
X
X
Vital signs d
X
X
X
X
X
Chest CT scan e
X
(X)
Pulmonary function tests f
X
(X)
Concomitant medications and 
procedures g
X
Adverse event reporting h
X
Electrocardiogram i
X
X
X
X
Admission to clinical site j
X
TAK-788 administration 
X
Pregnancy test k
X
X
Hematology/chemistry/coagulation l
X
X
X
X
Urinalysis l
X
X
X
X
Pharmacokinetic sampling m
X
X
X
X
Drug, alcohol, and tobacco testing n
X
X
Serology l
X
Follow-up questionnaire
X
X
Footnotes are on last table page.
continuous
continuous
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CONFIDENTIAL
CT, computed tomography; ICF, informed consent form.
An “X” in parentheses indicates that a procedure or test may be done under certain conditions. Note: If extenuating circumstances prevent a subject from beginning treatment or 
completing a scheduled procedure or assessment within this time, the subject may continue the study only with the permission of the medical monitor.
a Unless otherwise noted, the screening visit must occur within 21 days before the day of the first dose of study drug (Day 1). The ICF may be signed 2-28 days before Day 1, and the 
chest CT scan may be within 28 days from Day 1 dosing.
b Follow-up phone call to query subject about possible adverse events. This contact should take place 30 days after the last dose (window of up to 2 days after Day 38). 
c The Day-1 physical examination and weight are not required if the screening physical examination and weight were conducted within 4-7 days before administration of the first dose 
of study drug (Day 1) and in the opinion of the investigator, there is no reason to believe they have substantially changed. 
d Perform vital sign measurement before dosing. On Day 1 and Day 8, perform vital signs measurements between 4 and 6 hours postdose. Blood pressure should be determined with 
the subject in a seated position after sitting quietly for 5 minutes. See Section 9.4.6 for timing in relation to other tests and procedures. If vital sign measurement results are abnormal, 
a repeat measure may be taken within 30 minutes. 
e The screening chest CT scan can be a low-dose CT scan within 28 days from Day 1 dosing. The follow-up chest scan, if needed based on symptoms, should be a high-resolution 
chest CT scan with the appropriate dose of radiation. No IV contrast agent should be used. CT is to be performed on Day 3 or Day 10 if indicated based on pulmonary symptoms. 
f See Section 9.4.7. Perform spirometry, lung volumes, and diffusion capacity at screening but no more than 7 days before Day 1. 
g See Section 9.4.10. 
h See Section 9.4.11. 
i See Section 9.4.13. Triplicate 12-lead ECG measurements must be taken at screening and on Days -1, 1, 3, 7, 8, and 10. On Day 1 and Day 8, perform ECG measurements between 
4 and 6 postdose. 
j Subjects should be admitted to the clinical site on the day before each dosing day.
k A serum -human chorionic gonadotropin (-hCG) pregnancy test will be performed only for subjects of childbearing potential during screening and again at Day -1 (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-788 is administered (ie, 
within the 4 days before Day 1), or as otherwise required by local regulations. In Period 2, the results must be negative on Day 7 before the second single-dose of TAK-788 on Day 8 
is administered. Additional pregnancy testing may be performed during the study at the discretion of the investigator, upon request of an independent ethics committee 
(IEC)/institutional review board (IRB), or if required by local regulations. See Section 9.4.9. 
l Evaluations to be performed are listed in Table 9.a. On Day 1 only, perform these laboratory tests between 4 and 6 hours postdose unless the timing of test is specified in 
Section 9.4.15.
m Time points for blood samples for PK analysis will be collected as specified in Appendix A, Table 4. 
n See Sections 9.4.8. 
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CONFIDENTIAL
Table 3
Relative Bioavailability Study (Part 3)
Screening a
Period 1 
Day -1
Day 1
Day 2
Day 3
Day 8
Follow-up b
Period 2 
Day 7
Day 8
Day 9
Day 10
Day 15
Informed consent
X
Inclusion/exclusion criteria
X
X
Demographics
X
Medical history
X
Physical examination c
X
X
X
Height
X
Weight c
X
X
Vital signs d
X
X
X
X
X
Pulmonary function tests e
X
(X)
Concomitant medications and 
procedures f
X
Adverse event reporting g
X
ECG h
X
X
X
X
Admission to clinical site i
X
TAK-788 administration 
X
Pregnancy test j
X
X
Hematology/chemistry/coagulation k
X
X
X
X
Urinalysis k
X
X
X
X
PK sampling l
X
X
X
Drug, alcohol, and tobacco testing m
X
X
Serology k
X
Follow-up questionnaire
X n
X
Footnotes are on last table page.
continuous
continuous
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CONFIDENTIAL
ECG, electrocardiogram; ICF, informed consent form; PK, pharmacokinetic.
An “X” in parentheses indicates that a procedure or test may be done under certain conditions. Note: If extenuating circumstances prevent a subject from beginning treatment or 
completing a scheduled procedure or assessment within this time, the subject may continue the study only with the permission of the medical monitor.
a Unless otherwise noted, the screening visit must occur within 21 days before the day of the first dose of study drug (Day 1). The ICF may be signed 2-28 days before Day 1.
b Follow-up phone call to query subject about possible adverse events. This contact should take place 30 days after the last dose (window of up to 2 days after Day 38). 
c The Day -1 physical examination and weight are not required if the screening physical examination and weight were conducted within 4-7 days before administration of the first dose 
of study drug (Day 1) and, in the opinion of the investigator, there is no reason to believe they have substantially changed.
d Perform vital sign measurement before dosing. On Day 1 and Day 8, perform vital sign measurements between 4 and 6 hours postdose. Blood pressure should be determined with the 
subject in a seated position after sitting quietly for 5 minutes. See Section 9.4.6 for timing in relation to other tests and procedures. If vital sign measurement results are abnormal, a 
repeat measure may be taken within 30 minutes. 
e See Section 9.4.7. Perform spirometry, lung volumes, and diffusion capacity at screening but no more than 7 days before Day 1. 
f See Section 9.4.10. 
g See Section 9.4.11. 
h See Section 9.4.13. Triplicate 12-lead ECG measurements must be taken at screening and on Days -1, 1, 3, 7, 8, and 10. On Day 1 and Day 8, perform ECG measurements between 
4 and 6 postdose. 
i Subjects should be admitted to the clinical site on the day before each dosing day.
j A serum -human chorionic gonadotropin pregnancy test will be performed only for subjects of childbearing potential during screening and again at Day -1 (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-788 is administered (ie, 
within the 4 days before Day 1), or as otherwise required by local regulations. In Period 2, the results must be negative on Day 7 before the second single-dose of TAK-788 on Day 8 
is administered. 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. See Section 9.4.9. 
k Evaluations to be performed are listed in Table 9.a. On Day 1 only, perform these laboratory tests between 4 and 6 hours postdose unless the timing of test is specified in 
Section 9.4.15.
l Time points for blood samples for PK analysis will be collected as specified in Appendix A, Table 4. 
m See Sections 9.4.8.
n Day 15 safety conference call.
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TAK-788 (formerly AP32788)
Study No. TAK-788-1001
Page 79 of 92
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Table 4
Pharmacokinetic Plasma and Urine Concentration Sampling Schedule for 
Part 1
Study Day
Sample 
Collection Time
Time 
(Relative to Dosing)
h:min
Plasma Concentrations 
of TAK-788, AP32960, 
and AP32914
Urine Concentrations 
of TAK-788, AP32960, 
and AP32914
1
0 h
(predose)
00:00
(predose)

(predose void)
0.5 h
00:30 (±5 min)

1 h
01:00 (±10 min)

2 h
02:00 (±10 min)

4 h
04:00 (±10 min)

6 h
06:00 (±20 min)

8 h
08:00 (±20 min)

12 h
12:00 (±20 min)

(0-12 h ±30 min)
2
0 h
24:00 (±30 min)

(12-24 h ±30 min)
12 h
36:00 (±30 min)

(24-36 h ±30 min)
3
0 h
48:00 (±30 min)

(36-48 h ±30 min)
4
0 h
72:00 (±60 min)

5
0 h
96:00 (±60 min)

8
0 h
168:00 (±60 min)

Number of samples per profile:
14
4
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 timing of the morning visit on Days 4, 5, and 8 should occur at approximately the same time as the morning dosing 
time on Day 1. 
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Study No. TAK-788-1001
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Table 5
Pharmacokinetic Plasma Concentration Sampling Schedule for Parts 2 and 3
Study Day
Sample Collection Time
Time 
(Relative to Dosing)
h:min
Plasma Concentrations of 
TAK-788, AP32960, and AP32914
1
0 h
(predose)
00:00
(predose)

0.5 h
00:30 (±5 min)

1 h
01:00 (±10 min)

2 h
02:00 (±10 min)

4 h
04:00 (±10 min)

6 h
06:00 (±20 min)

8 h
08:00 (±20 min)

12 h
12:00 (±20 min)

2
0 h
24:00 (±30 min)

12 h
36:00 (±30 min)

3
0 h
48:00 (±30 min)

4
0 h
72:00 (±60 min)

5 b
0 h
96:00 (±60 min)

8 c
0 h
168:00 (±60 min) a
(predose)

0.5 h
00:30 (±5 min)

1 h
01:00 (±10 min)

2 h
02:00 (±10 min)

4 h
04:00 (±10 min)

6 h
06:00 (±20 min)

8 h
08:00 (±20 min)

12 h
12:00 (±20 min)

9
0 h
24:00 (±30 min)

12 h
36:00 (±30 min)

10
0 h
48:00 (±30 min)

11
0 h
72:00 (±60 min)

12 b
0 h
96:00 (±60 min)

15 b
0 h
168:00 (±60 min)

Number of samples per profile:
Part 2: 27
Part 3: 24
Note: The timing of the morning visit on Days 4, 5, and 8 should occur at approximately the same time as the morning dosing time 
on Day 1. Similarly, the timing of the morning visit on Days 11, 12, and 15 should occur at approximately the same time as the 
morning dosing time on Day 8. 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. 
a The predose PK sample must be collected before the next dose even though the collection window implies it can be taken after. 
The Day 8 dose must be administered shortly after the PK sample is taken.
b Part 3 removed PK sampling at 96-hour and 168-hour timepoints. Part 3 last PK sample is at the 72-hour timepoint
c Day 8, Part 3 will have predose sample, not the 168-hour sample.
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Appendix B
Responsibilities of the Investigator
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all applicable local 
laws and regulations. The responsibilities imposed on investigators by the US FDA are 
summarized in the “Statement of Investigator” (Form FDA 1572), which must be completed and 
signed before the investigator may participate in this study.
The investigator agrees to assume the following responsibilities by signing a Form FDA 1572:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff who will assist in the protocol.
3. Ensure that study related procedures, including study specific (nonroutine/nonstandard panel) 
screening assessments are NOT performed on potential subjects, before the receipt of written 
approval from relevant governing bodies/authorities.
4. Ensure that all colleagues and employees assisting in the conduct of the study are informed of 
these obligations.
5. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform to 
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.
10. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
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11. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor.
12. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours.
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Appendix C
Investigator Consent to Use of Personal Information
Takeda will collect and retain personal information of investigator, including his or her name, 
address, and other personally identifiable information. In addition, investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
UK, 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 trial registries, databases, and websites.
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in the investigator’s 
own country.
Investigator acknowledges and consents to the use of his or her personal information by Takeda 
and other parties for the purposes described above.
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TAK-788 (formerly AP32788)
Study No. TAK-788-1001
Page 84 of 92
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Appendix D
List of Strong Inhibitors and Inducers of CYP3A
Strong Inhibitors a
Strong Inducers b
Boceprevir
Carbamazepine
Clarithromycin
Enzalutamide
Cobicistat
Mitotane
Conivaptan
Phenytoin
Danoprevir and ritonavir
Rifampin
Diltiazem
St. John’s wort
Elvitegravir and ritonavir
Grapefruit juice
Idelalisib
Indinavir and ritonavir
Itraconazole
Ketoconazole
Lopinavir and ritonavir
Nefazodone
Nelfinavir
Paritaprevir and ritonavir and (ombitasvir and/or 
dasabuvir)
Posaconazole
Ritonavir
Saquinavir and ritonavir
Telaprevir
Tipranavir and ritonavir
Troleandomycin
Voriconazole
Abbreviation: CYP, cytochrome P450. 
a fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ 
ucm093664.htm#table3-2 (accessed 18 January 2018).
b fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ 
ucm093664.htm#table3-3 (accessed 18 January 2018). 
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Appendix E
Detailed Description of Amendments to Text
The primary section(s) of the protocol affected by the changes in Amendment 03 are indicated. 
The corresponding text has been revised throughout the protocol. 
Change 1: Addition of Part 3 to assess the relative bioavailability of TAK-788 capsules in healthy 
subjects.
The primary change occurs in the following sections:

Section 4.4 Rationale for the Proposed Study.

Section 4.4.4 Rationale for Relative Bioavailability Assessment (Part 3).

Section 5.0 STUDY OBJECTIVES AND ENDPOINTS.

Section 6.0 Study Design.

Section 6.1 Overview of Study Design.

New Section 6.1.3 Part 3 – Relative Bioavailability.

Section 6.2 Number of Subjects.

New Section 8.1.3 Relative Bioavailability (Part 3).

Section 8.10 Description of Investigational Agents.

Section 9.3 Treatment Group Assignments.

Section 9.4.7 Pulmonary Function Tests

Section 13.1.3 PK Analysis.

Section 13.2 Determination of Sample Size.

Appendix A Schedule of Events.
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Added text:Section 4.4 Rationale for the Proposed Study:
This study is, proposed to identify characterize safety and tolerability of a single oral 
dose of TAK-788, to identify a safe and tolerable dose of TAK-788 administered as 
a drug-in-capsule (DiC) formulation in healthy subjects and, to evaluate the effects of 
a low-fat meal on the PK of TAK-788 and its active metabolites, AP32960 and 
AP32916, and to assess the relative bioavailability of 2 DiCs of TAK-788. Part 1 of 
the study will use a randomized, double-blind, placebo-controlled, single rising dose 
escalation design to determine the safety and tolerability of TAK-788 and characterize 
the PK of TAK-788 and its active metabolites, and to identify a tolerable single dose 
in healthy subjects. Part 2 of the study will assess the effects of a low-fat meal on the 
PK of TAK-788 administered as a DiC formulation. Part 3 of the study will evaluate 
the relative bioavailability of a single dose of TAK-788 160 mg Process B DiC 
(test) versus a single dose of TAK-788 160 mg Process A DiC (reference).
Section 4.4.4 Rationale for Relative Bioavailability Assessment (Part 3)
Process A and Process B TAK-788 drug substance (succinate salt) are chemically 
identical but are synthesized by different synthetic routes. The physiochemical 
properties of Process A and Process B TAK-788 drug substance are, however, 
different. The API powder prepared via Process B has larger primary particles, 
lower specific surface area, and a higher bulk density than the API powder 
prepared via Process A. The rationale for Part 3 of the study is to perform 
relative bioavailability assessment of Process B versus Process A DiC to enable 
PK bridging across the patients who are using or will be using these 2 DiCs in the 
TAK-788 clinical development program. Part 3 of this study was added in 
Amendment 2 to assess the relative bioavailability of TAK-788 encapsulated in 
Process B DiC (test) and Process A DiC (reference) in healthy subjects.
Section 5.0 STUDY OBJECTIVES AND ENDPOINTS
Section 5.1.1 Primary Objectives
The primary objectives are: 
Part 1: to To assess safety and tolerability of TAK-788 and to identify a tolerable 
single oral dose of TAK-788 administered as a drug-in-capsule (DiC)
formulation in healthy subjects. 
Part 2: toTo characterize the effects of a low-fat meal on the PK of TAK-788 and its 
active metabolites, AP32960 and AP32914, administered as a DiC 
formulation in healthy subjects.
Part 3: To evaluate the bioavailability of a test (Process B) DiC of TAK-788 
relative to a reference (Process A) DiC of TAK-788 in healthy subjects.
Section 5.1.2 Secondary Objectives
The secondary objectives are: 
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Study No. TAK-788-1001
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Protocol Incorporating Amendment 03
13 November 2018
Part 1: to To characterize the PK of TAK-788 and its active metabolites, AP32960 
and AP32914, administered as a DiC formulation in healthy subjects.
Part 2: to/ Part 3:
To assess the safety of TAK-788 following a single dose of 
TAK-788 with or without a low-fat meal, administered as a DiC formulation
in healthy subjects.
Section 5.1.3 Exploratory Objectives
The exploratory objective is: 
Section 5.2 Endpoints
Section 5.2.1 Primary Endpoints
The primary endpoints are: 
Part 1: safety profile of orally administered TAK-788. 
•
number and percentage of subjects with 1 or more AEs.
•
number and percentage of subjects with 1 or more SAEs.
•
number and percentage of subjects with clinically defined abnormal laboratory 
values.
•
number and percentage of subjects with clinically defined abnormal vital signs.
Part 2: summary statistics of the PK parameters for TAK-788 and its 2 active 
metabolites, AP32960 and AP32914 under fasted conditions or following a low-fat 
meal. 
•
Cmax.
•
tmax.
•
AUCt (area under the concentration-time curve from time 0 to time t).
•
AUC∞ (area under the first moment concentration-time curve from time 0 to 
infinity calculated using the last quantifiable concentration.
•
t1/2z (terminal disposition phase half-life).
Part 3:summary statistics of the PK parameters for TAK-788 with different DiC 
under fasted conditions. 
•
Cmax.
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Property of Takeda: For non-commercial use only and subj
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TAK-788 (formerly AP32788)
Study No. TAK-788-1001
Page 88 of 92
Protocol Incorporating Amendment 03
13 November 2018
•
tmax.
•
AUCt.
•
AUC∞ (if data permitted).
•
t1/2z.
Section 5.2.2 Secondary Endpoints
The secondary endpoints are: 
Part 1: summary statistics of the PK parameters for TAK-788 and its 2 active 
metabolites, AP32960 and AP32914 under fasted conditions. 
•
Cmax.
•
tmax.
•
AUCt.
•
AUC∞.
•
t1/2z.
Part 2: safety profile of TAK-788 under fasted conditions or following a low-fat meal.
Part 3: safety profile of TAK-788 under fasted conditions.
Section 5.2.3 Exploratory Endpoints
The exploratory endpoint is: 
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Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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TAK-788 (formerly AP32788)
Study No. TAK-788-1001
Page 89 of 92
Protocol Incorporating Amendment 03
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Section 6.1 Overview of Study Design
This is a randomized, double-blind, randomized, placebo-controlled, single rising 
dose study, followed by aan open-label, crossover evaluation of the effects of a 
low-fat meal on the PK of TAK-788 PK and its 2 active metabolites in healthy 
subjects. , and a crossover evaluation of the relative bioavailability of TAK-788 
Process B DiC (test) versus Process A DiC (reference) in healthy subjects under 
fasting conditions. Following the completion of Part 1 (dose escalation phase) 
where a safe and tolerable dose in healthy subjects will be identified, Part 2 (food 
effect phase) and Part 3 (relative bioavailability of TAK-788 capsules) will be 
initiated where the effects of a low-fat meal on TAK-788 and the relative 
bioavailability of TAK-788 in test versus reference will be studied.
Section 6.1 Overview of the Design
…
Section 6.1.3 Part 3 – Relative Bioavailability
The purpose of Part 3 is to evaluate the bioavailability of a test DiC of TAK-788 
relative to a reference DiC of TAK-788. Part 3 of the study will be open-label. 
Subjects will be randomly assigned to a crossover sequence at a 1:1 ratio and 
administered a single dose of 160 mg TAK-788 capsule A DiC (reference) or 
160 mg TAK-788 capsule B DiC (test) on Day 1 in Period 1 and on Day 8 in 
Period 2 under fasting conditions, with a planned washout period of 7 days. 
PFTs (spirometry, lung volumes, and DLco) are required to be performed and 
assessed as normal at screening. PFTs will be performed on Day 3, Day 10, 
and/or Early Termination visit in Part 3 only if indicated on the basis of 
pulmonary symptoms; no chest CT scans will be done. Other clinical study 
procedures are the same as those in the dose escalation phase. Subjects will have 
PK collection samples collected during confinement, and the last PK sample will 
be collected at 72 hours postdose in each period. Subjects will be furloughed 
after the last PK sample collection in Period 1. Subjects will return to the clinical 
study site on Day 7 for Period 2 study. Subjects will be released from the clinical 
study site after the last PK sample collection in Period 2. Safety phone 
conferences will occur on Day 15 and 30 days after the last dose (window of up to 
2 days after Day 38).
Figure 6.c
Relative Bioavailability Schema (Part 3)
CCI
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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TAK-788 (formerly AP32788)
Study No. TAK-788-1001
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[New figure depicting Part 3 schema]
Section 6.2 Number of Subjects
...
Part 3:With a sample size of 10 healthy subjects, the 90% CI for the Cmax ratio is 
expected to be in the range of 87% to 115%, using an intrasubject Cmax
variability of 17% estimated in healthy subjects. After accounting for 2 potential 
dropouts in Part 3, the final sample size is up to 12 healthy subjects. This sample 
size assumes no replacement of subjects who may drop out of the study before 
the completing the PK sample collections in Part 3.
Section 8.1.3 Relative Bioavailability (Part 3)
Subjects in Part 3 will receive a single dose of TAK-788 160 mg test DiC 
(Process B) or a single dose of TAK-788 160 mg reference DiC (Process A) under 
fasted conditions on Day 1 or Day 8 following an overnight fast of at least 
10 hours. The drug product should be administered with 240 mL (8 fluid ounces) 
of water. No food should be allowed for at least 4 hours postdose.
Water can be allowed as desired except for 1 hour before and after drug 
administration. Subjects should receive standardized meals scheduled at the 
same time in each period of the study.
Section 8.10 Description of Investigational Agents
TAK-788 drug product is a nonsterile oral DiC formulation. The active study drug is 
available as 20 or 40 mg dosage strength capsules. The API has been synthesized 
using 2 different processes (Process A and Process B). Before Amendment 1, all 
subjects in Part 1 of this study received TAK-788 from Process B unmilled only with 
the capsule strength of 20 mg, and subjects in Part 2 received TAK-788 from 
Process A with capsule strength of 20 mg. After Amendment 1, some additional 
cohorts in Part 1 may receive TAK-788 from Process A.
Process A and Process B are the same succinate salt in chemical structure but 
synthesized with different physical properties. Process B incorporates optimizations 
in scale up, solvents, and reagents and implements a new step.processes. The API 
from Process B has larger particle size and higher bulk density than that from 
Process A. At the time of Amendment 1, preliminary PK data from this study and a 
phase 1/2 study in patients with NSCLC (Study AP32788-15-101) indicate 
approximately 30% to 60% lower exposures (TAK-788 AUC24) in healthy subjects 
receiving Process B unmilled TAK-788 DiC compared with patients with NSCLC 
receiving Process A TAK-788 DiC.
Section 9.3 Treatment Group Assignments
...
In Part 3, subjects will receive TAK-788 Process B DiC (test) or Process A DiC 
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(reference), then crossover to receive the alternate TAK-788 (test or reference) 
formulation after a washout of at least 7 days between doses of TAK-788.
Section 9.4.7 Pulmonary Function Tests
PFTs include spirometry, lung volumes, and DLco. In Part 1, PFTs will be performed 
at screening but no more than 7 days before Day 1, and at Day 3 before furlough. In 
Parts 2 and 3, PFTs will be performed at screening and at Day 3, Day 10, and/or 
Early Termination visit if indicated on the basis of pulmonary symptoms. 
Section 13.1.3 PK Analysis
Descriptive statistics, including arithmetic mean, geometric mean, SD, coefficient of 
variation (%CV), minimum, median, and maximum, will be calculated and presented 
by dose level in Part 1 and, for each treatment under fasted versus fed conditions in 
Part 2, and for each treatment (test vs reference drug formulation) under fasted 
conditions in Part 3 for plasma concentrations of TAK-788 and its 2 active 
metabolites, AP32960 and AP32914.
...
In Part 3, PK parameters (ln-transformed) of TAK-788 for the test formulation 
(Process B DiC) and the reference formulation (Process A DiC) will be compared 
using an ANOVA model. The ANOVA model will include treatment (test versus 
reference), period, and sequence as fixed effects and subject nested within 
sequence as a random effect. Each ANOVA will calculate the LSM, the 
difference between treatment LSMs, and the SE associated with the difference. 
Residual, subject nested within sequence, and intersubject variance, along with 
the intrasubject and intersubject CV, will be reported. Ratios of LSM will be 
calculated using the exponential function of the difference between treatment 
LSMs from the analyses on the ln-transformed Cmax, AUCt, and AUC∞(if data 
permitted).
Section 13.2 Determination of Sample Size
...
Part 3 With a sample size of 10 healthy subjects, the 90% CI for the Cmax ratio is 
expected to be in the range of 87% to 115%, using an intrasubject Cmax
variability of 17% estimated in healthy subjects. After accounting for 2 potential 
dropouts in Part 3, the final sample size allows for up to 12 healthy subjects. This 
sample size assumes no replacement of subjects who may drop out of the study 
before the completing the PK sample collections in Part 3.
Appendix A Schedule of Events
[Addition of Table 3 Relative Bioavailability Study (Part 3)]
[Revised Table 5 Pharmacokinetic Plasma Concentration Sampling Schedule for 
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Study No. TAK-788-1001
Page 92 of 92
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Parts 2 and 3 to include PK sampling for Part 3] 
Rationale for Change: The rationale for Part 3 of the study is to perform relative bioavailability 
assessment of Process B versus process A DiC to enable PK bridging across the patients who are 
using or will be using these 2 DiCs in the TAK 788 clinical development program.
The following sections also contain this change:

Study title.

Section 2.0 STUDY SUMMARY.

Section 6.3.1 Duration of an Individual Subject’s Study Participation.

Table 6.a Primary and Secondary Endpoints for Disclosures.

Section 7.1 Inclusion Criteria.

Section 9.4.7 Pulmonary Function Tests.

Section 9.4.8 Drug, Alcohol, and Tobacco Testing.

Section 9.4.9 Pregnancy Test.

Section 9.4.11 AEs.

Section 9.4.12 Enrollment.

Section 9.4.13 ECG.

Section 9.4.14 Chest CT Scan.

Section 9.4.16 PK Measurements.

Section 9.5 Completion of Study Treatment for Individual Subjects.

Section 9.6 Discontinuation of Treatment With Study Drug and Subject Replacement.

Section 13.1.1 Analysis Sets. 
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: Phase 1, Randomized, Double-blind, Placebo-Controlled, Single Rising Dose Study to 
Evaluate Pharmacokinetics, Safety, and Tolerability of TAK-788 Followed by Open-Label, 
Crossover Evaluation of the Effects of a Low-Fat Meal on TAK-788 Pharmacokinetics and 
Evaluation of Relative Bioavailability of TAK-788 Capsules in Healthy Subjects
NCT Number: NCT03482453
SAP Approve Date: 27 March 2019
Certain information within this Statistical Analysis Plan has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable (PPD) information 
or company confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.


1.0
TITLE PAGE
STATISTICAL ANALYSIS PLAN
STUDY NUMBER: TAK-788-1001
Phase 1, Open-Label, Single Rising Dose Study to Evaluate PK, Safety, and Tolerability of 
TAK-788 Followed by Crossover Evaluation the Effects of a Low-Fat Meal on TAK-788 
PK in Healthy Subjects
PHASE 1
Version: 1.0 
Date: 27 March 2019
Prepared by:
Based on:
Protocol Version: Amendment 03
Protocol Date: 13 November 2018
PPD
Property of Takeda: For non-commercial use o
 and subject to the applicable Terms of Use
PK, Saf
K, Sa
of a Low
f a Lo
cts
rsion
on: 1
te: 27 M
27 
n:
Proto
Pro
For non-com
rt


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2.0
TABLE OF CONTENTS
1.0
TITLE PAGE ..................................................................................................................1
2.0
TABLE OF CONTENTS.................................................................................................2
3.0
LIST OF ABBREVIATIONS..........................................................................................4
4.0
OBJECTIVES .................................................................................................................5
4.1
Primary Objectives ....................................................................................................5
4.2
Secondary Objectives.................................................................................................5
4.3
Exploratory Objectives ..............................................................................................5
4.4
Study Design .............................................................................................................5
5.0
ANALYSIS ENDPOINTS.............................................................................................10
5.1.1
Primary Endpoints .............................................................................................10
5.1.2
Secondary Endpoints..........................................................................................10
5.1.3
Exploratory Endpoints .......................................................................................11
6.0
DETERMINATION OF SAMPLE SIZE.......................................................................12
7.0
METHODS OF ANALYSIS AND PRESENTATION...................................................13
7.1
General Principles....................................................................................................13
7.1.1
Study Definitions ...............................................................................................13
7.1.2
Definition of Study Days....................................................................................13
7.1.3
Definition of Baseline Values.............................................................................13
7.1.4
Windowing of Visits ..........................................................................................13
7.1.5
Withdrawals, Dropouts, Loss to Follow-up ........................................................14
7.1.6
Imputations for Missing Dates ...........................................................................14
7.2
Randomization and Stratification.............................................................................15
7.3
Unblinding...............................................................................................................15
7.4
Statistical Software ..................................................................................................16
7.5
Analysis Sets ...........................................................................................................16
7.5.1
Randomized Population .....................................................................................16
7.5.2
Safety Analysis Set ............................................................................................16
7.5.3
Pharmacokinetic (PK)-Evaluable Population......................................................16
7.6
Disposition of Subjects ............................................................................................16
7.6.1
Subject Disposition ............................................................................................16
7.7
Demographic and Other Baseline Characteristics.....................................................16
7.7.1
Demographics....................................................................................................17
7.7.2
Inclusion/Exclusion Criteria...............................................................................17
7.7.3
Medical History .................................................................................................17
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7.7.4
Height................................................................................................................17
7.7.5
Concomitant Medications...................................................................................17
7.8
Study Drug Exposure and Compliance.....................................................................17
7.8.1
Extent of Exposure.............................................................................................17
7.8.2
Treatment Compliance and Modifications..........................................................17
7.9
Efficacy Analysis.....................................................................................................18
7.10
Pharmacokinetic Analysis........................................................................................18
7.11
Pharmacogenetic Analysis .......................................................................................19
7.12
Safety Analysis........................................................................................................19
7.12.1 Adverse Events ..................................................................................................19
7.12.2 Clinical Laboratory Evaluations .........................................................................20
7.12.3 Vital Signs .........................................................................................................20
7.12.4 CT Scans............................................................................................................21
7.12.5 12-Lead ECGs ...................................................................................................21
7.13
Interim Analysis ......................................................................................................21
7.14
Changes in the Statistical Analysis Plan...................................................................21
8.0
REFERENCES..............................................................................................................22
9.0
APPENDICES...............................................................................................................23
LIST OF IN-TEXT TABLES AND LISTINGS
Table 7.a
Abnormal values for vital signs..........................................................................21
Table 7.b
Abnormal values for 12-Lead ECGs...................................................................21
LIST OF IN-TEXT FIGURES
Figure 4.a
Study Schema for Single Rising Dose Phase (Part 1)............................................7
Figure 4.b
Study Schema for Food Effect Phase (Part 2).......................................................8
Figure 4.c
Study Schema for Relative Bioavailability Phase (Part 3).....................................9
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3.0
LIST OF ABBREVIATIONS
AE
adverse event
ANOVA
analysis of variance
AUC
area under the plasma concentration-time curve
AUCextrap%
area under the curve from the last quantifiable concentration to infinity calculated using the 
observed value of the last quantifiable concentration, expressed as a percentage of AUC∞
AUCt
area under the concentration-time curve from time 0 to time t
AUC∞
area under the concentration-time curve from time 0 to infinity, calculated using the observed 
value of the last quantifiable concentration
Cav
average plasma concentration
Cmax
maximum observed plasma concentration
CT
computed tomography
Ctrough
observed plasma concentration at the end of a dosing interval
CV
coefficient of variation
DiC
drug-in-capsule (formulation)
DLco
diffusion capacity
DLT
dose-limiting toxicity
ECG
electrocardiogram
eCRF
electronic case report form
EGFR
epidermal growth factor receptor
GI
gastrointestinal
ln
log-transformed
LSM
least-squares mean
MedDRA
Medical Dictionary for Regulatory Activities
PFT
pulmonary function test
PK
pharmacokinetic(s)
SAE
serious adverse event
SOP
standard operating procedure
t1/2z
terminal disposition phase half-life
TEAE
treatment-emergent adverse event
tmax
time to first occurrence of Cmax
WHO
World Health Organization
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4.0
OBJECTIVES
4.1
Primary Objectives
The primary objectives are:
Part 1: to assess safety and tolerability of TAK-788 and to identify a tolerable single oral dose 
of TAK-788 administered as a DiC formulation in healthy subjects.
Part 2: to characterize the effects of a low-fat meal on the PK of TAK-788 and its active 
metabolites, AP32960 and AP32914, administered as a DiC formulation in healthy 
subjects.
Part 3: To evaluate the bioavailability of a test (Process B) DiC of TAK-788 relative to a 
reference (Process A) DiC of TAK-788 in healthy subjects.
4.2
Secondary Objectives
The secondary objectives are:
Part 1: to characterize the PK of TAK-788 and its active metabolites, AP32960 and AP32914, 
administered as a DiC formulation in healthy subjects.
Part 2/ Part 3: To assess the safety of TAK-788 following a single dose of TAK-788 in healthy 
subjects.
4.3
Exploratory Objectives
The exploratory objective is:
4.4
Study Design
This is a randomized, double-blind, placebo-controlled single rising dose study, followed by an 
open-label, crossover evaluation of the effects of a low-fat meal on the PK of TAK-788 and its 
2 active metabolites in healthy subjects, and a crossover evaluation of the relative bioavailability 
of TAK-788 Process B DiC (test) versus Process A DiC (reference) in healthy subjects under 
fasting conditions. Following the completion of Part 1 (dose escalation phase) where a safe and 
tolerable dose in healthy subjects will be identified, Part 2 (food effect phase) and Part 3 (relative 
bioavailability of TAK-788 capsules) will be initiated where the effects of a low-fat meal on 
TAK-788 and the relative bioavailability of TAK-788 in test versus reference will be studied.
CCI
Property of Takeda: For no
Design
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TAK
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AK-788 
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Part 1 – Dose Escalation:
In the double-blind, randomized, placebo-controlled dose escalation phase, cohorts of 8 healthy 
subjects will be randomized: Under fasting conditions, 6 subjects will receive a single dose of 
TAK-788 and 2 subjects will receive placebo. The starting dose will be 20 mg, then with each 
subsequent 8-subject cohort the dose will escalate to a single dose of 40, 80, 120, up to 160 mg. 
Dose escalation can occur if there are no DLTs following the administration of TAK-788 and all 
Grade ≥2 treatment-related AEs resolve to Grade ≤1 or return to baseline by Day 5. If all 
treatment-related Grade ≥2 AEs have not resolved to Grade ≤1 or returned to baseline by Day 5, 
the assessment will be repeated on Day 8 and Day 15, if necessary, before proceeding to the next 
planned higher dose. The subjects will remain at the clinical study site for at least 48 hours 
postdose for close safety monitoring. The subjects will be furloughed from the site 48 hours 
postdose if there are no Grade ≥2 AEs. Subjects will return to the site for PK sample collection 
on Days 4, 5, and 8. A final safety phone conference will occur 30 days after the last dose 
(window of up to 2 days after Day 30). 
Additional cohorts may also be enrolled in Part 1 to assess the safety, tolerability, and PK of 
single-dose TAK-788 DiC containing TAK-788 active pharmaceutical ingredient (API) from a 
different synthetic process (such as Process A). The dose(s) of TAK-788 in the additional 
cohort(s) will be determined by the safety, tolerability, and PK exposure data from the completed 
cohorts in this study and the experience in the ongoing phase 1/2 study in patients with NSCLC 
(Study AP32788-15-101). The highest dose tested in Part 1 of the study will not exceed the unit 
dose of the MTD identified in Study AP32788-15-101.
To mitigate the risk of treatment, pulmonary function tests (PFTs: spirometry, lung volumes, and 
diffusion capacity [DLco]) and chest computed tomography (CT) scan are required to be 
performed and assessed to be normal (PFTs ≥80% of predicted normal) at screening no more 
than 7 days before Day 1. At 48 hours postdose before furlough, PFTs will be performed and 
pulmonary symptoms assessed. If the DLco has decreased by >20% from baseline or the subject 
reports pulmonary symptoms on Day 3, a chest CT scan will be performed. Any DLco 
abnormalities or chest CT scan abnormalities will be followed weekly until resolution. An 
appropriate treatment will be initiated by the investigator or attending pulmonologist in the event 
of clinically significant pulmonary symptoms, abnormal DLco, or abnormal chest CT scan.
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Figure 4.a
Study Schema for Single Rising Dose Phase (Part 1)
DiC, drug in capsule. 
Part 2 – Food Effect:
The purpose of Part 2 is to evaluate the effect of a low-fat meal on TAK-788 PK using a 2-way 
crossover design. The low-fat meal effect was assessed at 120 mg and 160 mg doses, which are 
identified as tolerable doses in Part 1.
In the food effects part of the study, subjects will be randomized to a crossover sequence at a 
1:1 ratio and administered the tolerable single dose on Day 1 in Period 1 and Day 8 in Period 2 
with a low-fat meal (Treatment A) or under fasting conditions (Treatment B) with a planned 
washout period of at least 7 days which may be updated pending the PK results from Part 1. The 
content of a low-fat meal is shown in Figure 4.b. The duration of washout will be adjusted to 
ensure that the Ctrough (observed plasma trough concentration) of TAK-788 at 168 hours postdose 
in Part 1 is <5% of the observed Cmax of TAK-788 at the dose of the food effect evaluation. The 
planned washout period used in Part 2 is 7 days. PFTs (spirometry, lung volumes, and DLco) and 
chest CT scan are required to be performed and be assessed as normal at screening. PFTs and 
chest CT scan will be done on Day 3, Day 10, and/or Early Termination visit in Part 2 only if 
indicated on the basis of pulmonary symptoms. Other clinical study procedures are the same as 
those in the dose escalation phase. Subjects will return to the site for the PK sample collection on 
Days 4, 5, 8, 11, 12, and 15. A final safety phone conference will occur 30 days after the last 
dose (window of up to 2 days after Day 38). 
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Figure 4.b
Study Schema for Food Effect Phase (Part 2)
Part 3 – Relative Bioavailability:
The purpose of Part 3 is to evaluate the bioavailability of a test DiC of TAK-788 relative to a 
reference DiC of TAK-788. Part 3 of the study will be open-label. 
Subjects will be randomly assigned to a crossover sequence at a 1:1 ratio and administered a 
single dose of 160 mg TAK-788 capsule A DiC (reference) or 160 mg TAK-788 capsule B DiC 
(test) on Day 1 in Period 1 and on Day 8 in Period 2 under fasting conditions, with a planned 
washout period of 7 days. PFTs (spirometry, lung volumes, and DLco) are required to be 
performed and assessed as normal at screening. PFTs will be performed on Day 3, Day 10, and 
Early Termination visit in Part 3 only if indicated on the basis of pulmonary symptoms; no chest 
CT scans will be done. Other clinical study procedures are the same as those in the dose 
escalation phase. Subjects will have PK collection samples collected during confinement, and the 
last PK sample will be collected at 72 hours postdose in each period. Subjects will be furloughed 
after the last PK sample collection in Period 1. Subjects will return to the clinical study site on 
Day 7 for Period 2 study. Subjects will be released from the clinical study site after the last PK 
sample collection in Period 2. Safety phone conferences will occur on Day 15 and 30 days after 
the last dose (window of up to 2 days after Day 38).
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Figure 4.c
Study Schema for Relative Bioavailability Phase (Part 3)
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5.0
ANALYSIS ENDPOINTS
5.1.1
Primary Endpoints
The primary endpoints are:
Part 1: safety profile of orally administered TAK-788. 

number and percentage of subjects with 1 or more AEs.

number and percentage of subjects with 1 or more SAEs.

number and percentage of subjects with clinically defined abnormal laboratory values.

number and percentage of subjects with clinically defined abnormal vital signs.
Part 2: summary statistics of the PK parameters for TAK-788 under fasted conditions or 
following a low-fat meal.

Cmax.

tmax.

AUCt (area under the concentration-time curve from time 0 to time t).

AUC∞(area under the first moment concentration-time curve from time 0 to infinity 
calculated using the last quantifiable concentration.

t1/2z (terminal disposition phase half-life).
Part 3: summary statistics of the PK parameters for TAK-788 with different DiC under fasted 
conditions. 

Cmax.

tmax.

AUCt.

AUC∞(if data permitted).

t1/2z.
5.1.2
Secondary Endpoints
The secondary endpoints are:
Part 1: summary statistics of the PK parameters for TAK-788 and its 2 active metabolites,
AP32960 and AP32914 under fasted conditions. 

Cmax.

tmax.

AUCt.
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!
AUC∞.
!
t1/2z.
Part 2: safety profile of TAK-788 under fasted conditions or following a low-fat meal.
Part 3: safety profile of TAK-788 under fasted conditions.
5.1.3
Exploratory Endpoints
The exploratory endpoint is: 
CCI
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6.0
DETERMINATION OF SAMPLE SIZE
Part 1: The estimated sample size of approximately 56 subjects is determined on the basis of 
clinical rather than statistical considerations. The number of subjects in this part of study is 
consistent with phase 1 dose-finding studies. 
Part 2: With a sample size of 14 healthy subjects, the 90% CI for the AUC ratio is expected to be 
in the range of 84%-119%, using an intrasubject AUC variability of 27% in patients with cancer 
and assuming a TAK-788 AUC ratio of 1 in the fed versus fasted comparison. After accounting 
for 2 potential dropouts in Part 2, the final sample size is 16 healthy subjects. Subjects who 
vomit within 8 hours after dosing will be considered nonevaluable for PK assessments. Subjects 
who are withdrawn from treatment before completing study-required PK assessments and 
subjects who are not non–PK-evaluable will not be replaced.
Part 3: With a sample size of 10 healthy subjects, the 90% CI for the Cmax ratio is expected to be 
in the range of 87% to 115%, using an intrasubject Cmax variability of 17% estimated in healthy 
subjects. After accounting for 2 potential dropouts in Part 3, the final sample size is up to 
12 healthy subjects. This sample size assumes no replacement of subjects who may drop out of 
the study before the completing the PK sample collections in Part 3. 
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7.0
METHODS OF ANALYSIS AND PRESENTATION
7.1
General Principles 
In general, summary tabulations will include the number of observations, (arithmetic) mean, 
standard deviation (SD), geometric mean and coefficient of variation (%CV) for PK related 
parameters, median, minimum, and maximum for continuous variables, and the number and 
percent (of non-missing) per category for categorical data, unless specified otherwise. Means and 
medians will be presented to 1 more decimal place than the recorded data. The standard 
deviations (SDs) will be presented to 2 more decimal places than the recorded data. Confidence 
intervals (CIs) about a parameter estimate will be presented using the same number of decimal 
places as the parameter estimate.
The PK parameters will be summarized with a precision of 3 significant digits, while tmax is 
presented with the number of relevant decimal places to specify the sampling time. Percent CV 
and frequency percentages will be presented as integers.
Summary statistics will be calculated by time point, if applicable.
All confidence intervals, statistical tests, and resulting P-values will be reported as 2-sided and 
will be assessed at α=0.1 significance level unless otherwise stated. P-values will be rounded to 3 
decimal places prior to assessment of statistical significance.
Screen failure subjects will be grouped and listed at the end.
Unless specified otherwise, analyses in Part 2 should be conducted by doses.
7.1.1
Study Definitions
A Subject is considered to be enrolled when the first dose of study drug has been administered. 
Study start date is defined as the date of first dose of study drug.
7.1.2
Definition of Study Days
Study Day 1 is defined as the date on which a subject is administered their first dose of the study 
drug. Other study days are defined relative to the Study Day 1 with Day 1 being Study Day 1 and 
Day -1 being the day prior to Study Day 1.
7.1.3
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.
7.1.4
Windowing of Visits
All data will be categorized based on the scheduled visit at which they were collected. The 
analysis of PK data and determination of PK parameters will be based on the actual elapsed time 
post dose relative to the first dosing.
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7.1.5
Withdrawals, Dropouts, Loss to Follow-up
Any subject who voluntarily withdraws consent or is discontinued (eg, because of an AE) from 
the study before completion will be considered withdrawn from the study. Treatment with study 
drug may also be discontinued for any of the following reasons:

AE.

Pregnancy.

Withdrawal by subject. 

Lost to follow-up.

Protocol violation. 

Termination of the study.

Other.
When an event such as a family emergency, a transient intercurrent illness (such as a cold) 
unrelated to study drug, or a remediable act of non-compliance prevents a subject from 
participating in a scheduled visit but the subject wishes to continue in the study, with the 
agreement of the investigator, the research site staff may attempt to reschedule the visit and 
retain the subject in the study. 
If a subject is prematurely discontinued from participation in the study for any reason after drug 
administration, the investigator or designee must make every effort to perform the assessments 
scheduled for the follow-up visit. The reason for withdrawal will be recorded in the eCRF and 
the subject’s source medical record.
Subjects in Part 2 and 3 who discontinue their participation in the study before receiving the Day 
8 dose will undergo the safety follow-up as specified in the Schedules of Events. 
Replacement of subjects is not planned but may occur under special circumstances at the 
sponsor’s discretion, in agreement with the investigator.
7.1.6
Imputations for Missing Dates
7.1.6.1
Analysis of Missing Adverse Event Dates

If the start date has month and year but day is missing, the event will be considered.
–
treatment emergent if both the month and year of the start date of the event are on or after 
the month and year of the date of the first dose of study drug, and on or before the month 
and year of the date of the last dose of study. 

If the start date has year, but day and month are missing, the event will be considered.
–
treatment emergent if the year of the start date of the event is on or after the year of the 
date of the first dose of study drug, and on or before the year of the date of the last dose 
of study drug plus 30 days.
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
If the start date of an event is completely missing, the event will be considered treatment 
emergent.
7.2
Randomization and Stratification 
Subjects in Part 1 will receive a single dose of TAK-788 or placebo under fasted conditions. 
In Part 2, subjects will receive TAK-788 under fed or fasted conditions then crossover to receive 
TAK-788 under the alternate condition (fed versus fasted) after a washout of at least 7 days 
between doses of TAK-788.
In Part 3, subjects will receive TAK-788 Process B DiC (test) or Process A DiC (reference), then 
crossover to receive the alternate TAK-788 (test or reference) formulation after a washout of at 
least 7 days between doses of TAK-788.
Before dosing on Day 1, subjects will be assigned a randomization number in accordance with 
the randomization code generated by the sponsor, the sponsor’s designee, or the clinical site. The 
randomization code will be maintained in a room with access restricted to pharmacy personnel 
only. 
Once a randomization number has been allocated to one subject, it may not be assigned to 
another subject. Subjects withdrawn prematurely from the study will not be replaced.
7.3
Unblinding
Part 1 of this study will be performed in a double-blind manner. 
Because TAK-788 and the placebo formulations may be different in appearance, all subjects will 
be blindfolded during dosing. An unblinded site pharmacist will dispense study drugs. These 
personnel will not be involved in any other study procedures (data collection, assessments, or 
documentation activities). 
One person in the bioanalytical laboratory will be unblinded to exclude the PK samples collected 
from subjects who were dosed with placebo from the bioanalysis. 
If needed, 1 or 2 PK scientists may also be unblinded to conduct the preliminary PK data 
analysis during the study. 
After the subjects’ furlough begins on Day 3 of Part 1, the double-blind will become single-
blind. The site staff, investigator(s), and sponsor will be unblinded on Day 3 but study subjects 
will remain blinded until after the follow-up phone call 30 days after their last dose. After 
furlough on Day 3, the overall randomization code will be broken for safety evaluation and 
reporting purposes only. 
The study blind should not be broken before Day 3 of Part 1 except in a medical emergency 
where knowledge of the treatment administered would affect the treatment of the emergency. 
The decision to break the blind will be made on a case-by-case basis, at the discretion of the 
investigator in collaboration with the sponsor/medical monitor. The applicable site standard 
operating procedure (SOP) will be followed for blind-breaking procedures.
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Part 2 and Part 3 are open-label. 
7.4
Statistical Software 
SAS version 9.4 (or higher) will be used for all analyses.
7.5
Analysis Sets
7.5.1
Randomized Population

All subjects who are randomized to receive study treatment in Part 1, Part 2, or Part 3.
7.5.2
Safety Analysis Set
All enrolled subjects who receive any study treatment in the treatment period.
7.5.3
Pharmacokinetic (PK)-Evaluable Population
All subjects in the Safety Population who have no major protocol deviations that would affect 
the PK analysis and who have sufficient data to calculate PK parameters. This population will be 
used for the PK analyses. Data from subjects who experience emesis within the first 8 hours 
following dosing may be excluded from the final analysis (to be evaluated on a case-by-case 
basis).
7.6
Disposition of Subjects
7.6.1
Subject Disposition
Tabulations of patient disposition data will be generated by sequences. 
Subject disposition data will include the number of subjects for the following categories: subjects 
treated, subjects in the PK-evaluable population, subjects who have completed treatment, 
subjects who discontinued study, and the primary reason off study. Subjects will be considered to 
have completed the study if they have completed the protocol-specified assessments within the 
protocol. Percentages will be based on the number of subjects in the safety populations.
Data concerning subject disposition (e.g., primary reason for discontinuation, population) will be 
presented in by-subject listings.
7.7
Demographic and Other Baseline Characteristics
Demographic and baseline characteristics will be summarized descriptively. Mean, SD, 
minimum, median and maximum will be calculated for continuous variables. Frequency and 
percentages will be calculated for categorical variables.
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7.7.1
Demographics
Demographics will be summarized for the total safety population by treatment arm in Part 1 and 
sequences in Part 2 and Part 3. Demographic data to be evaluated will include age at screening,
race, ethnicity, and sex.
No inferential statistics will be generated.
7.7.2
Inclusion/Exclusion Criteria 
All protocol deviations will be reviewed, and major protocol deviations will be identified and 
listed.
7.7.3
Medical History
Medical history abnormalities will be coded to MedDRA terms (version 20.0 or higher). Physical
examination abnormalities will also be listed.
7.7.4
Height
Subject height will be summarized for the total safety population by treatment/sequences.
7.7.5
Concomitant Medications
The original verbatim terms collected in the eCRF for concomitant medications will be coded
using the WHO Drug Dictionary into drug class (Anatomical Therapeutic Chemical 
classification level 2) and preferred term. Subjects are counted once for each WHO drug generic 
term. Concomitant procedures will not be coded.
Concomitant medication is defined as any medication that occurs after administration of the first
dose of study treatment and up through 30 days after the last dose of study drug. 
Concomitant therapies with start or end dates that are completely or partially missing will be 
analyzed using the same imputation rules as adverse events.
Concomitant medications and procedures will be presented in separate by-subject listings.
7.8
Study Drug Exposure and Compliance
7.8.1
Extent of Exposure
Subjects in Part 1 will receive a single dose of TAK-788 or placebo. Subjects in Part 2 will 
receive a tolerable single dose identified in Part 1 on Day 1 in Period 1 and on Day 8 in Period 2. 
Subjects in Part 3 will receive a single dose of TAK-788 160 mg administered as Process B 
drug-in-capsule(DiC) and a single dose of TAK-788 160 mg administered as Process A DiC. All 
study drug administration will be listed. Meal administration and consumption will be listed.
7.8.2
Treatment Compliance and Modifications
No dose modification will occur.
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7.9
Efficacy Analysis
There will be no efficacy analysis.
7.10
Pharmacokinetic Analysis
Descriptive statistics, including arithmetic mean, geometric mean, SD, coefficient of variation 
(%CV), minimum, median, and maximum, will be calculated and presented by dose level in Part 
1, for each treatment under fasted versus fed conditions in Part 2, and for each treatment (test vs 
reference drug formulation) under fasted conditions in Part 3 for plasma concentrations of 
TAK-788 and its 2 active metabolites, AP32960 and AP32914. 
Analysis of PK parameters will be performed for TAK-788, AP32960, and AP32914. The 
concentration-time profiles will be analyzed using noncompartmental methods to estimate PK 
parameters in plasma. The number of observations, arithmetic mean, geometric mean, SD, %CV, 
median, minimum, and maximum values will be calculated for the PK parameters Cmax, tmax, 
AUCt, AUC∞, t1/2z, AUCextrap% (area under the curve from the last quantifiable concentration to 
infinity calculated using the observed value of the last quantifiable concentration, expressed as a 
percentage of AUC∞), CL/F (apparent clearance after extravascular administration, calculated 
using the observed value of the last quantifiable concentration), Vz/F (apparent volume of 
distribution during the terminal disposition phase after extravascular administration, calculated 
using the observed value of the last quantifiable 
 
. Dose proportionality analysis by the power model will 
be performed for Cmax and AUC in Part 1.
In Part 2, PK parameters (natural log-transformed [ln]) of TAK-788, AP32960, and AP32914 
will be compared under fasted versus fed conditions using an analysis of variance (ANOVA) 
model separately by each dose. The ANOVA model will include fasted versus fed condition, 
period, and sequence as fixed effects and subject nested within sequence as a random effect. 
Each ANOVA will calculate the least-squares mean (LSM), the difference between treatment 
LSMs, and the standard error associated with the difference. Residual, subject nested within 
sequence, and intersubject variance, along with the intrasubject and intersubject CV, will be 
reported. Ratios of LSM will be calculated using the exponential function of the difference 
between treatment LSMs from the analyses on the ln-transformed Cmax, AUCt, and AUC∞. 
In Part 3, PK parameters (ln-transformed) of TAK-788 for the test formulation (Process B DiC) 
and the reference formulation (Process A DiC) will be compared using an ANOVA model. The 
ANOVA model will include treatment (test versus reference), period, and sequence as fixed 
effects and subject nested within sequence as a random effect. Each ANOVA will calculate the 
LSM, the difference between treatment LSMs, and the SE associated with the difference. 
Residual, subject nested within sequence, and intersubject variance, along with the intrasubject 
and intersubject CV, will be reported. Ratios of LSM will be calculated using the exponential 
function of the difference between treatment LSMs from the analyses on the ln-transformed 
Cmax, AUCt, and AUC∞ (if data permitted).
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Low-fat meal effect in Part 2 and similarity of 2 formulations in Part 3 will be concluded if the 
90% confidence interval (CI) for the ratio of population geometric means of primary PK 
parameters Cmax, AUC∞, and AUCt (only if AUC∞ is not available) between the 2 treatments 
(fasted versus fed in part 2 and Process A DIC vs Process B DIC) is contained in the equivalence 
limits of 80% to 125%. 
Tmax will not be transformed and will be analyzed using non-parametric analysis (Walsh averages 
and appropriate quartile of the Wilcoxon signed-rank test). Median (range) for each treatment 
and p-value will be presented.
7.11
Pharmacogenetic Analysis
Not applicable.
7.12
Safety Analysis
Safety and tolerability parameters will be listed by subject, study part, and treatment group, and 
displayed in summary tables using descriptive statistics. All subjects receiving placebo in Part 1 
will be pooled and analyzed as one placebo group. 
Safety analyses will be conducted separately for subjects who received TAK-788 and placebo.
Physical Examinations will be listed. Follow up Telephone contacts will be listed.
7.12.1 Adverse Events
Original terms used in the eCRFs by the investigator or designees to identify AEs will be coded
using MedDRA (version 20.0 or higher) terminology.
The number and percentage of subjects with TEAEs will be summarized by MedDRA System 
Organ Class and Preferred Term and study group and by study group by maximum severity and 
relationship to study treatment. A TEAE is any AE that is new in onset or was aggravated in 
severity or frequency following the first dose of study drug, up to and including the last visit of 
the study.
Adverse events with start dates that are completely or partially missing will be analyzed as 
described in section 7.1.6.
7.12.1.1 Overall Summary
An overall summary treatment-emergent AE table will include numbers and percentages of 
subjects who had any treatment-emergent AE, treatment-related treatment-emergent AE, grade 3 
or higher treatment-emergent AE, grade 3 or higher treatment-related treatment-emergent AE, 
serious AE (SAE), treatment-related SAE, treatment-emergent AE resulting in discontinuation, 
and on-study deaths.
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7.12.1.2 Serious Adverse Events
The number and percentage of subjects experiencing at least one treatment emergent serious AE 
(SAE) will be summarized by MedDRA SOC and PT. Similar summary will be generated for 
treatment emergent treatment-related SAEs.
By-subject listings of the SAEs will be presented (the subject listing will contain all SAEs 
regardless of treatment emergent AE status). The treatment-related SAEs will also be presented. 
7.12.1.3 DLTs
DLTs are not captured in the eCRFs.
7.12.1.4 Deaths
By-subject listings of the deaths will be presented. All deaths occurring on-study will be 
displayed (regardless of treatment emergent AE status). On-study death is defined as the death 
that occurs between the first dose of study drug and 30 days after the last dose of study drug.
7.12.1.5 Adverse Events Resulting in Discontinuation of Study Drug
The number and percentage of subjects experiencing at least one adverse event resulting in 
discontinuation of study drug will be summarized by MedDRA SOC and PT.
By-subject listing of AEs resulting in discontinuation of study drug will be presented. All AEs 
resulting in discontinuation of study drug occurring on-study will be displayed (regardless of 
treatment emergent AE status).
7.12.2 Clinical Laboratory Evaluations
For the purposes of summarization, all laboratory values will be converted to standardized units.
If a lab value is reported using a non-numeric qualifier (eg, less than (<) a certain value, or 
greater than (>) a certain value), the given numeric value will be used in the summarization, 
ignoring the non-numeric qualifier.
If a subject has repeated laboratory values for a given time point, the value from the last 
evaluation will be used.
Laboratory data will be summarized by the type of laboratory test and chronological time point.
Descriptive statistics and the number of subjects with laboratory test results below, within, and
above normal ranges will be tabulated by scheduled time. Abnormal findings in laboratory data
will be listed with a flag for Low, High or Abnormal.
7.12.3 Vital Signs
Descriptive statistics will be calculated for vital signs (blood pressure, pulse rate, and respiratory
rate) and PFTs (spirometry, lung volumes, and DLco), and will be presented for each time point 
by study group (absolute values and change from baseline). PFT abnormalities will be listed with 
a derived flag for any subject whose DLco has decreased by >20% from baseline. Vital sign 
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Statistical Analysis Plan Draft
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abnormalities will be listed with a derived flag for abnormalities based on the criteria specified in 
the following tables. 
Table 7.a
Abnormal values for vital signs
Vital Sign Parameter
Unit
Lower Criteria 
Upper Criteria
Pulse
bpm
<50
>120
Systolic Blood Pressure 
(BP)
mm Hg
<85
>180
Diastolic BP
mm Hg
<50
>110
Temperature
°F (°C)
<96.1 (<35.6)
>99.9 (>37.7)
7.12.4 CT Scans
Chest CT scan results will be described narratively if abnormalities are reported during the study.
7.12.5 12-Lead ECGs
ECG results (absolute values and change from baseline) will be summarized using descriptive
statistics; frequencies (numbers and percentages) will be calculated for the overall evaluation by
scheduled time and study group. ECGs are taken as triplicates. All triplicates and mean of 
triplicates will be listed. The mean values will be used for summaries. ECG abnormalities will be 
listed with a flag for Low, High or Abnormal.
Table 7.b
Abnormal values for 12-Lead ECGs
ECG Parameter
Unit
Lower Criteria
Upper Criteria
Heart Rate
bpm
<50
>120
PR Interval
msec
<120
>196
QRS Duratin
msec
<72
>112
RR Interval
msec
<600
>1200
QTcB
msec
<350
>446
QTcF
msec
<351
>438
7.13
Interim Analysis
No interim analysis is planned.
7.14
Changes in the Statistical Analysis Plan 
Not applicable.
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8.0
REFERENCES
Not applicable.
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9.0
APPENDICES
Not applicable.
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