A Phase 1/2 Study of the Oral EGFR/HER2 Inhibitor TAK-788 in Japanese Non-Small Cell Lung Cancer Patients
Phase: PHASE1
Conditions: Non-Small Cell Lung Cancer
Sponsor: Takeda

Title: A Phase 1/2 Study of the Oral EGFR/HER2 Inhibitor TAK-788 in Japanese Non-
Small Cell Lung Cancer Patients  
NCT Number: NCT03807778 
Protocol Approve Date: 12-JAN-2022 
Certain information within this protocol has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable 
information or company confidential information. 
This may include, but is not limited to, redaction of the following: 

Named persons or organizations associated with the study.

Patient identifiers within the text, tables, or figures or in by-patient data listings.

Proprietary information, such as scales or coding systems, which are considered
confidential information under prior agreements with license holder.

Other information as needed to protect confidentiality of Takeda or partners,
personal information, or to otherwise protect the integrity of the clinical study.
If needed, certain appendices that contain a large volume of personally identifiable 
information or company confidential information may be removed in their entirety if it 
is considered that they do not add substantially to the interpretation of the data (eg, 
appendix of investigator’s curriculum vitae). 

PROTOCOL 
A Phase 1/2 Study of the Oral EGFR/HER2 Inhibitor TAK-788 
in Japanese Non-Small Cell Lung Cancer Patients 
A Phase 1/2 Study of TAK-788 in Japanese Patients 
Sponsor: 
Takeda Pharmaceutical Company Limited. 
1-1, Doshomachi 4-chome, Chuo-ku, Osaka-shi, Osaka, Japan
Study Number: 
TAK-788-1003
EudraCT Number: 
Not applicable 
Compound: 
TAK-788 
Date: 
12 January 2022 
Amendment Number: 
06 
Amendment History: 
Date 
Amendment Number 
Region 
17 October 2018 
Initial Protocol 
All sites 
22 November 2018 
Amendment No. 01 
All sites 
20 December 2019 
Amendment No. 02 
All sites 
27 January 2020 
Amendment No. 03 
All sites 
25 June 2020 
Amendment No. 04 
All sites 
27 July 2020 
Amendment No. 05 
All sites 
12 January 2022 
Amendment No. 06 
All sites 
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Protocol Incorporating Amendment No. 06 
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1.0 
ADMINISTRATIVE INFORMATION 
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. 
The names and contact information for the medical monitor and responsible medical officer are 
in the protocol annex. 
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Protocol Incorporating Amendment No. 06 
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1.3 
Protocol Amendment 06 Summary of Changes 
This section describes the changes in reference from Amendment No. 05 to Amendment No. 06. 
Minor grammatical and editorial changes are included for clarification purposes only. Full details 
on changes of text are given in Appendix H. 
The primary reasons for this amendment are to: 
•
Add management and dose modification guidelines for decreased ejection fraction, cardiac
failure and QTc interval prolongation deemed TAK-788 related.
•
Update the list of drugs known to be associated with the development of Torsades de Pointes.
•
Incorporate changes due to coronavirus disease 2019 (COVID-19) public health emergency
including direct-to-patient (DTP) dispensing as an alternative method of dispensing self-
administered study drug, alternative methods for conducting patient visits, and
accommodations to allow local patient assessments.
Protocol Amendment 06 
Summary of Changes Since the Last Version of the Approved Protocol 
Sections Affected by Change 
Description of Each Change and Rationale 
Location 
Description 
Rationale 
Section 8.1 Study Drug Administration 
Section 9.4 Study Procedures 
Section 9.4.18 Disease Assessment 
Section 14.1 Study-Site Monitoring 
Visits 
Update text to include alternative 
methods for conducting patient 
visits and collecting data. 
To ensure patient monitoring and 
evaluation during the coronavirus 
disease 2019 (COVID-19) public 
health emergency. 
Section 8.4.1.1 Management of 
Selected Treatment-
Related Adverse Events 
Add dose modification table and 
supplemental description for 
loperamide dosing. 
To align the current protocol with 
newly available safety 
information, and to ensure 
consistency in dose modifications 
guidelines across the TAK-788 
program. 
Section 8.7.3 Concomitant Medications 
with QTc Interval 
Prolongation Potential 
Add additional guidance on the 
co-dosing of concomitant 
medications with QTc interval 
prolongation potential. 
To provide additional 
precautionary guidance for 
investigators regarding the 
concomitant dosing of 
medications with QTc interval 
prolongation potential. 
Section 8.13 Storage, Handling, and 
Accountability 
Update text to include direct-to-
patient as an alternative method 
for dispensing self-administered 
study drug. 
To ensure continuity of TAK-788 
treatment due to COVID-19 
related quarantines, cancellations 
of on-site visits, or concerns 
about possible COVID-19 
exposure. 
Appendix F Drugs with a Risk of 
Torsades de Pointes 
Replace the table with updated 
version. 
For consistency across the TAK-
788 program. 
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Protocol Incorporating Amendment No. 06 
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Protocol Incorporating Amendment No. 06 
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TABLE OF CONTENTS 
1.0 
ADMINISTRATIVE INFORMATION ..............................................................................2 
1.1 
Contacts..........................................................................................................................2 
1.2 
Approval ........................................................................................................................3 
1.3 
Protocol Amendment 06 Summary of Changes.............................................................4 
2.0 
STUDY SUMMARY.........................................................................................................11 
3.0 
STUDY REFERENCE INFORMATION .........................................................................20 
3.1 
Study-Related Responsibilities ....................................................................................20 
3.2 
Coordinating Investigator ............................................................................................20 
3.3 
List of Abbreviations ...................................................................................................21 
3.4 
Corporate Identification ...............................................................................................24 
4.0 
INTRODUCTION .............................................................................................................25 
4.1 
Background ..................................................................................................................25 
4.2 
Rationale for the Proposed Study ................................................................................26 
4.2.1 
Rationale for Dose .................................................................................................26 
4.2.2 
Benefit-Risk ...........................................................................................................26 
5.0 
STUDY OBJECTIVES AND ENDPOINTS .....................................................................28 
5.1 
Objectives ....................................................................................................................28 
5.1.1 
Phase 1 Part ............................................................................................................28 
5.1.2 
Phase 2 Part ............................................................................................................28 
5.2 
Endpoints .....................................................................................................................29 
5.2.1 
Phase 1 Part ............................................................................................................29 
5.2.2 
Phase 2 Part ............................................................................................................30 
6.0 
STUDY DESIGN...............................................................................................................31 
6.1 
Overview of Study Design ...........................................................................................31 
6.2 
Number of Patients ......................................................................................................32 
6.3 
Duration of Study .........................................................................................................33 
6.3.1 
Duration of an Individual Patient’s Study Participation ........................................33 
6.3.2 
Total Study Duration..............................................................................................33 
6.3.3 
Timeframes for Primary and Secondary Endpoints to Support Disclosures .........33 
6.3.4 
Post-trial Access.....................................................................................................35 
7.0 
STUDY POPULATION ....................................................................................................36 
7.1 
Inclusion Criteria .........................................................................................................36 
7.2 
Exclusion Criteria ........................................................................................................38 
8.0 
STUDY DRUG ..................................................................................................................41 
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8.1 
Study Drug Administration ..........................................................................................41 
8.2 
Definitions of DLT (Phase 1 Part only) .......................................................................41 
8.3 
Dose Escalation Rules (Phase 1 Part Only) .................................................................42 
8.3.1 
Intra-patient Dose Escalation (Phase 1 Part only) .................................................43 
8.4 
Dose Modification Guidelines .....................................................................................43 
8.4.1 
Dose Delays or Reductions ....................................................................................43 
8.4.2 
Dose Re-escalation.................................................................................................47 
8.4.3 
Criteria for Discontinuation of Study Drug ...........................................................47 
8.5 
Excluded Concomitant Medications and Procedures ..................................................48 
8.6 
Permitted Concomitant Medications and Procedures ..................................................49 
8.7 
Precautions and Restrictions ........................................................................................49 
8.7.1 
Pregnancy and Contraception ................................................................................49 
8.7.2 
Potential Drug Interactions ....................................................................................50 
8.7.3 
Concomitant Medications with QTc Interval Prolongation Potential....................51 
8.8 
Management of Clinical Events ...................................................................................51 
8.8.1 
Management of Adverse Drug Reactions ..............................................................51 
8.8.2 
Management of Selected Treatment-Related Adverse Events ...............................52 
8.9 
Blinding and Unblinding..............................................................................................52 
8.10 
Description of Investigational Agents .........................................................................52 
8.11 
Preparation, Reconstitution, and Dispensation ............................................................52 
8.12 
Packaging and Labeling ...............................................................................................52 
8.13 
Storage, Handling, and Accountability ........................................................................52 
8.13.1 Disposition of Used Supplies .................................................................................53 
8.13.2 Inventory of Unused Supplies ................................................................................53 
8.14 
Other Protocol-Specified Materials .............................................................................53 
9.0 
STUDY CONDUCT ..........................................................................................................54 
9.1 
Study Personnel and Organizations .............................................................................54 
9.2 
Arrangements for Recruitment of Patients ..................................................................54 
9.3 
Treatment Group Assignments ....................................................................................54 
9.4 
Study Procedures .........................................................................................................54 
9.4.1 
Informed Consent...................................................................................................55 
9.4.2 
Patient Demographics ............................................................................................55 
9.4.3 
Medical/Surgical History .......................................................................................55 
9.4.4 
Diagnosis and Cancer History ...............................................................................55 
9.4.5 
Mutation Status ......................................................................................................55 
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9.4.6 
Prior Cancer Therapy .............................................................................................56 
9.4.7 
Physical Examination.............................................................................................56 
9.4.8 
Height and Weight .................................................................................................56 
9.4.9 
Vital Signs and Auscultation .................................................................................56 
9.4.10 ECOG Performance Status ....................................................................................56 
9.4.11 Cardiac monitoring ................................................................................................56 
9.4.12 Clinical Laboratory Evaluations ............................................................................57 
9.4.13 Chest X-ray ............................................................................................................58 
9.4.14 Pregnancy Test .......................................................................................................58 
9.4.15 Electrocardiogram ..................................................................................................58 
9.4.16 Adverse Events ......................................................................................................58 
9.4.17 Concomitant Medications and Procedures.............................................................59 
9.4.18 Disease Assessment ...............................................................................................59 
9.4.19 Samples for Pharmacokinetic and Biomarker Analyses ........................................60 
9.4.20 Tumor Tissue Sample (Phase2 Part Only) .............................................................61 
9.4.21 Cerebrospinal Fluid (CSF) Collection ...................................................................61 
9.4.22 Patient-Reported Outcome Assessments (Phase 2 Part Only) ...............................61 
9.5 
Documentation of Subject Failure ...............................................................................62 
9.6 
Completion of Study Treatment (for Individual Patients) ...........................................63 
9.7 
Follow-Up After Last Dose .........................................................................................63 
9.8 
Completion of Study (for Individual Patients).............................................................63 
9.9 
Discontinuation of Treatment With Study Drug ..........................................................63 
9.10 
Withdrawal of Patients From Study .............................................................................64 
9.11 
Study Compliance ........................................................................................................64 
9.12 
Post-Treatment Follow-up Assessments (PFS and OS, Phase 2 Part Only) ................65 
10.0 
ADVERSE EVENTS .........................................................................................................66 
10.1 
Definitions....................................................................................................................66 
10.1.1 AE Definition .........................................................................................................66 
10.1.2 SAE Definition.......................................................................................................66 
10.2 
Procedures for Recording and Reporting AEs and SAEs ............................................67 
10.3 
Monitoring of AEs and Period of Observation ............................................................68 
10.4 
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events ..........68 
10.5 
Procedures for Reporting Product Complaints or Medication Errors (Including 
Overdose) .....................................................................................................................68 
10.6 
Safety Reporting to Investigators, IRBs, and Regulatory Authorities .........................69 
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11.0 
STUDY-SPECIFIC COMMITTEES .................................................................................70 
11.1 
Steering Committee .....................................................................................................70 
11.2 
IRC ...............................................................................................................................70 
12.0 
DATA HANDLING AND RECORDKEEPING ..............................................................71 
12.1 
eCRFs ...........................................................................................................................71 
12.2 
Record Retention .........................................................................................................71 
13.0 
STATISTICAL METHODS ..............................................................................................73 
13.1 
Statistical and Analytical Plans ....................................................................................73 
13.1.1 Analysis Sets ..........................................................................................................73 
13.1.2 Procedures for Handling Missing, Unused, and Spurious Data.............................74 
13.1.3 Analysis of Demographics and Other Baseline Characteristics ............................74 
13.1.4 Pharmacokinetic Analysis ......................................................................................74 
13.1.5 Efficacy Evaluation ................................................................................................75 
13.1.6 Safety Analysis ......................................................................................................76 
13.1.7 Patient-Reported Outcome Data Analysis (Phase 2 Part Only) .............................77 
13.2 
Interim Analysis and Criteria for Early Termination ...................................................78 
13.3 
Determination of Sample Size .....................................................................................79 
14.0 
QUALITY CONTROL AND QUALITY ASSURANCE .................................................80 
14.1 
Study-Site Monitoring Visits .......................................................................................80 
14.2 
Protocol Deviations ......................................................................................................80 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections ..................................80 
15.0 
ETHICAL ASPECTS OF THE STUDY ...........................................................................82 
15.1 
IRB Approval ...............................................................................................................82 
15.2 
Subject Information, Informed Consent, and Subject Authorization ..........................83 
15.3 
Subject Confidentiality ................................................................................................83 
15.4 
Publication, Disclosure, and Clinical Trial Registration Policy ..................................84 
15.4.1 Publication .............................................................................................................84 
15.4.2 Clinical Trial Registration......................................................................................84 
15.4.3 Clinical Trial Results Disclosure ...........................................................................84 
15.5 
Insurance and Compensation for Injury .......................................................................85 
16.0 
REFERENCES ..................................................................................................................86 
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LIST OF IN-TEXT TABLES 
Table 6.a 
Primary and Secondary Endpoints for Disclosures ...............................................34 
Table 8.a 
Dose Modifications ................................................................................................44 
Table 8.b 
Proposed Dose Reduction Level of Phase 2 Part ...................................................44 
Table 8.c 
TAK-788 Dose Modification for TEAEs of QTc Interval Prolongation and 
Heart Failure ..........................................................................................................45 
Table 9.a 
Clinical Chemistry and Hematology Tests ............................................................57 
Table 9.b 
Clinical Urinalysis Tests ........................................................................................57 
LIST OF APPENDICES 
Appendix A 
Schedule of Events .................................................................................................88 
Appendix B 
Responsibilities of the Investigator ........................................................................95 
Appendix C 
Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1).................96 
Appendix D 
ECOG Scale for Performance Status .....................................................................99 
Appendix E 
Drugs That Interact with the CYP3A Family of Cytochromes P450 ..................100 
Appendix F 
Drugs with a Risk of Torsades de Pointes ...........................................................102 
Appendix G 
Bayesian Logistic Regression Model...................................................................108 
Appendix H 
Detailed Description of Amendments to Text .....................................................111 
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Protocol Incorporating Amendment No. 06 
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2.0 
STUDY SUMMARY 
Name of Sponsor: 
Takeda Pharmaceutical Company Limited 
Compound: 
TAK-788 (formerly AP32788) 
Title of Protocol: 
A Phase 1/2 Study of the Oral EGFR/HER2 Inhibitor TAK-
788 in Japanese Non-Small Cell Lung Cancer Patients 
EudraCT No.: 
Not Applicable 
Study Number: TAK-788-1003 
Phase: 1/2 
Study Design: 
This is a Phase 1/2 study. Initially, the study started as a Phase 1 study to confirm the global recommended Phase 
2 dose (RP2D) of 160 mg once daily (QD) in Japanese patients. After it was confirmed that the RP2D in 
Japanese patients was the same as the global RP2D, a Phase 2 part was added; the Phase 2 part is designed to 
evaluate the efficacy and safety of TAK-788 in treatment naive Japanese non-small cell lung cancer (NSCLC) 
patients with epidermal growth factor receptor (EGFR) exon 20 insertion mutation 
Phase 1 Part 
The phase 1 part is an open-label, multicenter, dose-escalation part to evaluate the safety, tolerability and 
pharmacokinetics (PK) of TAK-788 in Japanese patients with locally advanced or metastatic NSCLC. The 
objectives of this part are to confirm 160 mg of TAK-788 orally administered QD, the maximum tolerated dose 
(MTD) for non-Japanese patients (hereinafter “global MTD”) determined by the phase 1/2 study (Study 
AP32788-15-101) is tolerable in Japanese patients, identify dose-limiting toxicities (DLTs); and determine a 
RP2D based on the safety/PK profile and preliminary anti-tumor activity in Japanese patients. 
The dose of TAK-788 will be started from 40 mg QD, followed by dose-escalation according to a Bayesian 
logistic regression model (BLRM) with overdose control escalation schema to confirm the tolerability of global 
MTD and determine RP2D in Japanese patients. BLRM in this study is based on the context of broader 
knowledge of safety, PK and anti-tumor activity of TAK-788 from the Study AP32788-15-101 and incorporates 
emerging information from this study. The study allows flexible cohort size, and approximately 3 DLT evaluable 
patients will be needed for each dose cohort. Safety data collected from patients enrolled at the starting dose will 
be added into BLRM, then the optimal route for escalation, ie, more patients should be enrolled at the starting 
dose or the dose should be escalated, will be determined. Alternative regimens/schedule, more conservative dose 
escalation, evaluation of intermediate doses, flexible number of DLT evaluable patients for any dose cohort, 
evaluation of different doses in parallel cohorts and expansion of an existing dose level would be permitted by 
the discussions between the sponsor and the investigators, if such measures are needed for patient safety or for a 
better understanding of the dose-toxicity and dose-exposure relationship of TAK-788. 
Before initiating the dosing of the next dose cohort, when Cycle 1 safety data are available for all patients in the 
current dose cohort (or dose cohorts if parallel dose cohorts are opened), an end of cohort meeting will be held. 
The study team consisting of sponsor representatives and investigators will review the safety of all treated 
patients and make decisions regarding dose escalation. In addition, the available PK and/or anti-tumor activity 
data will also be evaluated to support the dose escalation. Decisions from the end of cohort meeting for each 
dose will be documented in minutes and stored in the Trial Master File. 
Dose escalation will be continued until an MTD for Japanese patients is determined, or the global MTD (160 mg 
QD) is confirmed to be safe and tolerable in Japanese patients. An RP2D less than the MTD may be chosen if 
aspects of tolerability or efficacy not encompassed by the MTD determination suggest utilizing a lower dose. 
Further expansion of the cohort size may also occur at any dose to further confirm safety observations following 
identification of MTD/RP2D. 
Phase 2 Part 
The Phase 2 part is designed to evaluate the efficacy of TAK-788 at the RP2D (160 mg QD), which was 
determined in the Phase 1 part, in Japanese patients with locally advanced or metastatic NSCLC whose tumors 
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harbor EGFR exon 20 insertion mutations and who have not previously received systemic treatment for locally 
advanced or metastatic disease. All patients in the Phase 2 part will have a documented EGFR exon 20 insertion 
mutation by a local test prior to enrollment. The patients’ tumor specimen will also be retrospectively confirmed 
for EGFR exon 20 insertion mutations by an analytically validated central test, and those patients with centrally 
confirmed mutation will be defined as centrally confirmed population. 
The confirmed objective response rate (ORR), as assessed by Independent Review Committee (IRC) per 
RECIST v1.1, will be the primary endpoint in the Phase 2 part. The primary analysis will be conducted on 
centrally confirmed population. And, a secondary analysis will be performed on all enrolled patients who 
received at least one dose of TAK-788 (full analysis set [FAS]). 
Study Objectives: 
Phase 1 Part 
Primary: 
To confirm the tolerability of the global MTD (160 mg QD), identify DLTs, and determine RP2D of TAK-788 in 
Japanese NSCLC. 
Secondary: 
1.
To determine the safety profile of orally administered TAK-788 in Japanese NSCLC patients.
2.
To determine the PK of TAK-788 and its active metabolites (including, but not limited to, AP32960 and
AP32914) in Japanese NSCLC patients.
3.
To evaluate the anti-tumor activity of TAK-788 in Japanese NSCLC patients with EGFR or human
epidermal growth factor 2 (HER2) mutations.
Phase 2 Part 
Primary: 
To determine the efficacy of TAK-788 as first-line treatment in patients with locally advanced or metastatic 
NSCLC harboring EGFR in-frame exon 20 insertion mutations, as evidenced by confirmed objective response 
rate (ORR), as assessed by the independent review committee (IRC). 
Secondary: 
1.
To further characterize the efficacy of TAK-788 shown by confirmed ORR, as assessed by the investigator,
duration of response, progression free survival (PFS), disease control rate (DCR), time to response by both
investigator and IRC per RECIST v1.1 and overall survival (OS)
2.
To assess the safety and tolerability of TAK-788
3.
To collect sparse plasma concentration-time data of TAK788 and its active metabolites, (including, but not
limited to, AP32960 and AP32914), to contribute to population PK and exposure-response analyses
4.
To assess patient-reported symptoms (particular core symptoms of lung cancer), functioning, and health-
related quality of life (HRQoL) with the European Organisation for Research and Treatment of Cancer
(EORTC) Quality of Life Questionnaire (QLQ)-C30 and the EORTC lung cancer module QLQL-C13
Subject Population: 
Japanese male or female patients with locally advanced (and not a candidate for definitive therapy) (Stage IIIB) 
or metastatic NSCLC (Stage IV). 
Number of Subjects: 
Approximately 58 to 63 patients total in the 
study. 
1.
Phase 1 Part
Approximately 28 to 33 patients total
2.
Phase 2 Part
Number of Sites: 
Approximately 4 sites in Japan will participate in Phase 1 part. 
Approximately 25 sites in Japan will participate in Phase 2 part. 
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Approximately 30 patients 
Dose Levels: 
1.
Phase 1 Part
Starting TAK-788 at a dose of 40 mg
QD, and increasing until 160 mg QD.
2.
Phase 2 Part
160 mg QD
Route of Administration: 
oral 
Duration of Treatment: 
Patients will continue to be treated with 
TAK-788 until they experience progressive 
disease (PD) that requires an alternate 
therapy in the opinion of the investigator, 
intolerable toxicity, or another 
discontinuation criterion. Treatment may be 
continued after PD if, in the opinion of the 
investigator, the patient continues to 
experience clinical benefit. 
Period of Evaluation: 
It is anticipated that total duration of an individual patient’s study 
participation will be approximately 1.5 years in median duration, 
including a 2-3 week screening period, a treatment period with 
estimated average of 10-12 cycles (28 days each), and a follow-
up period for approximately 30 days after the last dose of TAK-
788. 
Only in the phase 2 part, the follow-up period for a patient begins 
after the last completed site visit and continues until patient 
contact ceases. The follow-up assessments (ie, contacting the 
patient for survival and subsequent anticancer therapy) must be 
performed every 12 weeks after the end of treatment (EOT). For 
patients who discontinue study treatment in the absence of PD, 
survival should be tracked and additional tumor assessment 
should be performed at the same time points as the study 
treatment (every 8 weeks until Week 56 [equivalent to Cycle 14 
Day 28] and every 12 weeks thereafter) until PD or the start of 
another systemic anticancer therapy. After that, survival must be 
tracked every 12 weeks, and subsequent anticancer therapy 
should be recorded. 
Approximate Duration of Study: 
For the Phase 1 part, the estimated time frame is approximately 3 years for completion, including 15 months to 
accrue patients and 1.5 years for the duration of the last patient’s study participation. 
For the Phase 2 part, The total estimated duration is approximately 4 years, including approximately 1 year to 
accrue patients and 3 years for treatment and follow-up of the last patient. 
Inclusion Criteria: 
General Inclusion Criteria (Both in Phase 1 and Phase 2 Part) 
All patients must meet all of the following general inclusion criteria for study entry. 
1.
Male or female patients ≥20 years old.
2.
Must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Previously
irradiated lesions may not be used for target lesions, unless there is unambiguous radiological progression
after radiotherapy.
3.
Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 (see Appendix D).
4.
Minimum life expectancy of 3 months or more.
5.
Adequate renal and hepatic function as defined by the following criteria:
- Total serum bilirubin ≤1.5 × upper limit of normal (ULN) (≤3.0 × ULN for patients with Gilbert
syndrome or if liver function abnormalities are due to underlying malignancy);
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × ULN (or ≤5 × ULN if liver
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function abnormalities are due to underlying malignancy); 
- Estimated creatinine clearance ≥30 mL/min (calculated by using the Cockcroft-Gault equation);
- Serum albumin ≥2 g/dL; and
- Serum lipase ≤1.5 × ULN; and
- Serum amylase ≤1.5 × ULN unless the increased serum amylase is due to salivary isozymes.
6.
Adequate bone marrow function as defined by the following criteria:
- Absolute neutrophil count ≥1.5 × 109/L;
- Platelet count ≥75 × 109/L in Phase 1 Part and ≥100 × 109/L in Phase 2 Part; and
- Hemoglobin ≥9.0 g/dL.
7.
Normal QT interval on screening electrocardiogram (ECG), defined as QTcF of ≤450 ms in males or
≤470 ms in females.
8.
Female patients who:
- Are postmenopausal (natural amenorrhea and not due to other medical reasons) for at least 1 year before
the screening visit, OR
- Are surgically sterile, OR
- If they are of childbearing potential, agree to practice 1 highly effective non-hormonal method of
contraception and 1 additional effective (barrier) method (see Section 8.7.1) at the same time, from the
time of signing the informed consent form (ICF) through 30 days after the last dose of study drug, OR 
- Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject.
Note: Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods), withdrawal,
spermicides only, and lactational amenorrhea are not acceptable methods of contraception.
Male patients, even if surgically sterilized (ie, status postvasectomy), who: 
- Agree to practice effective barrier contraception (see Section 8.7.1) during the entire study treatment
period and through 30 days after the last dose of study drug, OR
- Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject.
Note: Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods), withdrawal,
spermicides only, and lactational amenorrhea are not acceptable methods of contraception.
9.
Voluntary written consent must be given before performance of any study-related procedure not part of
standard medical care, with the understanding that consent may be withdrawn by the patient at any time
without prejudice to future medical care.
10. Willingness and ability to comply with scheduled visits and study procedures.
Phase-Specific Inclusion Criteria
In addition to the general inclusion criteria above, patients must also meet all criteria for the study phase in 
which their entry is proposed. 
Phase 1 Part 
1.
Have histologically or cytologically confirmed locally advanced (and not a candidate for definitive therapy)
(Stage IIIB) or metastatic NSCLC (Stage IV).
2.
Refractory to standard available therapies.
3.
All toxicities from prior therapy have resolved to ≤ grade 1 according to the National Cancer Institute
Common Terminology Criteria for Adverse Events (NCI CTCAE v5.0), or have resolved to baseline, at the
time of first dose of TAK-788. Note: treatment-related grade >1 alopecia or treatment-related grade 2
peripheral neuropathy are allowed if deemed irreversible.
Phase 2 Part
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1.
Histologically or cytologically confirmed locally advanced not suitable for definitive therapy, recurrent, or
metastatic (Stage IV) NSCLC.
2.
Not received prior systemic treatment for locally advanced or metastatic disease (with the exception below):
Neoadjuvant or adjuvant chemotherapy/immunotherapy for Stage I to III or combined modality
chemotherapy/radiation for locally advanced disease is allowed if completed >6 months before the
development of metastatic disease.
3.
A documented EGFR in-frame exon 20 insertion (including A763_Y764insFQEA, V769_D770insASV,
D770_N771insNPG, D770_N771insSVD, H773_V774insNPH, or any other in-frame exon 20 insertion
mutation) by a local test that has been analytically validated per local authority guidelines. The EGFR exon
20 insertion mutation can be either alone or in combination with other EGFR or HER2 mutations except
EGFR common mutations (exon 19 del or L858R).
4.
Adequate tumor tissue available, either from primary or metastatic sites, for central laboratory confirmation
of EGFR in-frame exon 20 insertion mutation (see laboratory manual). Note: confirmation of central test
positivity is not required before the first dose of TAK-788.
Exclusion Criteria: 
General Exclusion Criteria (Both in Phase 1 and Phase 2 Part) 
Patients are not eligible for participation in the study if they meet any of the following exclusion criteria: 
1.
Have been diagnosed with another primary malignancy other than NSCLC except for adequately treated
non-melanoma skin cancer or cervical cancer in situ; definitively treated non-metastatic prostate cancer; or
patients with another primary malignancy who are definitively relapse-free with at least 3 years elapsed
since the diagnosis of the other primary malignancy.
2.
Have undergone major surgery within 28 days prior to first dose of TAK-788. Minor surgical procedures,
such as catheter placement or minimally invasive biopsy, are allowed.
3.
Have current spinal cord compression (symptomatic or asymptomatic and detected by radiographic imaging)
or leptomeningeal disease (symptomatic or asymptomatic).
4.
Have significant, uncontrolled, or active cardiovascular disease, including, but not restricted to:
-
Myocardial infarction within 6 months prior to the first dose of study drug;
-
Unstable angina within 6 months prior to first dose;
-
Congestive heart failure within 6 months prior to first dose;
-
History of clinically significant (as determined by the treating physician) atrial arrhythmia;
-
Any history of ventricular arrhythmia; or
-
Cerebrovascular accident or transient ischemic attack within 6 months prior to first dose.
5.
Have uncontrolled hypertension. Patients with hypertension should be under treatment on study entry to
control blood pressure.
6.
Currently being treated with medications known to be associated with the development of Torsades de
Pointes (see Appendix F).
7.
Have an ongoing or active infection, including, but not limited to, the requirement for intravenous
antibiotics. Have a known history of HIV infection. Testing of HIV is not required in the absence of history.
Hepatitis B surface antigen (HBsAg) positive patients are allowed to enroll if hepatitis B virus (HBV)-DNA
is below 1000 copies/mL in the plasma.
Patients who have positive hepatitis C virus (HCV) antibody can be enrolled but must have HCV-RNA
undetectable in the plasma.
8.
Currently have or have a history of interstitial lung disease (ILD), radiation pneumonitis that required steroid
treatment, drug-related pneumonitis, or other clinically significant pneumonitis.
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9.
Female patients who are lactating and breastfeeding or have a positive serum pregnancy test during the
screening period.
Note: Female patients who are lactating will be eligible if they discontinue breastfeeding.
10. Have gastrointestinal illness or disorder that could affect oral absorption of TAK-788.
11. Have any condition or illness that, in the opinion of the investigator, might compromise patient safety or
interfere with the evaluation of the safety of the drug.
Phase-Specific Exclusion Criteria 
In addition to the general exclusion criteria above, patients are not eligible for participation in the study phase if 
they meet any of the following exclusion criteria for the study phase in which their entry is proposed. 
Phase 1 Part 
1.
Previously received TAK-788.
2.
Received small-molecule anticancer therapy (including cytotoxic chemotherapy and investigational agents)
within 14 days prior to the first dose of TAK-788 (except for reversible EGFR tyrosine kinase inhibitors
[TKIs; ie, erlotinib or gefitinib] up to 7 days prior to the first dose of TAK-788).
3.
Received antineoplastic monoclonal antibodies including immunotherapy within 28 days prior to the first
dose of TAK-788.
4.
Received radiotherapy within 14 days prior to the first dose of TAK-788. Stereotactic radiosurgery (SRS)
and stereotactic body radiosurgery are allowed up to 7 days prior to the first dose.
5.
Have symptomatic CNS metastases (parenchymal or leptomeningeal) at screening or asymptomatic disease
requiring corticosteroids to control symptoms within 7 days prior to the first dose of TAK-788.
Note: If a patient has worsening neurological symptoms or signs due to CNS metastases, the patient needs to
complete local therapy and be neurologically stable (with no requirement for corticosteroids or use of
anticonvulsants) for 7 days prior to the first dose of TAK-788. Patients with no prior history of signs or
symptoms of CNS metastases but who receive prophylactic steroids or anticonvulsants are allowed.
6.
Received a strong cytochrome P450 (CYP)3A inhibitor or strong CYP3A inducer within 2 weeks prior to
first dose of TAK-788.
Phase 2 Part
1.
Received radiotherapy within 14 days before the first dose of TAK-788 or has not recovered from
radiotherapy-related toxicities. Stereotactic radiosurgery, stereotactic body radiotherapy, or palliative
radiation outside the chest and brain is allowed up to 7 days before the first dose of TAK-788.
2.
Have known active brain metastases (have either previously untreated intracranial CNS metastases or
previously treated intracranial CNS metastases with radiologically documented new or progressing CNS
lesions). Brain metastases are allowed if they have been treated with surgery and/or radiation and have been
stable without requiring corticosteroids to control symptoms within 7 days before the first dose of TAK-788,
and have no evidence of new or enlarging brain metastases.
3.
Received a moderate or strong CYP3A inhibitor or moderate or strong CYP3A inducer within 10 days prior
to first dose of TAK-788.
4.
Have cardiac ejection fraction <50% by echocardiogram or multigated acquisition (MUGA) scan at
screening.
Main Criteria for Evaluation and Analyses: 
Phase 1 Part 
Primary Endpoint: 
RP2D of orally administered TAK-788 in Japanese NSCLC patients. 
Secondary Endpoints: 
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1.
Safety profile of orally administered TAK-788:
-
The number and percentage of patients with treatment-emergent adverse events (TEAEs).
-
The number and percentage of patients with first cycle DLTs.
2.
DLTs of orally administered TAK-788.
3.
MTD of orally administered TAK-788.
4.
Plasma PK parameters of TAK-788 and its active metabolites (including, but not limited to, AP32960 and
AP32914) after a single oral dose: Maximum plasma concentration (Cmax), time to Cmax (tmax), area under the
plasma concentration-time curve from time 0 to 24 hours (AUC24) and from time 0 to the time of the last
quantifiable concentration (AUClast), and dose proportionality for Cmax and AUC (if data allows).
5.
Plasma PK parameters of TAK-788 and its active metabolites (including, but not limited to, AP32960 and
AP32914) at steady state after multiple oral doses: Maximum plasma concentration at steady state (Cmax,ss),
time to Cmax,ss (tmax,ss), AUC24 at steady state (AUC24,ss), extent of accumulation ratio on multiple dosing
(Rac), and dose proportionality for Cmax and AUC (if data allows).
6.
Investigator assessed objective response rate (ORR) using Response Evaluation Criteria in Solid Tumors
(RECIST) v1.1 in patients with EGFR or HER2 mutations.
Safety Endpoints: 
The safety endpoints are: 
1.
Adverse events (AEs).
2.
Laboratory values.
3.
Vital signs.
4.
Electrocardiograms (ECGs).
Phase 2 Part
Primary Endpoint: 
Confirmed ORR, as assessed by the IRC, per RECIST v1.1. 
Secondary Endpoints:  
1.
Confirmed ORR, as assessed by the investigator, per RECIST v1.1.
2.
Duration of response, as assessed by the IRC and the investigator.
3.
Time to response, as assessed by the IRC and the investigator.
4.
DCR (the percentage of patients with best response of complete response [CR], partial response [PR], or
SD ), as assessed by the IRC and the investigator, per RECIST v1.1, for 42 days or more after initiation of
study drug.
5.
PFS, as assessed by the IRC and the investigator.
6.
Overall survival (OS).
7.
Patient-reported symptoms (particular core symptoms of lung cancer), functioning, and health-related quality
of life (HRQoL) with the European Organisation for Research and Treatment of Cancer (EORTC) Quality of
Life Questionnaire (QLQ)-C30 and the EORTC lung cancer module QLQ-LC13.
Safety Endpoints: 
1.
AEs.
2.
Laboratory values.
3.
Vital signs.
4.
Physical examination findings.
Statistical Considerations: 
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Phase 1 Part 
Descriptive statistics and analyses will be provided for each dose level, and for patients combined across dose 
levels where applicable. All patients who receive at least 1 dose of TAK-788 will be included in the safety 
analysis. 
The MTD will be determined based on the DLT within the first 28 days of treatment (end of Cycle 1). Evaluable 
patients must complete at least 75% of their planned doses, unless missed doses are due to AEs. An adaptive 
BLRM that implements escalation with overdose control will be used in this study for purposes of dose 
escalation recommendations and estimation of the MTD. Data from the Study AP32788-15-101 will be used as 
prior information in the BLRM. For each dose level, the posterior probability of having DLT rates that fall into 
the following intervals will be estimated: 
•
[0, 0.21): under-dosing.
•
[0.21, 0.33): target toxicity.
•
[0.33, 1.00]: excessive toxicity.
BLRM will recommend a dose which follows the Escalation With Overdose Control (EWOC) principle and has 
the highest posterior probability of having a DLT rate that falls into the interval [0.21, 0.33) as the target toxicity 
rate at MTD. Following the EWOC principle, the posterior probability of the recommended dose having a DLT 
rate above 0.33 must not exceed 30%. The selection of the next recommended dose will be determined along 
with other available information, such as safety, PK and efficacy. 
The MTD may be declared as the current dose if the following stopping rules is met: 
•
At least 9 patients are evaluable in the study and at least 6 patients are evaluable at the current dose, and the
current dose is the recommended dose for the next cohort.
Alternative stopping rules may also be considered following discussions between the sponsor and the 
investigators. 
Phase 2 Part 
For the primary endpoint, confirmed ORR as assessed by an IRC and its 2-sided 90% CI will be provided using 
centrally confirmed population, defined as patients who have confirmed harboring EGFR exon 20 insertion 
mutation by central test, and have received at least 1 dose of study drug. The secondary analysis will be 
performed on FAS population, defined as enrolled patients who received at least one dose of study drug. 
For the primary analysis in the phase 2 part, a 2-stage design [20] will be used. The first 14 “centrally 
confirmed” patients in the phase 2 part are included in Stage 1, and further patients will be continuously enrolled 
into Stage 2. An interim analysis for both futility and efficacy will be conducted in Stage 1. The proportion of 
patients achieving a confirmed objective response, per IRC, will be used as the endpoint for the interim analysis. 
The interim analysis will be performed when the first 14 “centrally confirmed” patients in the phase 2 part have 
had the opportunity to complete the Cycle 7 Day 1 disease assessment (i.e. 3rd disease assessment after initiation 
of the study treatment). Enrollment will not be suspended during evaluation of these 14 “centrally confirmed” 
patients; however, patients enrolled after the 14th patient in the phase 2 part will NOT be included in the interim 
analysis, even if their objective response results were available on the cutoff date. 
If the number of patients with confirmed objective response is 5 or fewer of the 14 “centrally confirmed” 
patients, enrollment will be stopped entirely for futility. Additionally, if the number of patients with confirmed 
objective response is 9 or more of the 14“centrally confirmed” patients, it will be decided that TAK-788 is 
efficacious in this population. 
In other cases (i.e. number of patients with confirmed objective response is between 6 to 8), the study will 
continue until the 26“centrally confirmed” patients have had the opportunity to complete the Cycle 7 Day 1 
disease assessment. If the number of patients with confirmed objective response in these 26 patients is 14 or 
more, it will be decided that TAK-788 has demonstrated sufficient efficacy to reject the null hypothesis. 
For the secondary endpoints except for quality of life (QOL), all variables will be summarized descriptively 
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using both the centrally confirmed population and FAS. QOL will be summarized descriptively using FAS. 
Continuous variables will be summarized using the number of patients, mean, standard deviation, median, 
minimum, and maximum, and categorical variables will be summarized using the number and percentage per 
category. Time-to-event variables will be summarized using Kaplan-Meier methodology, and Kaplan-Meier 
plots will be provided. Kaplan-Meier estimates and 95% CI will be calculated for quantiles and some specified 
time points. 
Pharmacokinetic Analysis 
The PK parameters for TAK-788 and its active metabolites, including, but not limited to, AP32960 and 
AP32914, will include (but are not limited to) the following. 
Following a Single Oral Dose in the Phase 1 Part: 
Maximum plasma concentration (Cmax), time to Cmax (tmax), and area under the plasma concentration-time curve 
from time 0 to 24 hours (AUC24) and from time 0 to the time of the last quantifiable concentration (AUClast). 
Dose proportionality for Cmax and AUC may be assessed if data allows. 
Following Multiple Oral Doses (Steady State) in the Phase 1 Part: 
Maximum plasma concentration at steady state (Cmax,ss), time to Cmax,ss (tmax,ss), AUC24 at steady state (AUC24,ss), 
and extent of accumulation ratio on multiple dosing (Rac). Dose proportionality for Cmax and AUC may be 
assessed if data allows. 
PK Analysis in the Phase 2 Part: 
The plasma concentration-time data of TAK-788 and its active metabolites, including, but not limited to, 
AP32960 and AP32914 will be pooled with data from other TAK 788 clinical studies in patients with cancer to 
contribute to population PK analyses. Results of the population PK analyses of data from this study will also 
contribute to exposure-response analyses of safety and efficacy. The analysis plans for the population PK and 
exposure-response analyses will be separately defined, and the results of these analyses will be reported 
separately. 
Sample Size Justification: 
Phase 1 Part 
The Phase 1 part will adopt an adaptive design using BLRM with safety data evaluation and other available 
information, such as PK and efficacy. The design allows flexible cohort size. The total number of subjects in this 
study is dependent on the observed safety profile and other available information, which will determine the 
number of patients per dose cohort, as well as the number of dose escalations required to achieve the MTD. It is 
anticipated that approximately 21 patients will be required to determine MTD. Assuming a 15% dropout rate and 
potentially up to 5 patients will be enrolled for any cohort to further confirm the safety, the total sample size for 
this study will be approximately 28-33. 
Phase 2 Part 
The purpose of the phase 2 part of this study is to determine the confirmed ORR of orally administered TAK-788 
as the first line treatment at RP2D determined in the Phase 1 part in patients with NSCLC with EGFR exon 20 
insertion mutations. The sample size was determined so that it would allow us to state that the true ORR is 
greater than threshold response rate of 35%. The expected true ORR of TAK-788 is 60% in treatment naive 
population. Twenty-six (26) patients with NSCLC with tumors harboring EGFR exon 20 insertion mutations 
with confirmation of central test will allow the study to have over 80% power to rule out an uninteresting rate of 
35% in this population with a 1-sided alpha of 0.05 according to the two-stage design (Mander and Thompson, 
2010) with futility and efficacy interim analysis described in the above “Statistical Consideration”. 
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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 
protocol annex. The vendors identified in the protocol annex will perform specific study-related 
activities either in full or in partnership with the sponsor. 
3.2 
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 (CSR) and by doing so agrees that it accurately 
describes the results of the study. 
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3.3 
List of Abbreviations 
Abbreviation Term 
AE 
adverse event 
AFIB 
atrial fibrillation 
AFL 
atrial flutter 
ALT 
alanine aminotransferase 
APL 
acute promyelocytic leukemia 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AUC24 
area under the concentration-time curve from time 0 to 24 hours 
AUC24,ss 
area under the concentration-time curve from time 0 to 24 hours, at steady state 
AUClast 
area under the concentration-time curve from time 0 to time of the last quantifiable concentration 
β-hCG 
beta-human chorionic gonadotropin 
BLRM 
Bayesian logistic regression model 
CI 
confidence interval 
CL/Fss 
apparent clearance at steady state 
Cmax 
maximum observed concentration 
Cmax,ss 
maximum observed concentration during a dosing interval, at steady state 
CNS 
central nervous system 
COVID-19 
coronavirus disease 2019 
CR 
complete response 
CRO 
contract research organization 
CSF 
cerebrospinal fluid 
CSR 
clinical study report 
CT 
computed tomography 
CTC 
Common Terminology Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
CxDx 
Cycle x Day x 
CYP 
cytochrome P450 
DCR 
disease control rate 
DDI 
drug-drug interaction 
DLT 
dose-limiting toxicity 
DTP 
direct-to-patient 
ECG 
electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EES 
erythromycin ethylsuccinate 
EGFR 
epidermal growth factor receptor 
EORTC 
European Organisation for Research and Treatment of Cancer 
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Abbreviation Term 
EOT 
end of treatment 
EWOC 
Escalation With Overdose Control 
FAS 
full analysis set 
FDA 
Food and Drug Administration (United States) 
FFPE 
formalin fixed paraffin embedded 
GCP 
Good Clinical Practice 
G-CSF
granulocyte-colony stimulating factor 
GERD
gastroesophageal reflux disease 
GI
gastrointestinal 
GM-CSF
granulocyte macrophage-colony stimulating factor 
HBsAg
hepatitis B surface antigen 
HBV
hepatitis B virus 
HCV
hepatitis C virus 
HER2
human epidermal growth factor 2 
HIV
human immunodeficiency virus 
HRQoL
health-related quality of life 
IBS
irritable bowel syndrome 
IC50
50% inhibitory concentration 
ICF
informed consent form 
ICH
International Council for Harmonisation 
ILD
interstitial lung disease 
IRB
Institutional Review Board 
IRC
independent review committee 
KL-6
Krebs von den Lungen-6 
LVEF
left ventricular ejection fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHRA 
Medicines and Healthcare products Regulatory Agency 
MI 
myocardial infarction 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
MUGA 
multigated acquisition 
N/A 
not applicable 
NCI 
National Cancer Institute (of the United States) 
NSCLC 
non-small cell lung cancer 
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease 
PFS 
progression free survival 
PJP 
pneumocystis jiroveci pneumonia 
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Abbreviation Term 
PK 
pharmacokinetic(s) 
PMDA 
Pharmaceuticals and Medical Devices Agency 
PONV 
post-operative nausea and vomiting 
PR 
partial response 
PSVT 
paroxysmal supraventricular tachycardia 
QD 
once daily 
QLQ 
Quality of Life Questionnaire 
QLQ-LC13 Quality of Life Questionnaire, lung cancer module 
QOL 
quality of life 
QT 
QT interval; a measure of the time between the start of the Q wave and the end of the T wave in the 
heart’s electrical cycle 
QTc 
heart rate-corrected QT interval (calculated) 
QTcF 
QT interval corrected (Fridericia) 
Rac 
accumulation ratio 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
recommended phase 2 dose 
SAE 
serious adverse event 
SD 
stable disease 
SP-D 
surfactant protein-D 
SRS 
stereotactic radiosurgery 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
TKI 
tyrosine kinase inhibitor 
tmax 
time of first occurrence of maximum observed concentration 
tmax,ss 
time of first occurrence of maximum observed concentration during a dosing interval, at steady state 
UK 
United Kingdom 
US 
United States 
ULN 
upper limit of normal 
VF 
ventricular fibrillation 
VT 
ventricular tachycardia 
WBRT 
whole brain radiation therapy 
WHO 
World Health Organization 
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3.4 
Corporate Identification 
Millennium 
Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda Pharmaceutical 
Company Limited 
TDC Japan 
Takeda Development Center Japan 
TDC Asia 
Takeda Development Center Asia, Pte Ltd 
TDC Europe 
Takeda Development Centre Europe Ltd 
TDC Americas 
Takeda Development Center Americas, Inc 
TDC 
TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as applicable 
Takeda 
Millennium Pharmaceuticals, Inc, TDC Japan, TDC Asia, TDC Europe and/or TDC 
Americas, as applicable 
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4.0 
INTRODUCTION 
4.1 
Background 
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 (ie, tyrosine kinase inhibitors [TKIs]). These include activating 
mutations in the epidermal growth factor receptor (EGFR), which have been identified in 21%-
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. 
Since inhibition of wild-type EGFR in normal tissues is associated with dose limiting toxicities, 
substantial clinical benefit has generally been associated with TKIs that inhibit specific, activated 
variants of EGFR more potently than they inhibit wild-type 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 about 90% of all EGFR 
activating mutations [3]. The remaining 10% to 15% of de novo EGFR mutations comprise a 
cluster of in-frame insertions in exon 20 that account for ~2% of all NSCLC [4][5][6] and the 
rarer EGFR ‘uncommon’ point mutations that account for the remainder (~1%). 
Unlike mutations in exons 19 or 21, almost all EGFR exon 20 insertions confer in vitro and 
primary clinical resistance to erlotinib, gefitinib, and afatinib [7][8][9]. Patients with NSCLC 
containing EGFR exon 20 insertions exhibit clinical characteristics similar to those carrying 
common EGFR mutations [4] (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 targeted 
therapies are approved for patients with EGFR exon 20 insertions or other uncommon EGFR 
mutations in Japan. 
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 NSCLC 
patients. These patients exhibit clinical characteristics similar to EGFR-mutated patients 
[10][11][12]. Currently, no targeted therapies are approved for use in NSCLC patients with 
HER2 activating mutations. 
To address limitations of existing therapies targeting EGFR and HER2, TAK-788 (formerly 
AP32788), a novel, synthetic, orally-administered TKI has been developed. In nonclinical 
studies, TAK-788 potently inhibits 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, as well as by amplification. TAK-788 inhibits all of these variants more potently than 
it inhibits wild-type EGFR, suggesting it may have the selectivity necessary to achieve levels of 
exposure required to inhibit all activated forms of these kinases. 
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4.2 
Rationale for the Proposed Study 
Based on the promising activity profile of TAK-788 in vitro and in vivo, as well as its 
toxicological profile, a phase 1/2 study of TAK-788 (Study AP32788-15-101) had been initiated 
in the United States, and maximum tolerated dose (MTD) was confirmed as 160 mg once daily 
(QD) (hereinafter “global MTD”). 
In order to confirm the global MTD is tolerable in Japanese patients and determine the 
recommended phase 2 dose (RP2D) in Japanese, a phase 1 study in Japanese NSCLC patients is 
proposed.  
Also, after the confirmation of RP2D in Japanese, phase 2 part to evaluate efficacy and safety of 
TAK-788 in treatment naive Japanese patients of NSCLC harboring EGFR exon 20 insertion 
mutations was added. 
In the phase 1 part, the patient population of the trial will include Japanese patients with locally 
advanced or metastatic NSCLC. The objectives of the phase 1 part are to confirm global MTD is 
tolerable in Japanese patients and to determine a RP2D based on the safety/pharmacokinetic 
(PK) profile and evaluate preliminary anti-tumor activity in Japanese patients.  
In the phase 2 part, treatment naive Japanese NSCLC patients with EGFR exon 20 insertion 
mutations will be included. The objectives of the phase 2 part are to confirm efficacy and safety 
of TAK-788 in Japanese patients and primary endpoint is the confirmed objective response rate 
(ORR) by RECIST v1.1 assessed by independent review committee (IRC). 
4.2.1 Rationale for Dose 
In Study AP32788-15-101, a total 38 dose-limiting toxicity (DLT) evaluable patients were 
enrolled to 5 to 180 mg dose cohort. No DLT were observed in the 5, 10, 20 and 40 mg dose 
cohort (3, 3, 5 and 6 evaluable subjects, respectively), but 1 DLT was observed in 1 of 6 
evaluable patients at each 80, 120, 160 mg dose cohort, and 2 DLTs were observed among 3 
evaluable patients at 180 mg dose cohort. While DLTs were observed at 80 mg or more, overall 
TAK-788 was well tolerable and class AE such as diarrhea is considered manageable. However, 
considering TAK-788 has never been administered in Japanese patients, 40 mg QD, which is the 
half of 80 mg QD and no DLT was observed, is considered to be an appropriate starting dose in 
the phase 1 part. 
In the phase 2 part, 160 mg QD, which is confirmed as the RP2D in Japanese patients in prior 
phase 1 part will be used. 
4.2.2 Benefit-Risk 
Clinical investigation of the potential benefit of TAK-788 is ongoing through a comprehensive 
and global development plan that involves Study AP32788-15-101 and TAK-788-3001. The 
current Investigator’s Brochure describes the known safety profile of TAK-788. The known 
safety profile indicates that the types of AEs reported with TAK-788 are generally manageable 
 
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and reversible. While some of these potential toxicities may be serious, they can be managed by 
clinical monitoring and standard medical intervention or dose modifications. 
Overall, the benefit-risk assessment for TAK-788 based on the available experience is expected 
to be favorable. 
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5.0 
STUDY OBJECTIVES AND ENDPOINTS 
5.1 
Objectives 
5.1.1 Phase 1 Part 
5.1.1.1 Primary Objective 
The primary objective is: 
•
To confirm the tolerability of the global MTD (160 mg QD), identify dose-limiting toxicities
(DLTs), and determine RP2D of TAK-788 in Japanese NSCLC patients.
5.1.1.2 Secondary Objectives 
The secondary objectives are: 
1. To determine the safety profile of orally administered TAK-788 in Japanese NSCLC
patients.
2. To determine the PK of TAK-788 and its active metabolites (including, but not limited to,
AP32960 and AP32914) in Japanese NSCLC patients.
3. To evaluate the anti-tumor activity of TAK-788 in Japanese NSCLC patients with EGFR or
HER2 mutations.
5.1.2 Phase 2 Part 
5.1.2.1 Primary Objectives 
To determine the efficacy of TAK-788 as first-line treatment in patients with locally advanced or 
metastatic NSCLC harboring EGFR in-frame exon 20 insertion mutations, as evidenced by 
confirmed objective response rate (ORR), as assessed by the independent review committee 
(IRC) per RECIST v1.1. 
5.1.2.2 Secondary Objectives 
1. To further characterize the efficacy of TAK-788 shown by confirmed ORR, as assessed by
the investigator, duration of response, progression free survival (PFS), disease control rate
(DCR), time to response by both investigator and IRC per RECIST v1.1 and overall survival
(OS).
2. To assess the safety and tolerability of TAK-788.
3. To collect sparse plasma concentration-time data of TAK788 and its active metabolites,
(including, but not limited to, AP32960 and AP32914), to contribute to population PK and
exposure-response analyses.
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4. To assess patient-reported symptoms (particular core symptoms of lung cancer), functioning,
and health-related quality of life (HRQoL) with the European Organisation for Research and
Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 and the EORTC
lung cancer module QLQ-LC13.
5.2 
Endpoints 
5.2.1 Phase 1 Part 
5.2.1.1 Primary Endpoint 
The primary endpoint is: 
•
RP2D of orally administered TAK-788 in Japanese NSCLC patients.
5.2.1.2 Secondary Endpoints 
The secondary endpoints are: 
1. Safety profile of orally administered TAK-788:
–
The number and percentage of patients with treatment-emergent adverse events (TEAEs).
–
The number and percentage of patients with first cycle DLTs.
2. DLTs of orally administered TAK-788.
3. MTD of orally administered TAK-788.
4. Plasma PK parameters of TAK-788 and its active metabolites after a single oral dose:
Maximum plasma concentration (Cmax), time to Cmax (tmax), area under the plasma
concentration-time curve from time 0 to 24 hours (AUC24) and from time 0 to the time of the
last quantifiable concentration (AUClast), and dose proportionality for Cmax and AUC (if data
allows).
5. Plasma PK parameters of TAK-788 and its active metabolites at steady state after multiple
oral doses: Maximum plasma concentration at steady state (Cmax,ss), time to Cmax,ss (tmax,ss),
AUC24 at steady state (AUC24,ss), extent of accumulation ratio on multiple dosing (Rac), and
dose proportionality for Cmax and AUC (if data allows).
6. Investigator assessed objective response rate (ORR) using Response Evaluation Criteria in
Solid Tumors (RECIST) v1.1 in patients with EGFR or HER2 mutations.
5.2.1.3 Safety Endpoints 
The safety endpoints are: 
1. Adverse events (AEs).
2. Laboratory values.
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3. Vital signs.
4. Electrocardiograms (ECGs).
5.2.2 Phase 2 Part 
5.2.2.1 Primary Endpoint: 
Confirmed ORR, as assessed by the IRC, per RECIST v1.1. 
5.2.2.2 Secondary Endpoints: 
1. Confirmed ORR, as assessed by the investigator, per RECIST v1.1.
2. Duration of response, as assessed by the IRC and the investigator.
3. Time to response, as assessed by the IRC and the investigator.
4. DCR (the percentage of patients with best response of complete response [CR], partial
response [PR], or SD of 42 days or longer), as assessed by the IRC and the investigator, per
RECIST v1.1.
5. PFS, as assessed by the IRC and the investigator.
6. OS.
7. Patient-reported symptoms (particular core symptoms of lung cancer), functioning, and
health-related quality of life (HRQoL) with the European Organisation for Research and
Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 and the EORTC
lung cancer module QLQ-LC13.
5.2.2.3 Safety Endpoints: 
1. AEs.
2. Laboratory values.
3. Vital signs.
4. Physical examination findings.
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6.0 
STUDY DESIGN 
6.1 
Overview of Study Design 
This is a Phase 1/2 study. Initially, the study started as a Phase 1 study to confirm the global 
RP2D of 160 mg QD in Japanese patients. After it was confirmed that the RP2D in Japanese 
patients was the same as the global RP2D, a Phase 2 part was added; the Phase 2 part is designed 
to evaluate the efficacy and safety of TAK-788 in treatment naive Japanese NSCLC patients with 
EGFR exon 20 insertion mutation. 
Phase 1 Part 
An open-label, multicenter, dose-escalation part to evaluate the safety, tolerability and 
pharmacokinetics (PK) of TAK-788 in Japanese patients with locally advanced or metastatic 
NSCLC. The objectives of Phase 1 part are to confirm 160 mg QD of TAK-788 orally 
administered, the MTD for non-Japanese patients (hereinafter “global MTD”) determined by the 
phase 1/2 study (Study AP32788-15-101) is tolerable in Japanese patients, identify DLTs; and 
determine a RP2D based on the safety/PK and preliminary anti-tumor activity in Japanese 
patients. 
Phase 1 part consists of screening period, treatment period, and follow-up period. The screening 
period begins when the informed consent form is signed, and continues until the first dose of 
study drug is administered at the Cycle 1, Day 1 (C1D1) visit. The follow-up period begins at the 
last dose of TAK-788 and continues until the 30 days after the last dose assessments. 
Subject eligibility will be determined during the screening period, which must be no more than 
14 days prior to the C1D1 visit. The allowable window for the tumor imaging screening 
assessment is 21 days prior to the C1D1 visit. Patients who meet all eligibility criteria and 
provide written informed consent will be enrolled in this study. 
All the enrolled subjects will receive TAK-788 orally once daily. Each 28-day dosing period is 
referred to as 1 cycle. The expected total duration of patient participation is approximately 
1.5 years, including a 2-3 week screening period, a treatment period with estimated average of 
10-12 cycles in responding patients (participation for patients who do not respond will likely be 
of shorter duration), and a follow-up period for approximately 30 days after the last dose of 
TAK-788.
The dose of TAK-788 will be started 40 mg QD, followed by dose-escalation according to a 
Bayesian logistic regression model (BLRM) with overdose control escalation schema to confirm 
the tolerability of global MTD and determine RP2D in Japanese patients. BLRM in this study is 
based on the context of broader knowledge of safety, PK and anti-tumor activity of TAK-788 
from the Study AP32788-15-101 and incorporates emerging information from this study. The 
study allows flexible cohort size, and approximately 3 DLT-evaluable patients will be needed for 
each dose cohort. Safety data collected from patients enrolled at the starting dose will be added 
into BLRM, then the optimal route for escalation, ie, more patients should be enrolled at the 
starting dose or the dose should be escalated, will be determined. Alternative regimens/schedule, 
 
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more conservative dose escalation, evaluation of intermediate doses, flexible number of DLT 
evaluable patients for any dose cohort, evaluation of different doses in parallel cohorts and 
expansion of an existing dose level would be permitted by the discussions between the sponsor 
and the investigators, if such measures are needed for patient safety or for a better understanding 
of the dose-toxicity and dose-exposure relationship of TAK-788. 
Before initiating the dosing of the next dose cohort, when Cycle 1 safety data are available for all 
patients in the current dose cohort (or dose cohorts if parallel dose cohorts are opened), an end of 
cohort meeting will be held. The study team consisting of sponsor representatives and 
investigators will review the safety of all treated patients and make decisions regarding dose 
escalation. In addition, the available PK and/or anti-tumor activity data will also be evaluated to 
support the dose escalation. Decisions from the end of cohort meeting for each dose will be 
documented in minutes and stored in the Trial Master File. 
Dose escalation will be continued until an MTD for Japanese patients is determined or the global 
MTD (160 mg QD) is confirmed to be safe and tolerable in Japanese patients. The RP2D is the 
MTD or less. An RP2D less than the MTD may be chosen if aspects of tolerability or efficacy 
not encompassed by the MTD determination suggest utilizing a lower dose. 
Further expansion of the cohort size may also occur at any dose to further confirm safety 
observations following identification of MTD/RP2D. 
Phase 2 Part 
The Phase 2 part is designed to evaluate the efficacy of TAK-788 at the RP2D (160 mg QD), 
which was determined in the Phase 1 part, in Japanese patients with locally advanced or 
metastatic NSCLC whose tumors harbor EGFR exon 20 insertion mutations and who have not 
previously received systemic treatment for locally advanced or metastatic disease. All patients in 
the Phase 2 part will have a documented EGFR exon 20 insertion mutation by a local test prior to 
enrollment. Also, the patient’s tumor specimen will be retrospectively confirmed for EGFR 
exon 20 insertion mutations by an analytically validated central test, and those patients with 
centrally confirmed mutation will be defined as centrally confirmed population. 
The confirmed ORR, as assessed by IRC per RECIST v1.1, will be the primary endpoint in the 
Phase 2 part. The primary analysis will be conducted on patients with centrally confirmed 
population. And, a secondary analysis will be performed on all enrolled patients who received at 
least one dose of TAK-788 (full analysis set [FAS]). 
6.2 
Number of Patients 
Approximately 58 to 63 patients in total in the study. 
Phase 1 Part 
It is anticipated that approximately 21 patients will be required for MTD determination in 
Phase 1 Part. Assuming a 15% dropout rate and potentially up to 5 patients will be enrolled for 
any cohort to further confirm the safety, approximately 28-33 patients will be enrolled in Phase 1 
Part. 
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Phase 2 Part 
Approximately 30 patients will be enrolled in Phase 2 Part. 
6.3 
Duration of Study 
6.3.1 Duration of an Individual Patient’s Study Participation 
Patients will continue to be treated with TAK-788 until they experience progressive disease (PD) 
that requires an alternate therapy in the opinion of the investigator, intolerable toxicity, or 
another discontinuation criterion. Treatment may be continued after PD if, in the opinion of the 
investigator, the patient continues to experience clinical benefit. 
It is anticipated that total duration of an individual patient’s study participation will be 
approximately 1.5 years in median duration, including a 2-3 week screening period, a treatment 
period with estimated average of 10-12 cycles (28 days each) and a follow-up period for 
approximately 30 days after the last dose of TAK-788. 
Only in the phase 2 part, the follow-up period for a patient begins after the last completed site 
visit and continues until patient contact ceases. The follow-up assessments (ie, contacting the 
patient for survival and subsequent anticancer therapy) must be performed every 12 weeks after 
the end of treatment (EOT). For patients who discontinue study treatment in the absence of PD, 
survival should be tracked and additional tumor assessment should be performed at the same 
time points as the study treatment (every 8 weeks until Week 56 [equivalent to Cycle 14 Day 28] 
and every 12 weeks thereafter) until PD or the start of another systemic anticancer therapy. After 
that, survival must be tracked every 12 weeks, and subsequent anticancer therapy should be 
recorded. 
6.3.2 Total Study Duration 
End of study (completion) date is defined as all patients have completed all study visits or have 
otherwise discontinued from the study. 
For the Phase 1 part, the estimated time frame is approximately 3 years for completion, including 
15 months to accrue patients and 1.5 years for the duration of the last patient’s study 
participation. 
For the Phase 2 part, the estimated duration is approximately 4 years, including approximately 1 
year to accrue patients and 3 years for treatment and follow-up of the last patient. 
6.3.3 Timeframes for Primary and Secondary Endpoints to Support Disclosures 
All primary and secondary endpoints for disclosure is summarized in Table 6.a. 
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PD, progressive disease; PFS, progression-free survival; PK, pharmacokinetic; PR, partial response; QLQ, Quality 
of Life Questionnaire; QLQ-LC13, Quality of Life Questionnaire, lung cancer module; RECIST, Response 
Evaluation Criteria in Solid Tumors; RP2D, recommended phase 2 dose; SD, stable disease; TEAE, treatment-
emergent adverse event. 
6.3.4 Post-trial Access 
Patients will be allowed to continue treatment with TAK-788 after the clinical study database is 
closed if, in the opinion of the investigator and confirmed by the sponsor, the patient has 
experienced a clinically important benefit from TAK-788, has no alternative therapeutic option, 
and would be harmed without continued access. 
Duration of Posttrial Access 
Continued access to TAK-788 for participants will be terminated for those individuals who no 
longer benefit from TAK-788, the benefit-risk no longer favors the individual, if TAK-788 
becomes available either commercially or via another access mechanism, or when an alternative 
appropriate therapy becomes available. Posttrial access may be terminated in Japan where 
marketing authorization has been rejected. 
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7.0 
STUDY POPULATION 
7.1 
Inclusion Criteria 
General Inclusion Criteria (Both in Phase 1 and Phase 2 Part) 
Each patient must meet all the following inclusion criteria to be enrolled in the study. 
1. Male or female patients ≥20 years old.
2. Must have measurable disease by RECIST v1.1. Previously irradiated lesions may not be
used for target lesions, unless there is unambiguous radiological progression after
radiotherapy (see Appendix C).
3. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 (see Appendix D).
4. Minimum life expectancy of 3 months or more.
5. Adequate renal and hepatic function as defined by the following criteria:
•
Total serum bilirubin ≤1.5 × upper limit of normal (ULN) (≤3.0 × ULN for patients with
Gilbert syndrome or if liver function abnormalities are due to underlying malignancy);
•
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × ULN (or
≤5 × ULN if liver function abnormalities are due to underlying malignancy);
•
Estimated creatinine clearance ≥30 mL/min (calculated by using the Cockcroft-Gault
equation);
•
Serum albumin ≥2 g/dL; and
•
Serum lipase ≤1.5 × ULN; and
•
Serum amylase ≤1.5 × ULN unless the increased serum amylase is due to salivary
isoenzymes.
6. Adequate bone marrow function as defined by the following criteria:
•
Absolute neutrophil count ≥1.5 × 109/L;
•
Platelet count ≥75 × 109/L in Phase 1 Part and ≥100 × 109/L in Phase 2 Part; and
•
Hemoglobin ≥9.0 g/dL.
7. Normal QT interval on screening ECG, defined as QTcF of ≤450 ms in males or ≤470 ms in
females.
8. Female patients who:
•
Are postmenopausal (natural amenorrhea and not due to other medical reasons) for at
least 1 year before the screening visit, OR
•
Are surgically sterile, OR
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•
If they are of childbearing potential, agree to practice 1 highly effective non-hormonal
method of contraception and 1 additional effective (barrier) method (see Section 8.7.1) at
the same time, from the time of signing the informed consent form (ICF) through 30 days
after the last dose of study drug, OR
•
Agree to practice true abstinence, when this is in line with the preferred and usual
lifestyle of the subject.
Note: Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation
methods), withdrawal, spermicides only, and lactational amenorrhea are not acceptable
methods of contraception.
Male patients, even if surgically sterilized (ie, status postvasectomy), who: 
•
Agree to practice effective barrier contraception (see Section 8.7.1) during the entire
study treatment period and through 30 days after the last dose of study drug, OR
•
Agree to practice true abstinence, when this is in line with the preferred and usual
lifestyle of the subject.
Note: Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation
methods), withdrawal, spermicides only, and lactational amenorrhea are not acceptable
methods of contraception.
9. Voluntary written consent must be given before performance of any study-related procedure
not part of standard medical care, with the understanding that consent may be withdrawn by
the patient at any time without prejudice to future medical care.
10. Willingness and ability to comply with scheduled visits and study procedures.
Phase-Specific Inclusion Criteria
In addition to the general inclusion criteria above, patients must also meet all criteria for the 
study phase in which their entry is proposed. 
Phase 1 Part 
1. Have histologically or cytologically confirmed locally advanced (and not a candidate for
definitive therapy) (Stage IIIB) or metastatic NSCLC (Stage IV).
2. Refractory to standard available therapies.
3. All toxicities from prior therapy have resolved to ≤ grade 1 according to the National Cancer
Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v5.0), or have
resolved to baseline, at the time of first dose of TAK-788. Note: treatment-related grade >1
alopecia or treatment-related grade 2 peripheral neuropathy are allowed if deemed
irreversible.
Phase 2 Part
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1. Histologically or cytologically confirmed locally advanced not suitable for definitive therapy,
recurrent, or metastatic (Stage IV) NSCLC.
2. Not received prior systemic treatment for locally advanced or metastatic disease (with the
exception below): Neoadjuvant or adjuvant chemotherapy/immunotherapy for Stage I to III
or combined modality chemotherapy/radiation for locally advanced disease is allowed if
completed >6 months before the development of metastatic disease.
3. A documented EGFR in-frame exon 20 insertion (including A763_Y764insFQEA,
V769_D770insASV, D770_N771insNPG, D770_N771insSVD, H773_V774insNPH, or any
other in-frame exon 20 insertion mutation) by a local test that has been analytically validated
per local authority guidelines. The EGFR exon 20 insertion mutation can be either alone or in
combination with other EGFR or HER2 mutations except EGFR common mutations (exon
19 del or L858R).
4. Adequate tumor tissue available, either from primary or metastatic sites, for central
laboratory confirmation of EGFR in-frame exon 20 insertion mutation (see laboratory
manual). Note: confirmation of central test positivity is not required before the first dose of
TAK-788.
7.2 
Exclusion Criteria 
General Exclusion Criteria (Both in Phase 1 and Phase 2 Part) 
Patients are not eligible for participation in the study if they meet any of the following exclusion 
criteria. 
1. Have been diagnosed with another primary malignancy other than NSCLC except for
adequately treated non-melanoma skin cancer or cervical cancer in situ; definitively treated
non-metastatic prostate cancer; or patients with another primary malignancy who are
definitively relapse-free with at least 3 years elapsed since the diagnosis of the other primary
malignancy.
2. Have undergone major surgery within 28 days prior to first dose of TAK-788. Minor surgical
procedures, such as catheter placement or minimally invasive biopsy, are allowed.
3. Have current spinal cord compression (symptomatic or asymptomatic and detected by
radiographic imaging) or leptomeningeal disease (symptomatic or asymptomatic).
4. Have significant, uncontrolled, or active cardiovascular disease, including, but not restricted
to:
•
Myocardial infarction within 6 months prior to the first dose of study drug;
•
Unstable angina within 6 months prior to first dose;
•
Congestive heart failure within 6 months prior to first dose;
•
History of clinically significant (as determined by the treating physician) atrial
arrhythmia;
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•
Any history of ventricular arrhythmia; or
•
Cerebrovascular accident or transient ischemic attack within 6 months prior to first dose.
5. Have uncontrolled hypertension. Patients with hypertension should be under treatment on
study entry to control blood pressure.
6. Currently being treated with medications known to be associated with the development of
Torsades de Pointes (see Appendix F).
7. Have an ongoing or active infection, including, but not limited to, the requirement for
intravenous antibiotics. Have a known history of HIV infection. Testing of HIV is not
required in the absence of history.
Hepatitis B surface antigen (HBsAg) positive patients are allowed to enroll if hepatitis B
virus (HBV)-DNA is below 1000 copies/mL in the plasma.
Patients who have positive hepatitis C virus (HCV) antibody can be enrolled but must have
HCV-RNA undetectable in the plasma.
8. Currently have or have a history of interstitial lung disease (ILD), radiation pneumonitis that
required steroid treatment, or drug-related pneumonitis.
9. Female patients who are lactating and breastfeeding or have a positive serum pregnancy test
during the screening period.
Note: Female patients who are lactating will be eligible if they discontinue breastfeeding.
10. Have gastrointestinal illness or disorder that could affect oral absorption of TAK-788.
11. Have any condition or illness that, in the opinion of the investigator, might compromise
patient safety or interfere with the evaluation of the safety of the drug.
Phase-Specific Exclusion Criteria 
In addition to the general exclusion criteria above, patients are not eligible for participation in the 
study phase if they meet any of the following exclusion criteria for the study phase in which their 
entry is proposed. 
Phase 1 Part 
1. Previously received TAK-788.
2. Received small-molecule anticancer therapy (including cytotoxic chemotherapy and
investigational agents) within 14 days prior to the first dose of TAK-788 (except for
reversible EGFR TKIs [ie, erlotinib or gefitinib] up to 7 days prior to the first dose of TAK-
788).
3. Received antineoplastic monoclonal antibodies including immunotherapy within 28 days
prior to the first dose of TAK-788.
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4. Received radiotherapy within 14 days prior to the first dose of TAK-788, Stereotactic
radiosurgery (SRS) and stereotactic body radiosurgery are allowed up to 7 days prior to the
first dose.
5. Have symptomatic CNS metastases (parenchymal or leptomeningeal) at screening or
asymptomatic disease requiring corticosteroids to control symptoms within 7 days prior to
the first dose of TAK-788.
Note: If a patient has worsening neurological symptoms or signs due to CNS metastases, the
patient needs to complete local therapy and be neurologically stable (with no 
requirement for corticosteroids or use of anticonvulsants) for 7 days prior to the first 
dose of TAK-788. Patients with no prior history of signs or symptoms of CNS 
metastases but who receive prophylactic steroids or anticonvulsants are allowed. 
6. Received a strong cytochrome P450 (CYP)3A inhibitor or strong CYP3A inducer within 2
weeks prior to first dose of TAK-788 (see Appendix E).
Phase 2 Part
1. Received radiotherapy within 14 days before the first dose of TAK-788 or has not recovered
from radiotherapy-related toxicities. Stereotactic radiosurgery, stereotactic body
radiotherapy, or palliative radiation outside the chest and brain is allowed up to 7 days before
the first dose of TAK-788.
2. Have known active brain metastases (have either previously untreated intracranial CNS
metastases or previously treated intracranial CNS metastases with radiologically documented
new or progressing CNS lesions). Brain metastases are allowed if they have been treated with
surgery and/or radiation and have been stable without requiring corticosteroids to control
symptoms within 7 days before the first dose of TAK-788, and have no evidence of new or
enlarging brain metastases.
3. Received a moderate or strong CYP3A inhibitor or moderate or strong CYP3A inducer
within 10 days prior to first dose of TAK-788 (see Appendix E).
4. Have cardiac ejection fraction <50% by echocardiogram or multigated acquisition (MUGA)
scan at screening.
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8.0 
STUDY DRUG 
8.1 
Study Drug Administration 
All protocol-specific criteria for administration of study drug must be met and documented 
before drug administration. Study drug will be administered only to eligible patients under the 
supervision of the investigator or identified sub-investigator(s). 
If emesis occurs after study drug ingestion, the dose will not be re-administered, and patients 
should resume dosing at the next scheduled time with the prescribed dosage. Patients should 
record the occurrence of the emesis in their patient diary. Under no circumstance should a patient 
repeat a dose or double-up doses. 
Phase 1 Part 
TAK-788 drug product will be administered orally. TAK-788 will be self-administered by the 
patient. The starting dose will be 40 mg orally administered once daily, and increasing up to 
160 mg which is MTD identified in non-Japanese patients. Each 28-day dosing period is referred 
to as 1 cycle. Patients will take the prescribed dose with water with or without a low-fat meal (ie, 
≤350 kcal and ≤15% of calories from fat). Patients who forget to take their scheduled dose of 
study drug should be instructed not to make up the missed dose (if >6 hours after scheduled time 
of administration). Missed doses should be recorded in an appropriate source record (eg, clinic 
chart), patient diary, and study drug administration electronic case report form (eCRF). 
Phase 2 Part 
TAK-788 drug product will be administered orally. TAK-788 will be self-administered by the 
patient. The dose will be 160 mg orally administered once daily. Each 28-day dosing period is 
referred to as 1 cycle. Patients will take the prescribed dose with water with or without a low-fat 
meal (ie, ≤350 kcal and ≤15% of calories from fat). Patients who forget to take their scheduled 
dose of study drug should be instructed not to make up the missed dose (if >6 hours after 
scheduled time of administration). Missed doses should be recorded in an appropriate source 
record (eg, clinic chart), patient diary, and study drug administration eCRF. 
In case of extenuating circumstances that prevent a patient from attending the study site (eg, the 
COVID-19 pandemic), drug packs and patient diaries should be returned at the next available on-
site clinic visit. 
8.2 
Definitions of DLT (Phase 1 Part only) 
A DLT is a drug-related toxicity that is observed to occur within the first 28 days of treatment 
(end of Cycle 1) as defined below. Toxicity grades will be defined by the NCI CTCAE v5.0. 
DLTs are defined by the following: 
 
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•
Non-hematologic toxicities
–
Any ≥ grade 3 non-hematologic toxicity, with the exception of self-limiting or medically
controllable toxicities (eg, nausea, vomiting, fatigue, electrolyte disturbances,
hypersensitivity reactions) lasting <3 days, and excluding alopecia.
•
Hematologic toxicities
–
Febrile neutropenia not related to underlying disease (fever, >101°F [>38.3°C]; absolute
neutrophil count <0.5 × 109/L);
–
Prolonged grade 4 neutropenia (≥7 days) (if granulocyte-colony stimulating factor [G-
CSF] is required, the event will be considered as DLT irrespective of the duration);
–
Neutropenic infection: ≥ grade 3 neutropenia with ≥ grade 3 infection;
–
Thrombocytopenia ≥ grade 3 with bleeding, ≥ grade 3 requiring platelet transfusion or
grade 4 without bleeding lasting ≥7 days.
Note: Prophylactic platelet transfusions or prophylactic use of hematopoietic growth
factors (such as thrombopoietin, G-CSF, and granulocyte macrophage-colony stimulating
factor [GM-CSF]*) is not permitted during the DLT evaluation period.
*thrombopoietin and GM-CSF have not been approved for the treatment of anemia
associated with cancer chemotherapy in Japan.
•
Missed ≥25% of planned doses of TAK-788 over 28 days due to treatment-related AEs in the
first cycle.
8.3 
Dose Escalation Rules (Phase 1 Part Only) 
The starting dose in the study will be 40 mg, followed by dose escalation up to 160 mg which is 
MTD identified in non-Japanese patients. The dose escalation steps after the starting dose will be 
modified as needed, using BLRM based on accumulating broader knowledge of safety, PK and 
anti-tumor activity of TAK-788 obtained from this study and the Study AP32788-15-101, which 
could potentially reduce the escalation steps and potentially decrease the number of patients 
exposed to subtherapeutic doses. 
The MTD will be determined based on the DLT within the first 28 days of treatment (end of 
Cycle 1). Evaluable patients must complete at least 75% of their planned doses, unless missed 
doses are due to AEs. An adaptive BLRM that implements escalation with overdose control will 
be used in this study for purposes of dose escalation recommendations and estimation of the 
MTD. Data from the Study AP32788-15-101 will be used as prior information in the BLRM. For 
each dose level, the posterior probability of having DLT rates that fall into the following 
intervals will be estimated: 
•
[0, 0.21): under-dosing.
•
[0.21, 0.33): target toxicity.
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•
[0.33, 1.00]: excessive toxicity.
BLRM will recommend a dose which follows the Escalation With Overdose Control (EWOC) 
principle and has the highest posterior probability of having a DLT rate that falls into the interval 
[0.21, 0.33) as the target toxicity rate at MTD. Following the EWOC principle, the posterior 
probability of the recommended dose having a DLT rate above 0.33 must not exceed 30%. The 
selection of the next recommended dose will be determined along with other available 
information, such as safety, PK and efficacy. Regarding the safety, all AEs observed in all of the 
enrolled patients, including those observed in DLT non-evaluable patients, will be evaluated in 
concert with DLTs when making the decision on selecting next dose level. 
More conservative dose escalation, evaluation of intermediate doses, and expansion of an 
existing dose level are all permissible following discussions between the sponsor and the 
investigators if such measures are needed for patient safety or for a better understanding of the 
dose-toxicity and dose-exposure relationship of TAK-788. 
The MTD may be declared as the current dose if the following stopping rules is met: 
•
At least 9 patients are evaluable in the study and at least 6 patients are evaluable at the
current dose, and the current dose is the recommended dose for the next cohort.
Alternative stopping rules may also be considered following discussions between the sponsor 
and the investigators. 
8.3.1 Intra-patient Dose Escalation (Phase 1 Part only) 
Intra-patient dose escalation will be allowed in each patient while on the study if all of the 
following conditions are met: 
1)
The patient tolerated his/her starting dose without a DLT.
2)
Cycle 2 PK samples have been drawn per protocol.
3)
The dose to be escalated had been evaluated to be safe, and the decision for intra-patient
dose escalation will be made together with the sponsor and the investigators in end of cohort
meeting.
8.4 
Dose Modification Guidelines 
8.4.1 Dose Delays or Reductions 
Dose delays or reductions will be implemented for patients who experience TEAEs as indicated 
in the following section and in Table 8.a. Proposed dose-reduction levels for the Phase 2 part are 
summarized in Table 8.b. 
After dose reduction, patients should continue therapy at the reduced dose. Dose reductions may 
be implemented a second time if additional toxicity ensues. If study drug is held for more than 
2 weeks, resumption of therapy must be discussed with the sponsor. In general, re-escalation of 
 
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doses will occur only in consultation with the sponsor, as stipulated in Section 8.4.2. If toxicity 
requiring dose reduction occurs in the first dose cohort (in phase 1 part), discontinue therapy. 
Table 8.a 
Dose Modifications 
Toxicity Grade 
Action 
Non-Hematologic Toxicity 
Grade 1 
Continue therapy at the same dose level. 
Grade 2 
Continue therapy at the same dose level. If symptoms are intolerable, recurrent, or not 
controlled by supportive care, withhold therapy until symptoms remit and reduce to next 
lower dose level. 
Grade 3 
Withhold therapy until toxicity is ≤ grade 1 or has returned to baseline, then resume 
therapy. Therapy may be resumed at the most recent dose or at the next lower dose level, 
based on the investigator’s judgment. 
Grade 4 
Withhold therapy until toxicity is ≤ grade 1 or has returned to baseline, then resume 
therapy at the next lower dose level. Therapy may also be discontinued based on the 
investigator’s judgment. 
Hematologic Toxicity 
Grade 1 
Continue therapy at the same dose level. 
Grade 2 
Continue therapy at the same dose level. 
Grade 3 
Withhold therapy until toxicity is ≤ grade 2 or has returned to baseline, then resume 
therapy. Therapy may be resumed at the most recent dose or at the next lower dose level, 
based on the investigator’s judgment. 
Grade 4 
Withhold therapy until toxicity is ≤ grade 2 or has returned to baseline, then resume 
therapy at the next lower dose level. Therapy may also be discontinued based on the 
investigator’s judgment. 
Table 8.b 
Proposed Dose Reduction Level of Phase 2 Part 
Dosing 
Dose Level 
Starting dose 
160 mg QD 
First dose reduction 
120 mg QD 
Second dose reduction 
80 mg QD 
Abbreviations: QD, once daily. 
8.4.1.1 Management of Selected Treatment-Related Adverse Events 
If selected treatment-related adverse events are occurred, they should be managed as below, 
Nausea and Emesis 
Standard antiemetics, such as prochlorperazine, may be used for the treatment of vomiting. 
Taking the medication with food may reduce nausea. Prophylactic antiemetics may be used. 
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Diarrhea 
Based on pre-clinical findings and known class effect, patients should be monitored for the onset 
of diarrhea. Symptomatic care, such as loperamide, may be given at first evidence of loose stool, 
increased frequency of bowel movement, or at grade 1 diarrhea, according to the investigator’s 
clinical judgment (not to exceed total dose of 16 mg over 24 hours). For grade 2 diarrhea, 
administer loperamide at 4 mg, then 2 mg every 2 to 4 hours until the patient is symptom-free for 
12 hours (not to exceed total dose of 16 mg over 24 hours). No dose modification is necessary 
unless the patient does not tolerate TAK-788 or the symptom recurs. For grade ≥3 diarrhea 
despite loperamide, treatment will be withheld until recovery to grade ≤1 diarrhea. Secondary 
prophylaxis in patients who have experienced diarrhea with TAK-788 treatment is allowed. 
Other medications (such as diphenoxylate hydrochloride with atropine sulfate) and supportive 
care may be added according to the institution’s standard of care. Primary prophylactic 
antidiarrheal medications may be used after discussion with the sponsor. 
Pneumonitis 
Withhold TAK-788 for acute onset of unexplained new or progressive pulmonary symptoms, 
such as dyspnea, cough, and fever and during diagnostic workup for pneumonitis/interstitial lung 
disease. For suspected cases of pneumonitis of any grade, investigators should rule out infection, 
PD, and pulmonary embolism as other etiologies for the pulmonary symptoms and should 
closely monitor the patient. If pneumonitis of any grade is confirmed, TAK-788 should be 
permanently discontinued. Treatment with corticosteroids should be considered as appropriate. 
Asymptomatic Lipase/Amylase Elevation 
In the event of grade 3 asymptomatic lipase/amylase elevation (>5.0 × ULN), withhold therapy 
until toxicity is ≤ grade 2. Therapy may be resumed at the same dose or at the next lower dose 
level, based on the investigator’s judgment. In the event of grade 2 asymptomatic lipase/amylase 
elevation (>2 to ≤5.0 × ULN), continue therapy at same dose level or at the next lower dose 
level, based on the investigator’s judgment. In either case, close monitoring of patients with 
respect of lipase/amylase levels and clinical symptoms are highly recommended. 
Cardiac Events: QTc Interval Prolongation and Heart Failure 
TAK-788 dose modification guidelines, outlined in Table 8.c, should be closely followed for 
patients who experience QTc interval prolongation or heart failure deemed related to TAK-788 
dosing. TAK-788 dose reduction levels should follow the schedule outlined in Table 8.b. 
Table 8.c 
TAK-788 Dose Modification for TEAEs of QTc Interval Prolongation and 
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Heart Failure 
Toxicity Grade 
Parameters 
TAK-788 Dose Modification 
QTc Interval Prolongation 
Grade 2 
QTc Interval of 481 to 500 msec. 
First Occurrence: 
• Withhold TAK-788 dosing until QTc
interval recovers to a ≤Grade 1 or
baseline.
• Once recovered, resume TAK-788 at the
most recent dose.
Recurrence: 
• Withhold TAK-788 until ≤ Grade 1 or
baseline.
• Once recovered, resume TAK-788
dosing at the next lower dose level or
permanently discontinue dosing, based
on clinical judgement.
Grade 3 
≥501 msec 
 or  
Increases of >60 msec from baseline. 
First Occurrence: 
• Withhold TAK-788 until ≤ Grade 1 or
baseline.
• Once recovered, resume TAK-788
dosing at the next lower dose level, or
permanently discontinue TAK-788
dosing, based on clinical judgement.
Recurrence: 
• Permanently discontinue TAK-788
dosing.
Grade 4 
Torsades de Pointes; polymorphic 
ventricular tachycardia; signs/symptoms of 
serious arrhythmias. 
Permanently discontinue TAK-788 dosing. 
Decreased Ejection Fraction 
Grade 2: 
Ejection fraction - 
asymptomatic.  
Resting ejection fraction 50% to 40% 
or 
Decrease from baseline 10% to 19%.  
• Withhold TAK-788 until recovered to
baseline.
• If the patient recovers to baseline within
2 weeks of dose interruption, resume
TAK-788 at the most recent dose level
or the next lower dose level, in
accordance with clinical judgement.
• If the patient does not resume to
baseline within 2 weeks of dose
interruption, permanently discontinue
TAK-788 dosing.
≥Grade 3:  
Ejection fraction - 
asymptomatic. 
Resting ejection fraction ≤39% 
or 
≥ 20% decrease from baseline. 
Permanently discontinue TAK-788 dosing. 
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Toxicity Grade 
Parameters 
TAK-788 Dose Modification 
Heart Failure 
Any Grade  
Heart failure - symptomatic 
Permanently discontinue TAK-788 dosing. 
QTc: corrected QT interval; TEAE: treatment-emergent adverse event. 
8.4.2 Dose Re-escalation 
Dosing reduced for toxicity may be re-escalated to the original dose only after discussion with 
the sponsor. For dose re-escalation, the following conditions have to be met. 
1)
The original dose does not exceed the MTD (160 mg QD).
2)
The patient recovered from the AE.
3)
The reduced dose is considered subtherapeutic in the opinion of the investigator.
4)
The AE is not considered clinically significant in the judgment of the investigator, with
exceptions such as ILD/pneumonitis, hepatic injury, acute pancreatitis.
For patients who continue the treatment despite radiologic PD (as described in Section 8.4.3), the 
dose may be escalated to a higher dose that is determined not to exceed the MTD, following 
discussion with the sponsor. 
8.4.3 Criteria for Discontinuation of Study Drug 
Patients will be discontinued from further study drug administration in the event of any of the 
following: 
•
Intolerable toxicity as determined by the investigator.
•
PD requiring an alternate therapy, in the opinion of the investigator.
Note: Treatment of patients with TAK-788 may be continued, despite progression by
RECIST v1.1, at the discretion of the investigator, if there is still evidence of clinical benefit.
•
Patient meets the discontinuation rules for pneumonitis (Section 8.4.1.1).
•
Entry into another therapeutic clinical study or start of new anticancer therapy.
•
Significant deviation from the protocol or eligibility criteria, in the opinion of the sponsor’s
medical monitor or investigator.
•
Noncompliance with study or follow-up procedures.
•
Pregnancy.
•
Patient withdrawal of consent or decision to discontinue participation.
•
Termination of the study by the sponsor.
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•
Any other reason that, in the opinion of the investigator, would justify removal of the patient
from the study.
8.5 
Excluded Concomitant Medications and Procedures 
The medications and procedures which a patient is not allowed to use at the time of screening 
and prior to the first dose of TAK-788 are described in inclusion and exclusion criteria. 
The following concurrent medications and procedures are prohibited until the study drug 
discontinuation described in Section 9.9. If a patient’s clinical condition requires treatment 
with one of the prohibited classes of medications specified below, the clinical details of the 
situation should be discussed with the medical monitor at the earliest possible time to determine 
whether it is safe for the patient to continue treatment with TAK-788. 
•
Any other anticancer therapy including, but not limited to, chemotherapeutic agents,
immunotherapy, biological response modifiers (excluding growth factors), radiotherapy,
and/or systemic hormonal therapy (with the exception of local therapies, including SRS, used
for palliative or symptomatic control of existing lesions, with appropriate treatment
interruption at the discretion of the investigator);
•
Use of any other investigational drug or device;
•
Medications that are known to be associated with the development of Torsades de Pointes.
Medications that prolong the QT interval, but are not known to be associated with Torsades
de Pointes, should be avoided but are not prohibited (see Appendix F);
•
Herbal preparations or related over-the-counter preparations containing herbal ingredients, or
other folk remedies;
•
Grapefruit or grapefruit-containing products, pomegranate, pomelo, or star fruit juice
containing products, and Seville oranges;
•
Extensive surgery requiring in-patient care (patients may have an interruption in therapy for
2 weeks should emergency surgery be required);
•
Medications that are moderate or strong inducers, or moderate or strong inhibitors of the
CYP3A family of Cytochromes P450 (see Appendix E), with the exception of nonsystemic
use (eg, topical);
•
Any illicit substance.
The following concurrent medications, exposure to which may be affected by TAK-788, may be 
allowed with caution, and patients should be closely monitored for signs of changed tolerability 
or effectiveness as a result of increased or decreased exposure of the concomitant medication 
while receiving TAK-788: 
•
Medications that are CYP3A substrates and which have narrow therapeutic index including
alfentanil, cyclosporine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and
tacrolimus, and all statins;
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•
CYP2C8 sensitive substrates, including repaglinide, dasabuvir and amodiaquine;
•
Warfarin, a CYP2C9 sensitive substrate;
•
S-mephenytoin, a CYP2C19 sensitive substrate.
8.6 
Permitted Concomitant Medications and Procedures 
Palliative therapy and supportive care are permitted during the course of the trial for 
management of symptoms and underlying medical conditions that may develop during the study. 
8.7 
Precautions and Restrictions 
8.7.1 Pregnancy and Contraception 
TAK-788 demonstrated embryo-fetal toxicity in rats and, similar to other EGFR inhibitors, has 
the potential to cause embryo-fetal harm; therefore, female patients participating in this study 
should avoid becoming pregnant, breastfeeding a baby, or donating eggs, and male patients 
should avoid impregnating a female partner and donating sperm for 30 days after the last dose of 
TAK-788. Female patients of childbearing potential and male patients will be informed as to the 
potential risk of conception while participating in this study and will be advised that they must 
use effective contraception (ie, results in a low failure rate when used consistently and correctly), 
as specified below. A pregnancy test will be performed on each pre-menopausal female patient 
of childbearing potential at screening, immediately prior to the first dose of study drug, once 
every 4 weeks while on treatment, and again at treatment discontinuation during the 
End-of-Treatment visit. A negative pregnancy test must be documented prior to administration of 
study drug. 
Female patients must meet 1 of the following: 
•
Postmenopausal for at least 1 year before the screening visit, OR
•
Surgically sterile, OR
•
If they are of childbearing potential, agree to practice the following 1 highly effective non-
hormonal method and 1 additional effective (barrier) method of contraception at the same
time, from the time of signing ICF through 30 days after the last dose of study drug, OR
Highly effective non-hormonal methods:
–
Intrauterine device (IUD).
–
Bilateral tubal occlusion.
–
Vasectomised sole sexual partner.
Additional effective (barrier) methods:
–
Male condom with or without spermicide.
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•
Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of
the subject.
Note: Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods),
withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of
contraception.
Male patients, even if surgically sterilized (ie, status postvasectomy), must agree to 1 of the 
following: 
•
Agree to practice effective barrier contraception (eg, latex condom with a spermicidal agent)
during the entire study treatment period and through 30 days after the last dose of study drug,
OR
•
Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of
the subject.
Note: Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods),
withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of
contraception.
If a patient is confirmed pregnant during the study, study drug administration must be 
discontinued immediately. The investigator must immediately notify the sponsor’s medical 
monitor of this event and record the pregnancy on the paper Pregnancy Form. Initial information 
regarding a pregnancy must be immediately sent to the Takeda Global Pharmacovigilance 
department or designee. 
The investigator must immediately report follow-up information to the sponsor regarding the 
course of the pregnancy, including perinatal and neonatal outcome. If the pregnancy results in 
the birth of a child, additional follow-up information may be requested. If the pregnancy results 
in spontaneous abortion or stillbirth, the event should be reported as an SAE. 
If a female partner of a male patient becomes pregnant during the male patient’s participation in 
this study, the sponsor must also be contacted immediately by sending a completed pregnancy 
form to the Takeda Global Pharmacovigilance department or designee. 
Pregnancy outcomes also must be collected for the female partners of any male patients who 
took study drug in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the female partner. 
It is not known whether TAK-788 passes into the breast milk. Mothers should not breastfeed 
during the entire study treatment period and through 30 days after the last dose of study drug. 
8.7.2 Potential Drug Interactions 
In vitro reaction phenotyping studies with human liver microsomes and selective CYP inhibitors, 
and recombinant human CYPs, indicate that TAK-788 is mostly metabolized by CYP3A4/5. 
Therefore, it is likely that orally administered CYP3A4/5 inhibitors and/or inducers may affect 
plasma drug levels of TAK-788 and its active metabolites (including, but not limited to, 
 
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AP32960 and AP32914) and cause potential clinical drug-drug interactions (DDIs). Medications, 
and dietary (grapefruit-containing products) or herbal products that are moderate or strong 
inhibitors, or moderate or strong inducers of CYP3A4/5 should be avoided (see Appendix E). 
Based on nonclinical in vitro data, TAK-788, AP32914, and AP32960 are not anticipated to 
inhibit CYP1A2-, CYP2C9-, CYP2C19-, or CYP2D6-mediated metabolism of co-administered 
drugs. Given the inhibition constant (Ki) values (IC50/2) and the expected plasma exposures of 
TAK-788, AP32914, and AP32960 in humans, TAK-788, AP32914, and AP32960 are not likely 
to exhibit DDIs due to inhibition of CYP2B6, CYP2C8, or CYP3A4/5. TAK-788 showed time-
dependent inhibition of CYP3A4/5 in vitro, with a 10-fold IC50 shift (22.3 to 2.51 µM 
[testosterone 6β-hydroxylation] and 19.7 to 1.98 µM [midazolam 1’-hydroxylation]). TAK-788 
and its active metabolites, AP32960 and AP32914, were potent inducers of CYP3A4 in vitro at 
concentrations ≥1 µM; however, the induction effect was much lower at concentrations ≤0.1 µM 
with little-to-no induction observed at 0.01 µM. Given that activation of the pregnane X receptor 
results in co-induction of CYP3A and CYP2C isozymes, it was considered likely that TAK-788 
and its metabolites could induce CYP2C isozymes. Testing of the potential of TAK-788 to 
induce CYP2C isozymes in vitro revealed weak induction of CYP2C isozymes at up to 5 μM 
TAK-788; however, TAK-788 metabolites have not been tested. Based on in vitro results, there 
is a potential DDI of TAK-788 and its active metabolites, AP32960 and AP32914, with CYP3A 
substrates as a perpetrator. 
TAK-788 induces CYP3A, 2C8, and 2C9 in vitro and may decrease concentrations of 
concomitantly administered CYP3A, 2C8, and 2C9 substrates. Based on emerging clinical PK 
data from this study, autoinduction of the apparent oral clearance of TAK-788 has been observed 
following multiple-dose administration at 160 mg QD, likely explained by induction of CYP3A 
by TAK-788. Coadministration of TAK-788 with substrates of CYP3A, including hormonal 
contraceptives, and other pregnane X receptor–inducible enzymes (eg, CYP2C9, CYP2C19) and 
transporters (eg, P-glycoprotein), may result in decreased concentrations and loss of efficacy of 
these coadministered drugs. 
8.7.3 Concomitant Medications with QTc Interval Prolongation Potential 
Investigators should provide close oversight of patients when co-dosing TAK-788 with 
concomitant medications with known QTc interval prolongation. Additional ECGs, as clinically 
indicated should be conducted in accordance with the investigator’s judgement. Dose 
modification for patients exhibiting QTc interval prolongation is outlined in Section 8.4.1.1. 
Restricted concomitant medications with a known risk of Torsades de Pointes are provided in 
Appendix F. 
8.8 
Management of Clinical Events 
8.8.1 Management of Adverse Drug Reactions 
Comprehensive assessments of any study drug-related AEs (adverse drug reactions) experienced 
by the patient will be performed throughout the course of the study. Anticipated adverse drug 
 
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reactions that may be experienced are described in the Investigator’s Brochure. The severity of 
the event, as well as clinical judgment, will be utilized to determine appropriate management of 
the patient for any AE experienced while participating in this study. 
8.8.2 Management of Selected Treatment-Related Adverse Events 
Management of selected treatment-related AEs are provided in Section 8.4.1.1. 
8.9 
Blinding and Unblinding 
This is an open-label study. 
8.10 
Description of Investigational Agents 
TAK-788 drug product is a nonsterile, oral, capsule dosage form, supplied in a white, opaque, 
hard gelatin capsule shell containing 40 mg (as free base) of TAK-788 succinate salt as 100% 
active pharmaceutical ingredient (API). No other ingredients are included in the drug product. 
For additional details, refer to the Investigator’s Brochure and Pharmacy Manual. 
8.11 
Preparation, Reconstitution, and Dispensation 
TAK-788 dosage forms will be provided in labeled bottles in accordance with all applicable 
regulations. Materials provided by the sponsor should be dispensed to patients with clear 
administration instructions from the investigator. 
Detailed instructions for dispensing TAK-788 dosage forms are provided in the Pharmacy 
Manual. 
TAK-788 is an anticancer drug, and as with other potentially toxic compounds, caution should be 
exercised when handling TAK-788. 
8.12 
Packaging and Labeling 
TAK-788 drug product will be provided by the sponsor. TAK-788 drug product will be supplied 
in white high density polyethylene bottles with child resistant caps with liner. 
Bottle labels will bear the appropriate label text as required by governing regulatory agencies. At 
a minimum, such text will include product name, product strength, number of capsules, and lot 
number. 
8.13 
Storage, Handling, and Accountability 
The recommended storage condition for TAK-788 drug product is at a temperature 
thermostatically maintained at the usual customary working environment of 1°C to 30°C, as 
experienced in pharmacies, hospitals, and warehouses. 
The study pharmacist or designee at the site will be responsible for handling and dispensing 
study drug and completing associated documentary paperwork. Supplies are shipped to the 
 
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investigative site at appropriate intervals, depending on patient accrual. The site must use an 
appropriate dispensing log/accountability form provided by the sponsor, or an acceptable 
substitute approved by the sponsor. Each time study medication is dispensed to a patient, the 
following information must be recorded: the patient identification number, drug product strength, 
quantity dispensed with the corresponding lot number, and the signs of the person dispensing the 
drug. These logs are to be maintained by the study pharmacist in the pharmacy throughout the 
duration of the study and will be periodically verified by a representative of the sponsor. 
Disruption to site visits due to the COVID-19 pandemic may require the site to use an alternative 
method for dispensing TAK-788 to ensure continuity of treatment. If allowed by country 
regulation/IRB, TAK-788 can be shipped DTP from the investigation site to the patient’s home 
address via courier if needed. 
The investigator is responsible for ensuring that the study drug provided to the patient and 
returned from the patient are accounted for and noted in source documentation. 
8.13.1 Disposition of Used Supplies 
All used bottles of study drug can 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 utilization of TAK-788 intended for use in this study is authorized by the sponsor. The 
principal investigator or his/her designee will be responsible for the appropriate handling of 
residual study drug.  
8.13.2 Inventory of Unused Supplies 
During the study and at termination, patients must return all unused study drug supplies, and the 
return of these unused study drug supplies must be recorded. Returned supplies must not be 
redispensed. 
The sponsor will confirm an inventory of unused study drug periodically during the study, and at 
the completion of the study, a final study drug accountability review will be conducted. Any 
discrepancies must be investigated. 
The on-site pharmacist will immediately return unused study drugs to the sponsor after the study 
is closed at the study site. 
Please refer to the Pharmacy Manual for additional instructions. 
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 Takeda clinician, other third-party vendors participating in the 
study as well as the list of investigators can be found in the protocol annex or Study Manual. 
9.2 
Arrangements for Recruitment of Patients 
Recruitment and enrollment strategies for this study may include recruitment from the 
investigator’s local practice or referrals from other physicians. If advertisements become part of 
the recruitment strategy, they will be reviewed by the institutional review board (IRB). 
9.3 
Treatment Group Assignments 
After written informed consent has been obtained, the patient will be assigned a patient 
identification number. 
Patients who meet all eligibility criteria and provide written informed consent will be enrolled in 
this study, and the treatment of TAK-788 will be started. In Phase 1 part, the dose level to be 
administered will be determined according to the dose escalation scheme outlined in Section 8.3. 
In Phase 2 part, the dose will be 160 mg orally administered once daily. 
Patients who screen fail may later be re-screened with prior sponsor approval. 
9.4 
Study Procedures 
The study procedures to be performed at screening and throughout the entire study are listed in 
the schedule of events (Appendix A), which is meant to provide a convenient display of the 
timing and scope of required assessments expected at each visit, but does not provide a 
comprehensive description of each assessment. Additional details are provided as necessary in 
the sections that follow. 
The ICF may be signed more than 21 days before C1D1. Screening assessments must be 
performed within 14 days before C1D1, with the exception of tumor imaging assessment, for 
which the allowable window is 21 days before C1D1. 
Investigators must be familiar with the details of this section and use it in conjunction with the 
table to adequately carry out the required study assessments. All study assessments should occur 
within ±3 days of the scheduled study day unless otherwise noted in the schedule of events 
descriptions or table. A cycle is defined as 28 days. 
In Phase 1, patients will be hospitalized during DLT evaluation in Cycle 1. If a patient needs to 
be discharged temporarily during the period, the investigator must obtain an approval from the 
sponsor. The investigator must document the confirmation record for stabilization of the 
 
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patient’s symptoms per the available data in an appropriate source record (eg, medical records) 
before the patient’s temporary discharge. 
Sites will make every effort to see patients in the clinic for assessments. In unavoidable 
circumstances, such as the COVID-19 public health emergency, exceptions can be made for 
alternative methods for conducting patient visits/assessments and ideally should be approved by 
the sponsor or designee. These methods may include remote visits being conducted by phone 
(eg, collection of AEs and monitoring) or video conferencing (Telehealth or Telemedicine, 
physician/patient preferred methodology), or alternative site/location (eg, collection of safety 
assessments). Remote visits and telemedicine must comply with national and local laws and 
regulations. Such instances will be documented in the study records. 
9.4.1 Informed Consent 
Each patient must provide written informed consent before any study-required procedures are 
conducted, unless those procedures are performed as part of the patient’s standard care. 
9.4.2 Patient Demographics 
The date of birth, sex, race, and ethnicity of the subject are to be recorded during screening. 
9.4.3 Medical/Surgical History 
During the screening period, a complete medical history will be compiled for each patient. 
Information to be recorded includes relevant past illnesses, smoking classification, ongoing 
medical conditions, and surgical procedures (not related to the primary diagnosis). 
9.4.4 Diagnosis and Cancer History 
The initial cancer diagnosis and the current cancer stage at the time of screening, along with 
tumor histology and all sites of disease, should be recorded. 
9.4.5 Mutation Status 
Mutation status at baseline (eg, activating mutations in EGFR or HER2, as well as other 
previously identified abnormalities in other genes) should be recorded if available. Information 
on the specific point mutations, deletions, insertions, or gene rearrangements observed should be 
recorded, if available. 
Phase 2 Part 
All patients in the Phase 2 part will have a documented EGFR exon 20 insertion mutation by a 
local test prior to enrollment, and the patient’s tumor specimen will be retrospectively confirmed 
for EGFR exon 20 insertion mutations by an analytically validated central test. Local testing can 
be technology agnostic (polymerase chain reaction, digital polymerase chain reaction, Sanger 
sequencing, or next-generation sequencing) as long as it is analytically validated and performed 
by an accredited local laboratory. Local mutation testing can be conducted from either tumor 
specimen or liquid biopsy. 
 
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9.4.6 Prior Cancer Therapy 
Information regarding prior cancer therapy will be taken at screening, and includes cancer-
related surgical procedures, radiation, and systemic therapies. Surgical procedures include 
curative and palliative, as well as diagnostic procedures (eg, biopsy). Radiation will include both 
definitive and palliative treatment. Systemic therapy includes all regimens given, type of regimen 
(eg, neo adjuvant, adjuvant, for advanced/metastatic disease), number of cycles administered for 
each regimen, each drug name in a regimen, the start and stop dates of each drug, the best 
response to the regimen, and the reason for discontinuation. Experimental or investigational 
therapy history must also be recorded. 
9.4.7 Physical Examination 
A complete physical examination must be performed at screening, the extent of which should be 
consistent with medical history and the patient’s underlying disease. Subsequent physical 
examinations as described in the schedule of events (Appendix A) may be directed to relevant 
findings. The End-of-Treatment physical examination should be a complete physical 
examination. The physical examination 30 days after last dose may be directed to any relevant 
findings. 
9.4.8 Height and Weight 
Height and weight will be measured during screening. Weight should be repeated on C1D1 prior 
to first dose, regardless of the time from screening, and it will also be assessed per the schedule 
of events (Appendix A) throughout the study. 
9.4.9 Vital Signs and Auscultation 
Vital signs include temperature, pulse, respiratory rate, blood pressure (when patient is seated), 
and percutaneous oxygen saturation. Vital signs and auscultation should be repeated on C1D1 
prior to first dose, regardless of the time from screening. Vital signs and auscultation will also be 
assessed per the schedule of events (Appendix A) throughout the study. 
9.4.10 ECOG Performance Status 
The patient’s performance status must be assessed using the ECOG performance scale during 
screening. ECOG performance status will also be assessed per the schedule of events (Appendix 
A) throughout the study. The ECOG performance scale is provided in Appendix D.
9.4.11 Cardiac monitoring 
Phase 1 Part 
Cardiac monitoring may be done according to medical judgement and as clinically indicated. 
Phase 2 Part 
 
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Conduct cardiac monitoring, including assessment of LVEF by ECHO/MUGA at baseline 
(screening), Cycle 2 Day 1, Cycle 4 Day 1, Cycle 7 Day 1 and the end of treatment (Appendix 
A). In addition, cardiac monitoring may be done at other times according to medical judgement 
and as clinically indicated. 
Both Phase 1 and Phase 2 Part 
Assess LVEF in patients who develop relevant cardiac signs or symptoms [13]. Any change in 
cardiac monitoring that is judged by the investigator as clinically significant will be recorded on 
both the source documentation and in the eCRF as an AE, and monitored as described in Section 
10.3. 
9.4.12 Clinical Laboratory Evaluations 
Clinical laboratory evaluations will be performed locally. Clinical laboratory evaluations will be 
performed as outlined below: 
9.4.12.1 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 (Appendix A).
Table 9.a 
Clinical Chemistry and Hematology Tests 
Hematology 
Serum Chemistry 
Hematocrit 
Hemoglobin 
Leukocytes with differential 
-
absolute neutrophil count
-
basophils count
-
eosinophils count
-
lymphocytes count
-
monocytes count
Platelet count 
Albumin 
Alkaline phosphatase (ALP) 
Alanine aminotransferase (ALT) 
Amylase 
Aspartate aminotransferase (AST) 
Bicarbonate (or carbon dioxide) (Option) 
Bilirubin (at least total and direct, or total 
and indirect) 
Blood urea nitrogen (BUN) 
Calcium 
Chloride 
Creatinine 
C-reactive protein (CRP)
Glucose
Lipase
Magnesium
Phosphate
Protein (total protein)
Potassium
Sodium
Table 9.b 
Clinical Urinalysis Tests 
Urinalysis 
Glucose 
Ketones 
Occult blood 
pH 
Protein 
Specific gravity 
Urobilinogen 
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9.4.12.2 Serology 
Serological assessments including HIV, HBsAg, HBV-DNA, HCV antibody, and HCV-RNA 
will be performed at screening. For patients who are positive for HBsAg or HCV antibody, the 
on-study testing should be performed according to the schedule of events (Appendix A). HIV 
test will not be required in the absence of HIV infection history. 
9.4.12.3 KL-6 and SP-D 
Krebs von den Lungen-6 (KL-6) and surfactant protein-D (SP-D) are used for evaluation of 
ILD/pneumonitis. Serum levels of KL-6 and SP-D will be assessed at screening, at 8-week 
intervals thereafter (on Day 1 [±3 days] of every even-numbered cycle), and at the time of 
diagnosis of ILD or pneumonitis (unscheduled collection). 
9.4.13 Chest X-ray 
Chest X-ray will be performed according to the schedule of events (Appendix A). 
9.4.14 Pregnancy Test 
The pregnancy test must be a beta-human chorionic gonadotropin (β-hCG) test, and either urine 
or serum can be used. Women who are not of childbearing potential (status post-hysterectomy, 
status post-bilateral oophorectomy, or post-menopausal [defined as amenorrhea for at least 
12 months]) and men do not need to have the test performed. 
Women of childbearing potential must be known to be negative pregnancy test at screening 
(serum test only) and within 7 days prior to the first dose of study drug (either urine or serum 
test). And the pregnancy test (either urine or serum test) must also be completed once every 
4 weeks thereafter and at the End-of-Treatment assessment. 
9.4.15 Electrocardiogram 
All ECGs must be 12-lead ECGs. An ECG is required at screening to determine eligibility; this 
may be a single ECG. Single ECGs will also be assessed per the schedule of events (Appendix 
A) throughout the study. In addition to the pre-specified time points, additional ECGs may be
performed at the investigator’s discretion to ensure patient safety. In particular, ECG monitoring
should be performed during the study if a patient has, during the study, been prescribed
medication that can prolong the QT interval or medication that can potentially alter the QT
interval (other than medications explicitly prohibited). ECGs will be recorded electronically and
will be evaluated locally. For consistency, the Fridericia correction – QTcF – method must be
used for all calculations of QTc intervals.
9.4.16 Adverse Events 
Monitoring of AEs, serious and nonserious, will be conducted from the date the informed 
consent is signed until 30 days after the last dose of study drug or before initiation of new 
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anticancer therapy (whichever comes first). Refer to Section 10.0 for details regarding 
definitions, documentation, and reporting of AEs and SAEs. 
9.4.17 Concomitant Medications and Procedures 
Concomitant treatments for all ongoing medical history conditions or AEs, as well as 
prophylactic treatments and supplements, must be reported from the date the informed consent is 
signed until 30 days after the last dose of study drug or before initiation of new systemic 
anticancer therapy (whichever comes first). 
9.4.18 Disease Assessment 
At screening, disease assessment must include imaging of the chest, abdomen, pelvis, and brain 
using appropriate radiological procedures (computed tomography [CT] scans or magnetic 
resonance imaging [MRI] with contrast, unless contrast media is contraindicated). Imaging of the 
brain (contrast-enhanced MRI is preferred) is required at screening for all patients, and will be 
repeated post-baseline for patients with CNS metastases at baseline. 
Patients must have at least 1 measurable lesion per RECIST v1.1 (see Appendix C). Previously 
irradiated lesions may not be used for target lesions, unless there is unambiguous radiological 
progression after radiotherapy. For Phase 1 part, brain lesions may be used as target lesions 
provided they are ≥10 mm and have not been: 1) previously treated with whole brain radiation 
therapy (WBRT) within 3 months, or 2) previously treated by SRS or surgical resection. 
Local site investigator/radiology assessment based on RECIST version 1.1 will be used to 
determine subject eligibility. In extenuating circumstances during the COVID-19 public health 
emergency, patients may use alternative site for imaging during the study period if approved by 
the sponsor or designee. 
Target and non-target lesions must be selected at study start and assessed throughout the course 
of treatment according to RECIST v1.1 guidelines. Disease assessment by CT and MRI scans 
will be performed at screening and at 8-week intervals thereafter (on Day 28 [±3 days in Phase 1 
part and ±7 days in Phase 2 part] of every even-numbered cycle) through cycle 14 after the initial 
dose of study drug, and every 3 cycles thereafter until PD. More frequent imaging is 
recommended at any time if clinically indicated. Imaging assessment will also be performed at 
End-of-Treatment if more than 4 weeks have passed since the last imaging assessment. The same 
imaging modality should be used at each assessment, if possible. 
PR and CR should be confirmed by a repeat tumor imaging assessment not less than 4 weeks 
from the date the response was first documented. The tumor imaging for confirmation of 
response may be performed at the earliest 4 weeks after the first indication of response, or at the 
next scheduled scan (ie, 8 or 12 weeks later), whichever is clinically indicated. Patients will then 
return to regular scheduled imaging, starting with the next scheduled imaging time point. 
Patients who obtain a confirmation scan or unscheduled scan do not need to undergo the next 
scheduled tumor imaging if it is <4 weeks later; tumor imaging may resume at the subsequent 
scheduled imaging time point. Imaging assessment will also be performed at end of treatment if 
 
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more than 4 weeks have passed since the last imaging assessment. The same imaging modality at 
the same institution should be used at each assessment, if possible, irrespective of study drug 
interruption or actual dosing. All radiographic images (eg, CT scan, MRI) performed during the 
study will be submitted to IRC for central review. The investigator assessment of the images will 
also be collected. 
9.4.19 Samples for Pharmacokinetic and Biomarker Analyses 
Primary Specimen Collection 
# 
Specimen Name in Schedule 
of Procedures 
Primary 
Specimen 
Primary 
Specimen 
Derivative 1 
Primary 
Specimen 
Derivative 2 
Description of 
Intended Use 
Sample Collection 
1 
Archival (Banked) Tumor 
Tissue Sample (surgical 
resection) 
FFPE block 
FFPE slides 
DNA 
RNA 
Biomarker 
measurements 
Mandatory 
2 
Fresh Tumor Tissue Biopsy 
Sample  
Fresh tumor 
tissue 
FFPE block 
FFPE slides 
DNA 
RNA 
Biomarker 
measurements 
Mandatory if 
archival (banked) 
tumor tissue is not 
available 
3 
Fresh Tumor Tissue Biopsy 
Sample at disease 
progression 
Fresh tumor 
tissue 
FFPE block 
FFPE slides 
Biomarker 
measurements 
Optional 
4 
Plasma Sample for Cell Free 
DNA 
Plasma 
DNA 
Biomarker 
measurements 
Mandatory 
5 
Plasma Sample for 
Cholesterol 
Plasma 
Biomarker 
measurements 
Mandatory 
6 
Plasma Samples for TAK-
788 PK 
Plasma 
PK measurements 
Mandatory 
7 
CSF sample for TAK-788 PK Cerebrospinal 
fluid 
PK measurements 
Optional 
8 
Matched Plasma Samples for 
TAK-788 PK 
Plasma 
PK measurements 
Mandatory if 
cerebrospinal fluid 
is collected 
Abbreviations: CSF, cerebrospinal fluid; FFPE, formalin fixed paraffin embedded; PK, pharmacokinetic(s). 
9.4.19.1 PK sample 
Phase 1 Part 
Blood samples will be collected at pre-specified time points (pre- and post-dosing) (see PK 
Sampling Time Points in Appendix A) to assess the plasma concentrations of TAK-788 and 
active metabolites (including, but not limited to, AP32960 and AP32914) and PK parameters 
following a single dose and multiple doses (steady state). 
Phase 2 Part 
The plasma concentrations of TAK-788 and active metabolites (including, but not limited to, 
AP32960 and AP32914) will be measured centrally. 
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Both Phase 1 Part and Phase 2 Part 
If lumbar puncture is performed as part of the standard of care, remaining CSF samples should 
be analyzed to determine the concentration of TAK-788 and its active metabolites, including, but 
not limited to, AP32914 and AP32960 (≥500 μL is sufficient), and these samples should have 
matched blood samples (for PK analyses) when possible (Section 9.4.21). 
9.4.19.2 Biomarker sample (Phase 2 Part Only) 
1) Plasma Samples for Cell Free DNA
Plasma samples will be collected for evaluating circulating cell-free DNA at the time points 
specified in the schedule of events (Appendix A). Only mutations associated with tumor DNA 
will be sequenced. Details regarding the preparation, handling, and shipping of the blood 
samples are provided in the laboratory manual. 
2) Plasma Samples for Cholesterol
Plasma samples will be collected for evaluating 4-beta-OH-cholesterol/cholesterol at the time 
points specified in the schedule of events (Appendix A). Details regarding the preparation, 
handling, and shipping of the blood samples are provided in the laboratory manual. 
9.4.20 Tumor Tissue Sample (Phase2 Part Only) 
All patients in the Phase 2 part must submit an available formalin fixed paraffin embedded 
(FFPE) tumor tissue sample during screening for confirmation of mutation status by central 
testing. The tumor tissue will also be used for exploratory biomarker studies, including but not 
limited to molecular genetic analysis of EGFR, HER2, and other genes implicated in tumor 
biology. An immunoprofiling study may be conducted if enough tissue is available. The tumor 
tissue may be archived tissue or fresh tissue if archived tumor tissue is not available. 
Patients who are not centrally confirmed to have EGFR exon 20 insertion mutations may 
continue to receive study drug if they are receiving clinical benefit at the discretion of the 
investigator and with the sponsor’s approval; these patients will continue in the study and have 
data collected per the schedule of events. 
9.4.21 Cerebrospinal Fluid (CSF) Collection 
If lumbar puncture is performed as part of the standard of care, remaining CSF samples should 
be analyzed to determine the concentration of TAK-788 and its active metabolites, including, but 
not limited to, AP32914 and AP32960 (≥500 μL is sufficient), and these samples should have 
matched blood samples (for PK analyses) when possible (Section 9.4.19.1). 
9.4.22 Patient-Reported Outcome Assessments (Phase 2 Part Only) 
Patient-reported outcomes will be collected by administering the following paper questionnaires: 
the EORTC QLQ-C30 (v3.0) and the lung cancer-specific module (the EORTC QLQ-LC13, 
v3.0) as described in the schedule of events (Appendix A). These assessments have been studied 
 
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extensively, have evidence of reliability and validity in the current patient population, and are 
suitable for use in global clinical studies. The questionnaires will be administered to patients in 
their local language, if available. 
On the study days they are administered, the questionnaires should be completed by patients 
prior to any testing or discussion with the physician. The patient should be given sufficient space 
and time to complete the questionnaires. The patient should complete the questionnaires on their 
own without any assistance from site staff or a caregiver. If the patients arrive for their scheduled 
visits, the questionnaires are intended to be self-reported and should not be interviewer-
administered. 
The EORTC QLQ-C30 is a cancer-specific questionnaire initially tested in lung cancer patients 
[14]. The EORTC QLQ-C30 will be scored for 5 functional scales (physical, role, cognitive, 
emotional, and social functioning); 3 symptom scales (fatigue, pain, and nausea/vomiting); and a 
global health status/QoL scale. Six single-item scales also are included (dyspnea, insomnia, 
appetite loss, constipation, diarrhea, and financial difficulties). 
The LC13 module was constructed in parallel with the core QLQ-C30. It comprises 13 questions 
assessing lung cancer-associated symptoms (cough, hemoptysis, dyspnea, and site-specific pain), 
treatment-related side effects (sore mouth, dysphagia, peripheral neuropathy, and alopecia), and 
use of pain medication [15][16]. The LC13 module incorporates 1 multi-item scale to assess 
dyspnea, and a series of single items assessing pain, coughing, sore mouth, dysphagia, peripheral 
neuropathy, alopecia, and haemoptysis.  
For both the QLQ-C30 and QLQ-LC13, raw scores are converted into scale scores ranging from 
0 to 100. For the functional scales and the global health status scale, higher scores represent 
better HRQoL, whereas for the symptom scales lower scores represent better HRQoL. All items 
in this questionnaire relate to a recall period of 1 week. 
Note: Signs and symptoms assessed with the patient-reported outcome questionnaires will not be 
considered AEs unless entered as such into the eCRF. 
9.5 
Documentation of Subject Failure 
Investigators must account for all subjects who sign informed consent. 
If the subject is found to be not eligible before the first dose, the investigator should complete the 
applicable eCRF. 
The primary reason for subject failure is recorded in the eCRF using the following categories: 
•
Death.
•
AE.
•
Screen failure (failed inclusion criteria or did meet exclusion criteria).
•
Protocol deviation.
•
Lost to follow-up.
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•
Withdrawal by subject.
•
Study terminated by sponsor.
Patient identification codes assigned to subjects who fail screening should not be reused.
9.6 
Completion of Study Treatment (for Individual Patients) 
Patients will be considered to have completed study treatment if they receive the study treatment 
until PD that requires an alternate therapy in the opinion of the investigator, intolerable toxicity, 
or until they discontinue treatment for other reasons. 
End-of-Treatment assessments (see Appendix A) must be performed within 14 days of the 
patient’s last dose of study drug or the patient/investigator decision to discontinue study 
treatment, whichever occurs later. Physical examinations, laboratory tests (hematology, 
chemistry, urinalysis), and ECG can be omitted if they had been previously performed within 14 
days since the last assessments and if, in the investigator’s judgment, significant change is 
unlikely. For the End-of-Treatment assessments, information may be collected from tests 
performed for the study or as part of the patient’s routine medical care. 
9.7 
Follow-Up After Last Dose 
The 30 Days After Last Dose assessments (see Appendix A) must be performed within 30 days 
(±7 days) after the last dose of study treatment. Physical examinations, laboratory tests 
(hematology, chemistry, urinalysis), and ECG can be omitted if the visit occurs within 10 days of 
the End-of-Treatment assessment and there have been no clinically significant findings. Any new 
systemic anticancer therapies that the patient has begun to receive since the end of treatment 
should be reported at this visit. For the 30 Days After Last Dose assessments, information may 
be collected from tests performed for the study or as part of the patient’s routine medical care. 
Follow-up assessments for PFS and OS are performed in the Phase 2 Part. Detailed information 
is provided in Section 9.12. 
9.8 
Completion of Study (for Individual Patients) 
Phase 1 Part 
Patients will be considered to have completed the study if they complete the 30 Days After Last 
Dose assessments. 
Phase 2 Part 
Patients will be considered to have completed the study if they are followed until death or until 
the sponsor terminates the study. 
9.9 
Discontinuation of Treatment With Study Drug 
Treatment with study drug may also be discontinued for any of the following reasons: 
 
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•
AE.
•
Protocol deviation.
•
PD.
•
Symptomatic deterioration.
•
Lack of efficacy.
•
Pregnancy (patient must be discontinued).
•
Study terminated by sponsor.
•
Withdrawal by subject.
•
Lost to follow-up.
•
Other.
Once study drug has been discontinued, all study procedures outlined for the end-of-treatment 
visit will be completed as specified in the schedule of events. The primary reason for study drug 
discontinuation will be recorded on the eCRF. 
In the case of study termination by the sponsor, eligible patients may have continued access to 
TAK-788 as described in Section 6.3.4. 
9.10 
Withdrawal of Patients From Study 
A patient may be withdrawn from the study for any of the following reasons: 
•
Lost to follow-up.
•
Study terminated by sponsor.
•
Withdrawal by subject.
•
Death.
•
Other.
The consequence of study withdrawal is that no new information will be collected from the 
withdrawn patient and added to the existing data or any database. 
9.11 
Study Compliance 
Study drug will be administered or dispensed only to eligible patients under the supervision of 
the investigator or identified sub-investigator(s). The appropriate study personnel will maintain 
records of study drug receipt and dispensing. 
Patients will be provided a patient diary in which the date and time of study drug administration 
will be recorded. Patients who forget to take or miss their dose should not make up the missed 
dose. Any missing doses must be recorded in an appropriate source record (eg, clinic chart), 
 
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patient diary card, and study drug administration eCRF. In addition, patients will be instructed to 
use the diary card to record whether the dose was taken with or without a low-fat meal. Training 
of patients should be documented in the appropriate source record (eg, clinic chart). When 
possible, patients should take the study drug under observation during scheduled study visits to 
the clinic where a predose blood sample is collected. The investigator is responsible for ensuring 
that the patient diary card(s) are accounted for and noted in source documentation. 
9.12 
Post-Treatment Follow-up Assessments (PFS and OS, Phase 2 Part Only) 
Only in the phase 2 part, patients who stop treatment for any reason other than PD will continue 
to have PFS follow-up visits and OS follow-up visits. 
The PFS follow-up visit should be performed every 8 weeks until Week 56 (equivalent to Cycle 
14 Day 28), and every 12 weeks (±14 days) thereafter, from the EOT visit to the occurrence of 
documented PD or the start of subsequent anticancer therapy. 
After the occurrence of documented PD or the start of subsequent anticancer therapy, patients 
will continue to have OS follow-up visits. The OS follow-up visits should be performed every 12 
weeks (±14 days) until death, loss to follow-up, consent withdrawal, study termination, or any of 
the circumstances described in Section 9.10 occur.  
The duration of OS follow-up will be 3 years after enrollment of the last patient, or until all 
patients have discontinued study treatment, whichever occurs later. 
Survival information and death details may be collected by methods that include, but are not 
limited to, telephone, email, and mail.  
NOTE: Related SAEs must be reported to the Takeda Global Pharmacovigilance department or 
designee. This includes deaths that the investigator considers related to study drug that occur 
during the post-treatment follow-up. Details about definition, documentation, and reporting of 
SAEs are provided in Section 10.1.2 and Section 10.2. 
 
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10.0 
ADVERSE EVENTS 
10.1 
Definitions 
10.1.1 AE Definition 
An AE is defined as any untoward medical occurrence in a clinical investigation subject who has 
signed informed consent to participate in a study; it does not necessarily have to have a causal 
relationship with this treatment or study participation. 
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant 
abnormal laboratory finding), symptom, or disease temporally associated with the study 
participation whether or not it is considered related to the drug. 
This includes any newly occurring event, or a previous condition that has increased in severity or 
frequency since the study participation. 
An abnormal laboratory value will not be assessed as an AE unless that value leads to 
discontinuation or delay in treatment, dose modification, therapeutic intervention, or is 
considered by the investigator to be a clinically significant change from baseline. 
10.1.2 SAE Definition 
SAE means any untoward medical occurrence that at any dose: 
•
Results in death.
•
Is life-threatening (refers to an AE in which the patient was at risk of death at the time of the
event. It does not refer to an event which hypothetically might have caused death if it were
more severe).
•
Requires inpatient hospitalization or prolongation of an existing hospitalization (see
clarification in the paragraph in Section 10.2 on planned hospitalizations).
•
Results in persistent or significant disability or incapacity. (Disability is defined as a
substantial disruption of a person’s ability to conduct normal life functions).
•
Is a congenital anomaly/birth defect.
•
Is a medically important event. This refers to an AE that may not result in death, be
immediately life-threatening, or require hospitalization, but may be considered serious when,
on the basis of appropriate medical judgment, it may jeopardize the patient, 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 room or at
home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the
development of drug dependency or drug abuse; any organism, virus, or infectious particle
(eg, prion protein transmitting transmissible spongiform encephalopathy), pathogenic or
nonpathogenic, is considered an infectious agent.
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In this study, intensity for each AE, including any lab abnormality, will be determined using the 
NCI CTCAE, version 5.0, effective 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 patient/event outcome or action criteria described above and is usually associated with 
events that pose a threat to a patient’s life or ability to function. A severe AE (Grade 3 or 4) does 
not necessarily need to be considered serious. For example, a white blood cell count of 
1000/mm3 to less than 2000/mm3 is considered Grade 3 (severe) but may not be considered 
serious. Seriousness (not intensity) serves as a guide for defining regulatory reporting 
obligations. 
10.2 
Procedures for Recording and Reporting AEs and SAEs 
All AEs spontaneously reported by the patient or in response to an open question from study 
personnel or revealed by observation, physical examination, or other diagnostic procedures will 
be recorded on the appropriate page of the eCRF (see Section 10.3 for the period of observation). 
Any clinically relevant deterioration in laboratory assessments or other clinical finding is 
considered an AE. When possible, signs and symptoms indicating a common underlying 
pathology should be noted as a single comprehensive event. 
Regardless of causality, SAEs (as defined in Section 10.1.2) 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 may be requested by 
Takeda. Information in the SAE report must be consistent with the data provided on the eCRF. 
SAE Reporting Contact Information 
BELLSYSTEM24, Inc. 
Toll-free fax: 
 
Planned hospital admissions or surgical procedures for an illness or disease that existed before 
the patient was enrolled in the trial are not to be considered AEs unless the condition deteriorated 
in an unexpected manner during the trial; eg, surgery was performed earlier or later than planned. 
For both serious and nonserious AEs, the investigator must determine both the severity (toxicity 
grade) of the event and the relationship of the event to study drug administration. 
Severity (toxicity grade) for each AE, including any lab abnormality, will be determined using 
the NCI CTCAE, version 5.0, effective 27 November 2017 [17]. 
 
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Relationship of the event to study drug administration (ie, its causality) will be determined by 
the investigator responding yes (related) or no (unrelated) to this question: Is there a reasonable 
possibility that the AE is associated with the study drug? 
10.3 
Monitoring of AEs and Period of Observation 
AEs, both nonserious and serious, will be monitored throughout the study as follows: 
•
AEs will be reported from the signing of ICF through 30 days after administration of the last
dose of study drug or before initiation of new anticancer therapy (whichever comes first) and
recorded in the eCRFs.
•
SAEs will be reported to the Takeda Global Pharmacovigilance department or designee from
the signing of ICF through 30 days after administration of the last dose of study drug or
before initiation of new anticancer therapy (whichever comes first) and recorded in the
eCRF. After this period, only related SAEs must be reported to the Takeda Global
Pharmacovigilance department or designee. SAEs should be monitored until they are
resolved or are clearly determined to be due to a patient’s stable or chronic condition or
intercurrent illness(es).
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 sending a completed pregnancy form to the 
Takeda Global Pharmacovigilance department or designee (see Section 10.2). The pregnancy 
must be followed for the final pregnancy outcome. 
If a female partner of a male patient becomes pregnant during the male patient’s participation in 
this study, the sponsor must also be contacted immediately by faxing a completed pregnancy 
form to the Takeda Global Pharmacovigilance department or designee (see Section 10.2). Every 
effort should be made to follow the pregnancy for the final pregnancy outcome. 
10.5 
Procedures for Reporting Product Complaints or Medication Errors (Including 
Overdose) 
A product complaint is a verbal, written, or electronic expression that implies dissatisfaction 
regarding the identity, strength, purity, quality, or stability of a drug product. Individuals who 
identify a potential product complaint situation should immediately report this via the phone 
numbers or e-mail addresses provided below. 
A medication error is a preventable event that involves an identifiable patient and leads to 
inappropriate medication use, which may result in patient harm. Whereas overdoses and 
underdoses constitute medication errors, doses missed inadvertently by a patient do not. 
Individuals who identify a potential medication error (including overdose) situation should 
immediately report this via the phone numbers or email addresses provided below. 
 
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Call Center 
Phone Number 
Email 
Fax 
Dohmen Life Science 
Services (DLSS) 
Non-toll-free number:
 
 
Product complaints and medication errors in and of themselves are not AEs. If a product 
complaint or a medication error results in an SAE, an SAE Form should be completed and sent to 
BI Medical, Inc (refer to Section 10.2). 
10.6 
Safety Reporting to Investigators, IRBs, 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 
and/or the head of each study site, 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 expedited reports within 7 days for fatal and life-threatening events and within 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. 
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11.0 
STUDY-SPECIFIC COMMITTEES 
For the Phase 1 part, no steering committee, data safety monitoring committee, or clinical 
endpoint committee will be used. 
For the Phase 2 part, an IRC and a steering committee will be formed. 
11.1 
Steering Committee 
A steering committee will be established for the Phase 2 part. Its purpose is to function in an 
advisory capacity to 1) provide input on study conduct and progress; 2) ensure scientific and 
ethical integrity of the study; and 3) provide ongoing oversight of safety and efficacy in this 
open-label study. The steering committee will include clinicians who are experts in the clinical 
care and investigation of the targeted patient population and will also include sponsor 
representatives. In addition to general study oversight, the committee will be responsible for 
periodic review of study data to evaluate the safety profile of TAK-788, assess accumulating 
signals of efficacy, evaluate data quality, and provide input on operational aspects of the study. 
The committee may make recommendations for the sponsor’s consideration based on periodic 
review. The steering committee charter will define the responsibilities of the committee. 
11.2 
IRC 
A central blinded IRC with no knowledge of the patients’ status on treatment will evaluate all 
images collected during the study for all IRC-assessed endpoints. An IRC charter defines the 
procedures used by the committee. 
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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, medical history, and concurrent conditions will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA). Drugs will be coded using the World 
Health Organization (WHO) Drug Dictionary. 
12.1 
eCRFs 
Completed eCRFs are required for each subject who signs an ICF. 
The sponsor or its designee will allow the study sites to have 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 principal investigator must review the eCRFs for completeness and accuracy and must sign 
and date the appropriate eCRFs as indicated. Furthermore, the principal investigator must retain 
full responsibility for the accuracy and authenticity of all data entered on the eCRFs. 
eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The sponsor or its designee will be permitted to review the subject’s medical 
and hospital records pertinent to the study to ensure accuracy of the eCRFs. The completed 
eCRFs are the sole property of the sponsor and should not be made available in any form to third 
parties, except for authorized representatives of appropriate governmental health or regulatory 
authorities, without written permission of the sponsor. 
12.2 
Record Retention 
The investigator and the head of the institution agree 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, electronic 
copies 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 
 
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E6 Section 4.9.5 requires the investigator and the head of the institution to retain essential 
documents specified in ICH E6 (Section 8) until at least 2 years after the last approval of a 
marketing application for a specified drug indication being investigated or, if an application is 
not approved, until at least 2 years after the investigation is discontinued and regulatory 
authorities are notified. In addition, ICH E6 Section 4.9.5 states that the study records should be 
retained until an amount of time specified by applicable regulatory requirements or for a time 
specified in the clinical study site agreement between the investigator and/or the head of the 
institution and sponsor. 
Refer to the clinical study site agreement for the sponsor’s requirements on record retention. The 
investigator and the head of the institution should contact and receive written approval from the 
sponsor before disposing of any such documents. 
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13.0 
STATISTICAL METHODS 
13.1 
Statistical and Analytical Plans 
A statistical analysis plan will be prepared and finalized before the formal interim analysis. 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 
Phase 1 Part 
•
Safety population:
The safety population is defined as all patients who receive at least 1 dose of TAK-788.
•
Pharmacokinetic population:
The pharmacokinetic population is defined as all patients for whom there are sufficient
dosing and TAK-788 concentration-time data to reliably estimate the PK parameter(s). This
population will be used for analyses of PK parameters.
•
DLT-evaluable population:
The DLT-evaluable population is defined as all patients who receive at least 75% of their
planned TAK-788 doses for their first cycle of treatment (unless interrupted by study drug-
related AEs). Patients who receive <75% of doses of TAK-788 in Cycle 1 for reasons other
than study drug-related AEs are not evaluable for DLT. Patients will be analyzed by the dose
level to which they were originally assigned, including those who receive subsequent
treatment at a lower or higher dose level.
•
Response-evaluable population:
The response-evaluable population is defined as patients who receive at least 1 dose of TAK-
788, have measurable disease at baseline, and at least 1 post-baseline response assessment.
The response-evaluable population will be used for the analysis of ORR.
Phase 2 Part 
•
Safety population:
The safety population is defined as all patients who receive at least 1 dose of TAK-788.
•
Pharmacokinetic population:
The pharmacokinetic population is defined as patients who receive at least 1 dose of TAK-
788 and have at least 1 plasma concentration data after administration of TAK-788. This
population will be used for population PK analyses.
•
Centrally confirmed population:
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The centrally confirmed population is defined as the first 26 patients who have confirmed 
harboring EGFR exon 20 insertion mutation by central test and have received at least 1 dose 
of TAK-788. 
•
FAS:
FAS is defined as all patients who received at least one dose of TAK-788.
13.1.2 Procedures for Handling Missing, Unused, and Spurious Data 
All available safety, tolerability, efficacy, and PK data will be included in data listings and 
tabulations. No imputation of values for missing data will be performed. The relevance of 
missing sample data will be assessed. 
Data that are potentially spurious or erroneous will be examined according to standard data 
management operating procedures. 
13.1.3 Analysis of Demographics and Other Baseline Characteristics 
Demographic (age, sex, and other parameters as appropriate) and baseline disease characteristics 
(weight, height, and other parameters as appropriate) will be summarized for the Phase 1 part 
and Phase 2 part separately. For continuous variables, descriptive statistics (number, mean, 
standard deviation, median, minimum, and maximum) will be provided. For categorical 
variables, patient counts and percentages will be provided. Categories for missing data will be 
presented as needed. 
13.1.4 Pharmacokinetic Analysis 
Where possible, the following PK parameters (as appropriate) will be determined for TAK-788 
and its active metabolites, including, but not limited to, AP32960 and AP32914, respectively. 
Phase 1 Part 
Following a single oral dose in the Phase 1 part: 
•
Cmax
•
tmax
•
AUC24
•
AUClast
•
Dose proportionality for Cmax and AUC may be assessed if data allows.
Following multiple oral doses (steady state) in the Phase 1 part: 
•
Cmax,ss
•
tmax,ss
•
AUC24,ss
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•
Rac
•
Dose proportionality for Cmax and AUC may be assessed if data allows.
PK parameters will be summarized using descriptive statistics. Individual TAK-788 
concentration-versus-time data and individual PK parameters will be presented in listings and 
also tabulated using summary statistics by dose cohort. Individual and mean plasma 
concentration-time profiles will be plotted by dose cohort. 
Phase 2 Part 
The plasma concentration-time data of TAK-788 and its active metabolites, including AP32960 
and AP32914, will be pooled with data from other TAK-788 clinical studies to contribute to 
population PK analyses. Results of the population PK analyses of data from this study will also 
contribute to exposure-response analyses of safety and efficacy. The analysis plans for the 
population PK and exposure-response analyses will be separately defined, and the results of 
these analyses will be reported separately. 
13.1.5 Efficacy Evaluation 
13.1.5.1 Primary Endpoint and Analytical Methods (Phase 2 Part Only) 
The primary endpoint is confirmed ORR, as assessed by IRC per RECIST v1.1. 
Primary Analysis 
The primary analysis will be conducted using centrally confirmed population. The point estimate 
and 90% 2-sided CI for the confirmed ORR as assessed by an IRC will be provided based on 
stage-wise ordering [18]. 
Secondary Analysis 
Confirmed ORR as assessed by an IRC and its 2-sided 95% exact binominal CI will be provided 
using FAS. 
13.1.5.2 Secondary Endpoints and Analytical Methods 
Phase 1 Part 
Investigator assessed ORR using RECIST v1.1 will be evaluated. The estimate of the ORR will 
be presented with 2-sided 95% exact binomial confidence intervals for each cohort and each 
mutation type. 
Phase 2 Part 
Confirmed ORR assessed by the investigator in the centrally confirmed population and the FAS, 
and the 2-sided 95% CIs will be calculated. 
DCR assessed by the investigator and the IRC in the centrally confirmed population and the 
FAS, and the 2-sided 95% CIs will be calculated. 
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For time-to-event efficacy endpoints including PFS, OS, and duration of response, survival 
curves and median values (if estimable), along with their 2-sided 95% CIs will be computed 
using Kaplan-Meier method in the centrally confirmed population and the FAS. The PFS rates, 
OS rates, and duration of response rates at 12 and 24 months and the associated 2-sided 95% CIs 
will be computed using the Kaplan-Meier method. Time to response will be summarized only for 
responders using descriptive statistics. 
13.1.6 Safety Analysis 
Phase 1 Part 
Safety will be evaluated by the incidence of TEAEs, defined as any AEs that occur after 
administration of the first dose of study drug and up through approximately 30 days after the last 
dose of study drug, and severity, as well as by changes from baseline in the patient’s vital signs, 
weight, ECG, and clinical laboratory results using the Safety population. Safety will be 
summarized by dose level within each dose cohort. 
TEAEs will be tabulated according to the MedDRA by system organ class, and preferred terms 
and will include the following categories: 
•
TEAEs.
•
Drug-related TEAEs.
•
Grade ≥3 TEAEs.
•
Grade ≥3 drug-related TEAEs.
•
The most commonly reported TEAEs (≥10% of all patients).
•
SAEs.
A listing of TEAEs resulting in study drug discontinuation will be provided.
And the incidence of DLT (as defined in Section 8.2) will be tabulated for each dose cohort. In 
addition, to assess the relationship between toxicities and TAK-788 dose, the preferred term of 
individual toxicities will be summarized by their frequency and intensity for each dose cohort. 
The DLT-evaluable population will be used for the analysis of DLT. 
Descriptive statistics for the actual values of clinical laboratory parameters (and/or change from 
baseline in clinical laboratory parameters) and other safety parameters deemed appropriate will 
be presented for all scheduled measurements over time. Mean laboratory values over time will be 
plotted for key laboratory parameters. 
ECG intervals (QT and QTcF, and PR), QRS duration, and ventricular rate will be summarized 
at each scheduled time point, along with mean change from baseline to each posttreatment time 
point. The number and percentage of patients with ECG abnormalities will be summarized at 
each time point. 
 
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Additional safety analyses may be performed to more clearly enumerate rates of toxicities and to 
further define the safety profile of TAK-788. 
Phase 2 Part 
Safety will be evaluated by the incidence of TEAEs, defined as any AEs that occur after 
administration of the first dose of study drug and up through approximately 30 days after the last 
dose of study drug, and severity, as well as by changes from baseline in the patient’s vital signs, 
weight, ECG, and clinical laboratory results using the Safety population. 
TEAEs will be tabulated according to the MedDRA by system organ class, and preferred terms 
and will include the following categories: 
•
TEAEs.
•
Drug-related TEAEs.
•
Grade ≥3 TEAEs.
•
Grade ≥3 drug-related TEAEs.
•
The most commonly reported TEAEs (≥10% of all patients).
•
SAEs.
A listing of TEAEs resulting in study drug discontinuation will be provided.
Descriptive statistics for the actual values of clinical laboratory parameters (and/or change from 
baseline in clinical laboratory parameters) and other safety parameters deemed appropriate will 
be presented for all scheduled measurements over time. Mean laboratory values over time will be 
plotted for key laboratory parameters. 
ECG intervals (QT and QTcF, and PR), QRS duration, and ventricular rate will be summarized 
at each scheduled time point, along with mean change from baseline to each posttreatment time 
point. The number and percentage of patients with ECG abnormalities will be summarized at 
each time point. 
Additional safety analyses may be performed to more clearly enumerate rates of toxicities and to 
further define the safety profile of TAK-788. 
13.1.7 Patient-Reported Outcome Data Analysis (Phase 2 Part Only) 
The main patient-reported outcomes endpoints of interest for the Phase 2 Part will be the core 
symptoms of lung cancer (eg, dyspnea, cough, and chest pain) as measured by EORTC QLQ-
C30 and QLQ LC13. The QLQ-C30 will be scored according to the EORTC QLQ-C30 (v3.0) 
Scoring Manual [19] including transformation of responses into scores for analysis and the 
handling of missing data. The EORTC QLQ-C30 (v3.0) Scoring Manual also includes 
instructions for scoring the QLQ-LC13. 
The actual value and change from baseline of the subscale scores for EORTC QLQ-C30 and 
QLQ LC13 will be summarized using descriptive statistics over time. 
 
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More details will be provided in the statistical analysis plan. 
13.2 
Interim Analysis and Criteria for Early Termination 
Phase 1 Part 
No interim analysis is planned. 
Phase 2 Part 
For the primary analysis in the Phase 2 part, 2-stage design [20] will be used. The first 14 
“centrally confirmed” patients in the Phase 2 part are to be included in Stage 1, and further 
patients will be continuously enrolled into Stage 2. An interim analysis for both futility and 
efficacy will be conducted in Stage 1. The proportion of patients achieving an objective 
response, per IRC, will be used as the endpoint for the interim analysis. The interim analysis will 
be performed when the first 14 “centrally confirmed” patients in the Phase 2 part have had the 
opportunity to complete the Cycle 7 Day 1 disease assessment (i.e. third disease assessment after 
initiation of the study treatment). Enrollment will not be suspended during evaluation of these 14 
“centrally confirmed” patients; however, patients enrolled after the 14th patient in the Phase 2 
part will NOT be included in the interim analysis, even if their objective response were available 
on the cutoff date. 
If the number of patients with confirmed objective response is 5 or fewer in the 14 “centrally 
confirmed” patients, enrollment will be stopped entirely for futility. Additionally, if the number 
of patients with confirmed objective response is 9 or more in the 14“centrally confirmed” 
patients, it will be decided that TAK-788 is efficacious in this population. 
In other cases (i.e. number of patients with confirmed objective response is between 6 to 8 in the 
14), the study will continue until 26 “centrally confirmed” patients have had the opportunity to 
complete the Cycle 7 Day 1 disease assessment. If the number of patients with confirmed 
objective response in these 26 patients is 14 or more, it will be decided that TAK-788 has 
demonstrated sufficient efficacy to reject the null hypothesis. For this analysis, the best overall 
response for the first 14 “centrally confirmed” patients at the interim analysis will be used 
without any update. 
To maintain confidentiality of interim result and to preserve trial integrity, the interim analysis 
will be conducted by an independent statistical center. Until the analysis for the 26 “centrally 
confirmed” patients (Stage 1 + Stage 2; conducted when all 26 patients had an opportunity to 
complete the Cycle 7 Day 1 disease assessment),  the sponsor and its designee will not have any 
access to the efficacy data based on IRC assessment, except for the written notification from the 
independent statistical center that tells whether the results of the interim analysis met predefined 
criteria of futility, efficacy, or not met both. However, if the futility or efficacy is confirmed at 
the interim analysis, the IRC-assessed efficacy data will be fully disclosed to the sponsor 
immediately after the written notification is provided. 
 
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13.3 
Determination of Sample Size 
Phase 1 Part 
Phase 1 part will adopt an adaptive design using BLRM with safety data evaluation and other 
available information, such as PK and efficacy. The design allows flexible cohort size. The total 
number of subjects in Phase 1 part is dependent on the observed safety profile and other 
available information, which will determine the number of patients per dose cohort, as well as 
the number of dose escalations required to achieve the MTD. It is anticipated that approximately 
21 patients will be required to determine MTD. Assuming a 15% dropout rate and potentially up 
to 5 patients will be enrolled for any cohort to further confirm the safety, the total sample size for 
Phase 1 part will be approximately 28-33. 
The description, prior calibration and operating characteristics of the BLRM are included in 
Appendix G. 
Phase 2 Part 
The purpose of the Phase 2 part of this study is to determine the confirmed ORR of orally 
administered TAK-788 as the first line treatment at RP2D determined in the Phase 1 part in 
patients with NSCLC with EGFR exon 20 insertion mutations. The sample size was determined 
so that it would allow us to state that the true ORR is greater than threshold response rate of 
35%. The expected true ORR of TAK-788 is 60% in treatment naive population. Twenty-six (26) 
patients with NSCLC with tumors harboring EGFR exon 20 insertion mutations with 
confirmation of central test will allow the study to have over 80% power to rule out an 
uninteresting rate of 35% in this population with a 1-sided alpha of 0.05 according to the two-
stage design with futility and efficacy interim analysis described in Section 13.2. 
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14.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
14.1 
Study-Site Monitoring Visits 
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and institution guarantee access to source documents by the sponsor or its 
designee (CRO) and by the IRB. 
All aspects of the study and its documentation will be subject to review by the sponsor or 
designee including, but not limited to, the investigator’s binder, study medication, subject 
medical records, informed consent documentation, 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. 
In the event a monitor cannot visit the site in a timely manner due to the COVID-19 pandemic, 
alternative monitoring approaches such as remote source data verification or telephone contact 
may be used to ensure data quality and integrity and maintain patient safety. Alternative 
monitoring approaches should be used only where allowed by applicable local regulations and 
permitted by the IRB. 
14.2 
Protocol Deviations 
The investigator can deviate and change from the protocol for any medically unavoidable reason, 
for example, to eliminate an immediate hazard to study subjects, without prior written agreement 
with the sponsor or prior approval from IRB. In the event of a deviation or change, the principal 
investigator should notify the sponsor and the head of the site of the deviation or change and its 
reason in a written form, and then retain a copy of the written form. When necessary, the 
principal investigator may consult and agree with the sponsor on a protocol amendment. If the 
protocol amendment is appropriate, the amendment proposal should be submitted to the head of 
the site as soon as possible, and approval from IRB should be obtained. 
The investigator should document all protocol deviations. 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections 
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, 
including those of foreign governments (eg, the United States [US] Food and Drug 
Administration [FDA], the United Kingdom [UK] Medicines and Healthcare products 
Regulatory Agency [MHRA], the Pharmaceuticals and Medical Devices Agency of Japan 
[PMDA]). If the study site is contacted for an inspection by a regulatory body, the sponsor 
 
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should be notified immediately. The investigator and institution guarantee access for quality 
assurance auditors to all study documents as described in Section 14.1. 
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15.0 
ETHICAL ASPECTS OF THE STUDY 
This study will be conducted with the highest respect for the individual participants (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will conduct 
the study according to applicable local or regional regulatory requirements and align his or her 
conduct in accordance with the responsibilities of the investigator that are listed in Appendix B. 
The principles of Helsinki are addressed through the protocol and through appendices containing 
requirements for informed consent and investigator responsibilities. 
15.1 
IRB Approval 
IRBs must be constituted according to the applicable local requirements of each participating 
region. The sponsor or designee will require documentation noting all names and titles of 
members who make up the respective IRB. If any member of the IRB has direct participation in 
this study, written notification regarding his or her abstinence from voting must also be obtained. 
The sponsor or designee will supply relevant documents for submission to the respective IRB 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 advertisements and other documents 
required by all applicable laws and regulations must be submitted to a central or local IRB for 
approval. The IRB’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 approval 
must refer to the study by its exact protocol title, number, and version date; identify versions of 
other documents (eg, ICF) reviewed; and state the approval date. If required by country or 
regional regulations or procedures, approval from the competent regulatory authority will be 
obtained before commencement of the study or implementation of a substantial amendment. 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 the 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. This may include 
notification to the IRB 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, and 
submission of the investigator’s final status report to IRB. All IRB approvals and relevant 
documentation for these items must be provided to the sponsor (or designee). 
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB 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 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 further explain the nature of the study, its objectives, and potential risks and 
benefits, and the date informed consent is given. The ICF will detail the requirements of the 
participant and the fact that he or she is free to withdraw at any time without giving a reason and 
without prejudice to his or her further medical care. 
The investigator is responsible for the preparation, content, and IRB approval of the ICF. The 
ICF must be approved by both the IRB and the sponsor before use. 
The ICF must be written in a language fully comprehensible to the prospective subject. It is the 
responsibility of the investigator to explain the detailed elements of the ICF to the subject. 
Information should be given in both oral and written form whenever possible and in the manner 
deemed appropriate by the IRB. 
The subject must be given ample opportunity to (1) inquire about details of the study and (2) 
decide whether to participate in the study. If the subject determines that he or she will participate 
in the study, then the ICF must be signed and dated by the subject at the time of consent and 
before the subject enters into the study. The subject should be instructed to sign using their legal 
names, not nicknames, using a ballpoint pen with either blue or black ink. The investigator must 
also sign and date the ICF at the time of consent and before the subject enters into the study. 
Once signed, the original ICF will be stored in the investigator’s site file. The investigator must 
document the date the subject signs the informed consent in the subject’s medical record. Copies 
of the signed ICF shall be given to the subject. 
All revised ICFs must be reviewed and signed by relevant subjects in the same manner as the 
original informed consent. The date the revised consent was obtained should be recorded in the 
subject’s medical record, and the subject should receive a copy of the revised ICF. 
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 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 MHRA, Japan PMDA), the sponsor’s 
designated auditors, and the appropriate IRBs to review the subject’s original medical records 
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(source data or documents) including, but not limited to, laboratory test result reports, ECG 
reports, admission and discharge summaries for hospital admissions occurring during a subject’s 
study participation, and autopsy reports. Access to a subject’s original medical records requires 
the specific authorization of the subject as part of the informed consent process (see Section 
15.2). 
Copies of any subject source documents that are provided to the sponsor must have certain 
identifying personal information removed, eg, 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. 
15.4.2 Clinical Trial Registration 
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations, and guidance, Takeda will, at a minimum, register 
interventional clinical trials it sponsors anywhere in the world on ClinicalTrials.gov or other 
publicly accessible websites on or before start of study, as defined by Takeda policy/standards. 
Takeda contact information, along with facility name, investigator’s city, country, and recruiting 
status will be registered and available for public viewing. 
15.4.3 Clinical Trial Results Disclosure 
Takeda will post the results of clinical trials on ClinicalTrials.gov and other publicly accessible 
websites (including the Takeda corporate site) and registries, as required by Takeda 
policy/standards, applicable laws, and/or regulations. 
Data Sharing 
 
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The sponsor is committed to responsible sharing of clinical data with the goal of advancing 
medical science and improving patient care. Qualified independent researchers will be permitted 
to use data collected from patients during the study to conduct additional scientific research, 
which may be unrelated to the study drug or the patient’s disease. The data provided to external 
researchers will not include information that identifies patients personally. 
15.5 
Insurance and Compensation for Injury 
Each subject in the study must be insured in accordance with the regulations applicable to the 
site where the subject is participating. If a local underwriter is required, then the sponsor or 
sponsor’s designee will obtain clinical study insurance against the risk of injury to clinical study 
subjects. Refer to the clinical study site agreement regarding the sponsor’s policy on subject 
compensation and treatment for injury. If the investigator has questions regarding this policy, he 
or she should contact the sponsor or sponsor’s designee. 
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16.0 
REFERENCES 
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multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA.
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[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 IJ, 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] 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.
[5] 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.
[6] Mitsudomi T, Yatabe Y. Epidermal growth factor receptor in relation to tumor development:
EGFR gene and cancer. FEBS. J 2010;277(2):301-8.
[7] 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.
[8] 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.
[9] 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.
[10] 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.
[11] 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.
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[12] 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.
[13] Yu AF, Yin A, Steingart RM. Cost Effectiveness of Cardiotoxicity Monitoring. American
College of Cardiology 2017.
[14] Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, et al. The European
Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument
for use in international clinical trials in oncology. Journal of the National Cancer Institute
1993;85(5):365-76.
[15] Aaronson N, Cull A, Ahmedzai S, editors. The European Organization for Research and
Treatment of Cancer (EORTC) modular approach to quality of life assessment in oncology:
an update. 2nd ed. Quality of Life and Pharmacoeconomics in Clinical Trails. Philadelphia:
Lippincott - Raven Publishers;1996.
[16] Bergman B, Aaronson NK, Ahmedzai S, Kaasa S, Sullivan M. The EORTC QLQ-LC13: a
modular supplement to the EORTC Core Quality of Life Questionnaire (QLQ-C30) for use
in lung cancer clinical trials. EORTC Study Group on Quality of Life. European Journal of
Cancer 1994;30A(5):635-42.
[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.
[18] Jennison C, Turnbull BW. Group sequential methods with applications to clinical trials.
Boca Raton, Florida:Chapman-Hall/CRC, 2000.
[19] Fayers PM, Aaronson NK, Bjordal K, Groenvold M, Curran D, Bottomley A, et al. EORTC
QLQ-C30 Scoring Manual. 3rd ed. Brussels:EORTC;2001.
[20] Mander AP, Thompson SG. Two-stage designs optimal under the alternative hypothesis for
phase II cancer clinical trials. Contemporary Clinical Trials. 2010;31:572-8.
[21] Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New
response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J
Cancer. 2009;45(2):228-47.
[22] Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and
response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol.
1982;5(6):649-55.
[23] Neuenschwander B, Branson M, Gsponer T. Critical aspects of the Bayesian approach to
phase I cancer trials. Stat Med. 2008;27(13):2420-39.
[24] Babb J, Rogatko A, Zacks S. Cancer phase I clinical trials: efficient dose escalation with
overdose control. Stat Med. 1998;17(10):1103-20.
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Appendix A Schedule of Events 
Phase 1 Part 
Day (D) (a) 
Screening 
(b) 
Treatment period 
Follow-up period 
Cycle 1 
Cycle 2 
Cycle 3 and Subsequent Cycles 
End of 
Treatment (g) 
30 Days After 
Last Dose (h) 
D1 (c) 
D2 
D8 
D15 
D22 
D1 (c) 
D2 
Every 4 wks (d) Every 8 wks (e) 
Every 12 wks 
(f) 
Informed consent 
X 
Demographics 
X 
Medical/surgical history 
X 
Diagnosis and cancer history 
X 
Mutation status (i) 
X 
Prior cancer therapy 
X 
Physical examination 
X 
X 
X 
X 
(X) 
(X) 
Height 
X 
Weight, Vital signs and auscultation 
X 
X 
X 
X 
X 
X 
X 
ECOG Performance Status 
X 
X 
X 
X 
X 
X 
Cardiac monitoring (including LVEF by 
ECHO/MUGA) 
Cardiac monitoring may be done during treatment according to medical judgement and as clinically indicated 
Hematology/chemistry/urinalysis 
X 
X 
X 
X 
X 
(X) 
(X) 
Serology 
X 
X (j) 
KL-6, SP-D 
X 
X 
X (k) 
Chest X-ray 
X 
X 
X 
X 
Pregnancy test (l) 
X (m) 
X (n) 
X 
X 
X 
ECG 
X 
X 
X 
(X) 
(X) 
TAK-788 administration 
X (once daily) 
Adverse events/Concomitant medications 
Throughout study (o) 
PK sampling (Plasma samples for TAK-
788 PK) (p) 
X 
X (q) 
X 
X 
X 
X 
X (q) X (C3D1 only) 
Disease assessment 
X 
X (r) 
X (r) 
X 
CSF collection (CSF sample for TAK-788 
PK) (s) 
As determined by the investigator (as part of standard of care) 
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Abbreviations: AE, adverse event; CSF, cerebrospinal fluid; CT, computed tomography; CxDx, Cycle x Day x; ECG, electrocardiogram; ECHO, echocardiogram; ECOG, Eastern Cooperative Oncology 
Group; eCRF, electronic case report form; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus; ICF, informed consent form; ILD, interstitial lung disease; KL-6, Krebs von den Lungen-6; MRI, 
magnetic resonance imaging; MTD, maximum tolerated dose; MUGA, multigated acquisition; PD, progressive disease; PK, pharmacokinetic(s); SP-D, surfactant protein-D. 
(a) All study assessments should occur within ±3 days of the scheduled study day unless otherwise noted. A cycle is defined as 28 days. 
(b) Unless otherwise noted, the screening visit must occur within 14 days before the day of the first dose of study drug (C1D1). The ICF may be signed more than 21 days before C1D1. 
(c) Unless otherwise noted, it must occur before TAK-788 administration. 
(d) Unless otherwise noted, it must occur on Day 1 (±3 days) of every cycles 
(e) Unless otherwise noted, it must occur on Day 1 (±3 days) of every even-numbered cycles (ie, Cycles 4, 6, 8 and thereafter every 2 cycles) 
(f) Unless otherwise noted, it must occur on Day 1 (±3 days) of every 3 cycles (ie, Cycles 3, 6, 9 and thereafter every 3 cycles). 
(g) End-of-Treatment assessments must be performed within 14 days of the patient’s last dose of study drug or the patient/investigator decision to discontinue study treatment, whichever occurs later. 
Physical examinations, laboratory tests (hematology, chemistry, urinalysis), and ECG can be omitted if they had been previously performed within 14 days since the last assessments and if, in the 
investigator’s judgment, significant change is unlikely. For the End-of-Treatment assessments, information may be collected from tests performed for the study or as part of the patient’s routine
medical care. 
(h) The 30 Days after last dose assessments must be performed within 30 days (±7 days) after the last dose of study treatment. Physical examinations, laboratory tests (hematology, chemistry, 
urinalysis), and ECG can be omitted if the visit occurs within 10 days of the End of Treatment assessment and there have been no clinically significant findings. Any new systemic anticancer 
therapies that the patient has begun to receive since the end of treatment should be reported at this visit. For the 30 Days After Last Dose assessments, information may be collected from tests
performed for the study or as part of the patient’s routine medical care. 
(i) Only for patients who have information of mutation status 
(j) For patients who are positive for HBsAg or HCV antibody at screening, the on-study testing should be performed in cycles 3, 6, 9 and thereafter every 3 cycles. 
(k) Serum levels of KL-6 and SP-D will be assessed on Day 1 (±3 days) of every even-numbered cycles. And unscheduled collection may be allowed in case of occurrence of ILD or pneumonitis
occurs. 
(l) Only for females of childbearing potential. Unless otherwise noted, either urine or serum can be used. 
(m) Females of childbearing potential must be negative pregnancy test using serum. 
(n) Females of childbearing potential must be negative pregnancy test (using either urine or serum test) within 7 days prior to the first dose of study drug. 
(o) AEs and concomitant treatments will be recorded in the eCRF from the date the informed consent is signed until 30 days after the last dose of study drug or before initiation of new anticancer 
therapy (whichever comes first). 
(p) Blood samples will be collected immediately prior to the first dose (time 0; pre-dose), and at 0.5, 1 hour (±5 minutes), 2, 4, 6, 8 hours (±10 minutes), and 24 hours (±60 minutes) after the first dose
on C1D1. The 24 hour sample will be collected prior to drug administration on C1D2. Blood samples will be collected prior to dosing on C1D8, C1D15, and C1D22. Blood samples will also be
collected pre-dose and at 0.5, 1 hour (±5 minutes), 2, 4, 6, 8 hours (±10 minutes), and 24 hours (±60 minutes) after administration of TAK-788 on C2D1. The 24-hour sample will be collected prior 
to drug administration on C2D2. A PK sample will also be collected pre-dose on C3D1. The sampling time point is summarized in the table on the next page. 
(q) Blood samples will be collected 24 hours (±60 minutes) after the dose on C1D1 or C2D1. 
(r) Disease assessment by CT and MRI scans will be performed at screening and at 8-week intervals thereafter (on Day 28 [±3 days] of every even-numbered cycle) through cycle 14 after the initial 
dose of study drug, and every 3 cycles thereafter until PD. 
(s) If lumbar puncture is performed as part of the standard of care, remaining CSF samples should be analyzed to determine the concentration of TAK-788 and its active metabolites, including, but not
limited to, AP32914 and AP32960 (≥500 μL is sufficient), and these samples should have matched blood samples (for PK analyses) when possible. 
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Phase 2 Part 
Screening (a) 
Treatment period 
Follow-up period 
Cycle 1 
Cycle 2 
Cycle 3 and Subsequent Cycles 
End of 
Treatment (b) 
30 Days After 
Last Dose (c) 
PFS 
(d) 
Overall 
Survival 
(e) 
Every  
4 wks 
Every  
8 wks 
Every 
12 wks 
Day (D) (f) 
D1 (g) 
D15 
D1  
D1  
D1  
D1  
D1  
Visit Window 
±3 days 
±3 days 
±3 days 
±3 days 
±3 days 
+14 days 
±7 days 
±14 days 
±14 days 
Informed consent (a) 
X 
Demographics 
X 
Medical/surgical history 
X 
Diagnosis and cancer history 
X 
Mutation status (based on local test)  
X 
Prior cancer therapy 
X 
Patient reported outcome (h) 
X 
X (i) 
X 
X  
(up to C14) 
X 
(Starting 
C15) 
X 
X 
Physical examination 
X 
X (i) 
X 
X 
(X) 
(X) 
Height 
X 
Weight, Vital signs and auscultation 
X 
X 
X 
X 
X 
X 
X 
ECOG Performance Status 
X 
X (i) 
X 
X 
X 
X 
Cardiac monitoring (including LVEF by 
ECHO/MUGA) (j) 
X 
X 
X  
(C4D1, 
C7D1 only) 
X 
Hematology/chemistry/urinalysis 
X 
X (i) 
X 
X 
X 
(X) 
(X) 
Serology 
X 
X (k) 
KL-6, SP-D 
X 
X 
X (l) 
Chest X-ray 
X 
X 
Pregnancy test (m) 
X (n) 
X (o) 
X 
X 
X 
ECG 
X 
X 
X 
(X) 
(X) 
TAK-788 administration 
X (once daily) 
Adverse events/Concomitant medications 
Throughout study (p) 
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Phase 2 Part (Cont.) 
Screening (a) 
Treatment period 
Follow-up period 
Cycle 1 
Cycle 2 
Cycle 3 and Subsequent Cycles 
End of 
Treatment (b) 
30 Days After 
Last Dose (c) 
PFS 
(d) 
Overall 
Survival 
(e) 
Every  
4 wks 
Every  
8 wks 
Every 
12 wks 
Day (D) (f) 
D1 (g) 
D15 
D1  
D1  
D1  
D1  
D1  
Visit Window 
±3 days 
±3 days 
±3 days 
±3 days 
±3 days 
+14 days 
±7 days 
±14 days ±14 days 
PK sampling (Plasma sample for TAK-
788 PK) (q) 
X 
X  
X 
X 
(C3D1, 
C4D1, 
C5D1 only) 
Biomarker (r) 
Plasma sample for Cholesterol 
X 
X 
Plasma sample for Cell Free DNA 
X 
X 
X 
(C5D1 only) 
X 
Archival banked tumor tissue sample (s) 
X 
Fresh tumor tissue biopsy sample at 
disease progression (t) 
X 
(at PD) 
Disease assessment 
X 
X (u) 
X (u) 
X (v) 
X 
CSF collection (CSF sample for TAK-788 
PK and matched plasma sample for TAK-
788 PK) (w) 
As determined by the investigator (as part of standard of care) 
Subsequent anticancer therapy/survival 
X 
Abbreviations: AE, adverse event; CSF, cerebrospinal fluid; CT, computed tomography; CxDx, Cycle x Day x; ECG, electrocardiogram; ECHO, echocardiogram; ECOG, Eastern Cooperative Oncology 
Group; eCRF, electronic case report form; EORCT, European Organisation for Research and Treatment of Cancer; EOT, End of Treatment; FFPE, formalin fixed paraffin embedded; HBsAg, hepatitis B 
surface antigen; HCV, hepatitis C virus; ICF, informed consent form; ILD, interstitial lung disease; KL-6, Krebs von den Lungen-6; MRI, magnetic resonance imaging; MTD, maximum tolerated dose; 
MUGA, multigated acquisition; PD, progressive disease; PFS, progression free survival; PK, pharmacokinetic(s); QLQ, Quality of Life Questionnaire; QLQ-LC30, Quality of Life Questionnaire, lung 
cancer module; SP-D, surfactant protein-D. 
(a) Screening assessments must be performed within 14 days before C1D1. The allowable window for the disease assessment is 21 days before C1D1. However, whenever feasible, baseline imaging 
should be performed as close as possible to C1D1. Informed consent may be signed more than 21 days before C1D1 and must be signed before performance of any study-related procedure not part of 
standard medical care. 
(b) End-of-Treatment assessments must be performed within 14 days of the patient’s last dose of study drug or the patient/investigator decision to discontinue study treatment, whichever occurs later. 
Physical examinations, laboratory tests (hematology, chemistry, urinalysis), and ECG can be omitted if they had been previously performed within 14 days since the last assessments and if, in the 
investigator’s judgment, significant change is unlikely. For the End-of-Treatment assessments, information may be collected from tests performed for the study or as part of the patient’s routine
medical care. 
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(c) The 30 Days after last dose assessments must be performed within 30 days (±7 days) after the last dose of study treatment or until the start of new systemic anticancer treatment, whichever occurs 
first. Physical examinations, laboratory tests (hematology, chemistry, urinalysis), and ECG can be omitted if the visit occurs within 10 days of the End of Treatment assessment and there have been
no clinically significant findings. For the 30 Days After Last Dose assessments, information may be collected from tests performed for the study or as part of the patient’s routine medical care. 
(d) Every 8 weeks until Week 56 (equivalent to Cycle 14 Day 28), and every 12 weeks (±14 days) thereafter, from the EOT visit to the occurrence of PD or the start of subsequent anticancer therapy. 
(e) Every 12 weeks (±14 days) until death, loss to follow-up, consent withdrawal, study termination, or any of the circumstances described in Section 9.10 occur, after the occurrence of documented PD 
or the start of subsequent anticancer therapy. 
(f) A cycle is defined as 28 days. A day is defined as a calendar day. Visit windows are as specified in the table, unless noted otherwise. Disease assessments have a ±7-day visit window. 
(g) Unless otherwise noted, it must occur before TAK-788 administration. 
(h) EORTC QLQ-C30 and EORTC QLQ-LC13 should be administered to patients when they arrive for their scheduled visits, before any clinical measurements, assessments, evaluations, or procedures
being performed. 
(i) Does not need to be performed on C1D1 if performed for screening within 7 days before C1D1, and, in the opinion of the investigator, there is no reason to believe the assessment has substantially
changed. 
(j) Cardiac monitoring must be performed on baseline (screening), C2D1, C4D1, C7D1 and EOT. In addition to these timepoints, Cardiac monitoring may be done at additional timepoints according to
medical judgement and as clinically indicated. 
(k) For patients who are positive for HBsAg or HCV antibody at screening, the on-study testing should be performed in cycles 3, 6, 9 and thereafter every 3 cycles. 
(l) Serum levels of KL-6 and SP-D will be assessed on Day 1 of every even-numbered cycles. And unscheduled collection may be allowed in case of occurrence of ILD or pneumonitis occurs.
(m) Only for females of childbearing potential. Unless otherwise noted, either urine or serum can be used. 
(n) Females of childbearing potential must be negative pregnancy test using serum. 
(o) Females of childbearing potential must be negative pregnancy test (using either urine or serum test) within 7 days prior to the first dose of study drug. 
(p) AEs and concomitant treatments will be recorded in the eCRF from the date the informed consent is signed until 30 days after the last dose of study drug or before initiation of new anticancer 
therapy (whichever comes first). 
(q) The sampling time point is summarized in the table on PK Sampling Time Points. 
(r) Plasma samples will be collected for evaluating circulating biomarkers including 4-beta-OH-cholesterol/cholesterol and cell free DNA. Collection at C1D1 should be collected prior dosing; plasma
for cell free DNA should be double spun.
(s) Remaining tissue at initial diagnosis or archival tissue can be used. If it is not available, fresh tumor tissue sample correction (FFPE slides or FFPE block) is needed. 
(t) An optional tumor tissue biopsy (FFPE) will be obtained at the time of disease progression. 
(u) Disease assessment by CT and MRI scans will be performed at screening and at 8-week intervals thereafter (on Day 28 [±7 days] of every even-numbered cycle) through cycle 14 after the initial 
dose of study drug, and every 3 cycles thereafter until PD. 
(v) It will also be performed at EOT if more than 4 weeks have passed since the last imaging assessment. 
(w) If lumbar puncture is performed as part of the standard of care, remaining CSF samples should be analyzed to determine the concentration of TAK-788 and its active metabolites, including, but not
limited to, AP32914 and AP32960 (≥500 μL is sufficient), and these samples should have matched blood samples (for PK analyses) when possible. 
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PK Sampling Time Points 
Phase 1 Part 
PK Sampling Time Points 
Cycle 1 
Cycle 2 
Cycle 3 
Day 1 
Day 2 
Day 8 
Day 15 
Day 22 
Day 1 
Day 2 
Day 1 
Predose 
X 
(X) (a)
X 
X 
X 
X 
(X) (b)
X 
0.5 hours postdose (±5 min) 
X 
X 
1 hour postdose (±5 min) 
X 
X 
2 hours postdose (±10 min) 
X 
X 
4 hours postdose (±10 min) 
X 
X 
6 hours postdose (±10 min) 
X 
X 
8 hours postdose (±10 min) 
X 
X 
24 hours postdose (±60 min) 
X 
(predose on C1D2) 
X 
(predose on C2D2) 
Abbreviations: CxDx, Cycle x Day x; PK, pharmacokinetic. 
(a)
This is the same sample as the one to be collected 24 hours after the dose on C1D1.
(b)
This is the same sample as the one to be collected 24 hours after the dose on C2D1.
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Phase 2 Part 
PK Sampling Time Points 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Day 1 
Day 15 
Day 1 
Day 1 
Day 1 
Day 1 
Predose (as close as possible to 24 hours 
after previous dose) 
X 
X 
X 
X 
X 
1 to 2 hours postdose (±10 min) 
X 
X 
2 to 4 hours postdose (±20 min) 
X 
X 
4 to 6 hours postdose (±30 min) 
X 
X 
Abbreviations: CxDx, Cycle x Day x; eCRF, electronic case report form; PK, pharmacokinetic. 
The pre-dose samples should be collected as close as possible to 24 hours after the prior dose of TAK-788. The exact dates and times of each PK sample 
collection should be recorded on the electronic case report form (eCRF). On the PK sampling days and clinic visit days, patients should take the study drug at the 
clinic. The exact dates and times of the 2 prior doses of TAK-788 taken at home and 1 prior dose taken in the clinic on each PK sampling day (except C1D1) 
should be recorded on the eCRF. The exact dates and times of all doses taken at home should be recorded on the patient diary card. 
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Appendix B Responsibilities of the Investigator 
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. The investigator agrees to assume the following responsibilities: 
1. Conduct the appropriate study in accordance with the protocol and GCP considering the
rights, safety and wellbeing of human subjects.
2. When a part of the important activities related to the study are delegated to the sub-
investigator or the study collaborator, prepare the lists of activities to be delegated and
responsible personnel, submit the lists to the head of the study in advance to get them
accepted.
3. Prepare a written informed consent form and other written information, and update as
appropriate.
4. Confirm the contents of the clinical study agreement.
5. Provide necessary information on the protocol, medications and responsibilities of individual
personnel to the investigator and study collaborator, and provide guidance and supervision.
6. Screen subjects who meet the requirements of the protocol, provide the explanation of the
study in writing and obtain the written consent.
7. Assume responsibility for all the medical judgement related to the study.
8. Ensure in collaboration with the head of the study that sufficient medical care on all
clinically significant adverse events related to the study are provided to subjects throughout
and beyond the period when subjects participate in the study.
9. If a subject consults other medical institution or other department, notify the physician of the
medical institution or department of the subject’s participation in the study upon obtaining
the consent of the subject, as well as the end and termination of the study in writing, and
document such records.
10. In case of urgent report of a SAE, immediately notify the head of the study and the sponsor
in writing.
11. Prepare correct and complete (e)CRFs, and submit them to the sponsor with electronic
signature.
12. Check and confirm the contents of (e)CRFs prepared by the sub-investigator or transcribed
from the source data by the study collaborator, and submit them to the sponsor with
electronic signature.
13. Discuss any proposal from the sponsor including update of the protocol.
14. Notify the director of the site of the end of the study in writing.
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Appendix C Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) 
Choosing Target Lesions 
•
Select up to 5 lesions (up to 2 per organ)
•
Select largest reproducibly measurable lesions
•
If the largest lesion cannot be measured reproducibly, select the next largest lesion which can
be
•
Add up longest diameters (LD) of non-nodal lesions (axial plane)
•
Add short axis diameters of nodes
•
This is the “sum of the longest diameters” (SLD)
Non-Target Lesions
•
All other sites of disease present at baseline and not classified as target lesions will be
classified as non-target lesions, including any measurable lesions that were not chosen as
target lesions
•
It is possible to record multiple non-target lesions involving the same organ as a single item
on the eCRF (eg, “multiple enlarged pelvic lymph nodes”)
Determining Response 
•
Assess at baseline and on study with consistent modalities (CT, MRI, PET/CT)
–
Measure target lesions and calculate SLD
–
Visually assess non-target lesions
–
Search for new lesions
–
Combine these assessments into the overall response
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Target Lesion Response 
Complete Response (CR) 
•
Disappearance of all extranodal target lesions.
•
All pathological lymph nodes must have decreased to <10 mm in short axis
Partial Response (PR) 
•
At least a 30% decrease in the SLD of target lesions, taking as reference the
baseline sum diameters
Progressive Disease (PD) 
•
SLD increased by at least 20% from the smallest value on study (including
baseline, if that is the smallest)
•
The SLD must also demonstrate an absolute increase of at least 5 mm. (Two
lesions increasing from 2 mm to 3 mm, for example, does not qualify)
Stable Disease (SD) 
•
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify
for PD
Non-evaluable (NE) 
•
One or more lesions cannot be evaluated due to missing data or poor image
quality unless a convincing argument can be made that the contribution of the
individual missing lesion(s) would not change the assigned time point response
(eg, PD based on other findings)
Non-Target Lesion Response 
Complete Response (CR) 
•
Disappearance of all extranodal non-target lesions
•
All lymph nodes must be non-pathological in size (<10 mm short axis)
•
Normalization of tumor marker level
Non-CR/Non-PD 
•
Persistence of one or more non-target lesions(s) and/or maintenance of tumor
marker level above the normal limits
Progressive Disease (PD) 
•
Unequivocal progression of existing non-target lesions. (Subjective judgment
by experienced reader)
Unable to Evaluate (UE) 
•
One or more lesions cannot be evaluated due to missing data or poor image
quality unless a convincing argument can be made that the contribution of the
individual missing lesion(s) would not change the assigned time point response
(eg, PD based on other findings)
New Lesions 
•
Should be unequivocal and not attributable to differences in scanning technique or findings
that may not be a tumor (does not have to meet criteria to be “measurable”).
•
If a new lesion is equivocal, continue to next time point. If confirmed at that time, PD is
assessed at the date when the lesion was first seen.
•
Lesions identified in anatomic locations not scanned at baseline are considered new.
•
New lesions on ultrasound should be confirmed on CT or MRI.
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Evaluation of Overall Time Point Response for Patients with Measurable Disease at 
Baseline 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
NE 
No 
PR 
PR 
Non-PD or NE 
No 
PR 
SD 
Non-PD or NE 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
NE=Not Evaluable 
Source: Eisenhauer EA, 2009 [21]. 
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Appendix D ECOG Scale for Performance Status 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all predisease performance without restriction. 
1 
Symptoms but ambulatory. Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature (eg, light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care but unable to carry out any 
work activities. Up and about more than 50% of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined to bed or chair more than 
50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair. 
5 
Dead. 
Source: Oken MM, 1982 [22]. 
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Appendix E Drugs That Interact with the CYP3A Family of Cytochromes P450 
Drugs listed below that are moderate or strong inducers, or moderate or strong inhibitors of the 
CYP3A family of Cytochromes P450 are prohibited as concomitant medications with TAK-788, 
with the exception of nonsystemic use. 
Drugs Inducing or Inhibiting CYP3A Metabolism That Are Prohibited as Concomitant 
Medications with TAK-788, with the Exception of Nonsystemic Use 
Moderate CYP3A Inducers (a) 
bosentan 
efavirenz 
etravirine 
phenobarbital 
primidone 
Strong CYP3A Inducers (a) 
apalutamide 
carbamazepine 
enzalutamide 
mitotane 
phenytoin 
rifampin 
St John’s Wort 
Moderate CYP3A Inhibitors (b) 
aprepitant 
ciprofloxacin 
conivaptan 
crizotinib 
cyclosporine 
diltiazem 
dronedarone 
erythromycin 
fluconazole 
fluvoxamine 
imatinib 
tofisopam 
verapamil 
Strong CYP3A Inhibitors (b) 
boceprevir 
cobicistat 
danoprevir and ritonavir 
elvitegravir and ritonavir 
grapefruit juice 
indinavir and ritonavir 
itraconazole 
ketoconazole 
lopinavir and ritonavir 
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Strong CYP3A Inhibitors (b) 
paritaprevir and ritonavir and (ombitasvir and/or dasabuvir) 
posaconazole 
ritonavir 
saquinavir and ritonavir 
telaprevir 
telithromycin 
tipranavir and ritonavir 
troleandomycin 
voriconazole 
Note: This list is not intended to be exhaustive, and a similar restriction will apply to other agents that are known to 
strongly or moderately modulate CYP3A activity. Appropriate medical judgment is required. Please contact the 
sponsor’s medical monitor with any queries. 
(a)
fda.gov/Drugs/ drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-
and-inducers#table3-3 (accessed 05 December 2019).
(b)
fda.gov/Drugs/ drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-
and-inducers#table3-2 (accessed 05 December 2019)
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Generic Name 
Brand Name 
General Indication a 
Source a 
Chlorpromazine 
Thorazine, Largactil, 
Megaphen 
Treatment of (1) various psychoses, 
and psychomotor agitation 
excitement in accordance with the 
approved label, (2) intractable 
hiccups, (3) nausea/vomiting 
associated with terminal illness. 
Thorazine 
(chlorpromazine 
hydrochloride for 
injection) PI 
Cilostazol 
Pletal 
Reduction of symptoms related to 
intermittent claudication. 
Pletal (cilostazol) PI 
Droperidol 
Inapsine, Droleptan, 
Dridol, Xomolix 
Inaspsine, Droleptan, Xomolix: 
reduction of PONV. 
Dridol: treatment of 
hypoparathyroidism, refractory 
rickets, and familial 
hypophosphatemia. 
Dridol (droperidol 
for injection) PI 
Levomepromazine 
Nosinan, Nozinan, 
Levoprome 
Supportive treatment for terminally 
ill patients for (1) intractable nausea 
and vomiting, (2) management of 
pain,(3) restlessness, and distress. 
Levomepromazine 
(Levomepromazine 
Maleate) PI 
Levomethadyl 
acetate 
Orlaam 
For the management of opiate 
dependencies. 
Orlaam 
(levomethadyl 
acetate 
hydrochloride) PI 
Levosulpiride 
Lesuride, Levazeo, Enliva 
(with rabeprazole) 
Treatment of various psychiatric and 
GI disorders in accordance with the 
approved label. 
Levosulpiride PI 
Methadone 
Dolophine, Symoron, 
Amidone, Methadose, 
Physeptone, Heptadone 
(1)Treatment of severe pain, (2)
supportive treatment in the
detoxification of opioid addiction.
Dolophine 
hydrochloride 
(methadone 
hydrochloride) PI 
Papaverine HCl 
(Intra-coronary) 
None 
For treatment of (1) erectile 
dysfunction, (2) arrhythmias due to 
MI. Prophylaxis for peripheral atrial
catheter patency.
Papaverine HCL PI 
Probucol 
Lorelco 
Treatment for lowering cholesterol. 
Lorelco (probucol) 
PI 
Terlipressin 
Teripress, Glypressin, 
Terlipin, Remestyp, 
Tresil, Teriss, and others 
Treatment of bleeding oesophageal 
varices. 
Teripress 
(teripressin) PI 
Terodiline 
Micturin, Mictrol (not 
bethanechol) 
Muscle relaxant/bladder spasm 
Not available 
Ibogaine 
None 
Not available 
AFIB: atrial fibrillation; AFL: atrial flutter; APL: acute promyelocytic leukemia; EES: erythromycin ethylsuccinate; 
GERD: gastroesophageal reflux disease; GI: gastrointestinal; IBS: irritable bowel syndrome; MI: myocardial 
infarction; PJP: pneumocystis jiroveci pneumonia; PONV: post-operative nausea and vomiting; PSVT: paroxysmal 
supraventricular tachycardia; VF: ventricular fibrillation; VT: ventricular tachycardia. 
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a Refer to the most current package insert/summary of product characteristics as relevant to the specific prescribing 
agent and region for the approved indication and safety-related dosing guidance. 
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Appendix G Bayesian Logistic Regression Model 
An adaptive BLRM with overdose control will be used to guide dose escalation. BLRM with 
overdose control principle [23][24] informs dose escalation decisions and MTD estimation, 
along with consideration of other available information, such as safety, PK and efficacy. 
The 2-parameter logistic regression model used is as follows: 
ln ൬
πi
1 −πi
൰=  ln(α) +  β ln ൬dosei
doseref
൰,
α > 0, β > 0 
where πi is the DLT rate for dose i, doseref is a reference dose, and ln is the natural log function. 
The MTD for TAK-788 in a global study AP32788-15-101 has been identified as 160 mg QD. A 
total of 38 DLT evaluable patients were enrolled in the global study, and 5 DLTs were observed. 
There are 3, 3, 5 and 6 evaluable patients at 5 mg, 10 mg, 20 mg and 40 mg, and no DLT was 
observed for these doses. There are 6 evaluable patients each at 80 mg, 120 mg and 160 mg, and 
1 DLT was observed for each of these three doses. Two DLTs were observed among the 3 
evaluable patients at 180 mg. The global MTD will be assigned as the reference dose in this 
study. A post-hoc BLRM analysis was conducted for the DLT data in the global study, and the 
posterior distribution of ln(α) and ln(β) conditional on the global study data was obtained by 
using a quantile-based, weakly informative, bivariate normal prior 
BVN ቆቀ−1.33
−1.27ቁ, ቂ3.19
−4.28
−4.28
20.0 ቃቇ 
for ln(α) and ln(β), which was assigned based on pre-study estimates of median DLT rate (0.02, 
0.04, 0.06, 0.08, 0.14, 0.16, 0.18, and 0.4) at doses (5, 10, 20, 40, 80, 120, 160 and 180 mg), as 
described in Neuenschwander 2008 [23]. The global posterior distribution of ln(α) and ln(β) is 
BVN ቆቀ−1.12
0.098ቁ, ቂ0.38
0.45
0.45
2.45ቃቇ, 
which will be assigned as the prior distribution of ln(α) and ln(β) in this study. 
The model will be updated after each group of approximately 3-5 patients are enrolled in the 
current dose. A different cohort size may also be considered. Each subject will participate in only 
1 dose cohort. For each dose, the posterior probability of having DLT rates that fall into the 
following intervals will be estimated: 
•
[0, 0.21): underdosing.
•
[0.21, 0.33): target toxicity.
•
[0.33, 1.00]: excessive toxicity.
The next recommended dose will be selected as described in Section 8.3.
The simulation to evaluate the operating characteristics is performed based on provisional doses 
(40, 80, 120, and 160 mg QD). For each cohort in the simulation, 5 patients will be enrolled and 
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each patient is assumed to have 80% probability of being DLT evaluable (there is less than 6% 
chance that the number of evaluable patients will be less than 3, so for simplicity a minimum of 
3 DLT evaluable patients was applied in the simulation, however, the study may consider a 
flexible cohort size), which results in a flexible cohort size of 3-5 evaluable patients. Escalation 
from 40 mg QD directly to 160 mg QD is not allowed in the simulation. In addition to the MTD 
rule specified in the protocol, a dose can be claimed as the MTD if the observed DLT rate at that 
dose is lower than 33%. The simulation is performed based on 5 scenarios of the assumed true 
DLT rates at doses (40, 80, 120, and 160 mg), representing various distributions of toxicity 
across doses, detailed as shown in the following:. 
Dose Escalation Simulation Study of the Probability of Dose-Limiting Toxicity 
Dose Level 
True P(DLT) at each scenario 
1 
2 
3 
4 
5 
40 mg (a) 
0.01 
0.05 
0.08 
0.10 
0.15 
80 mg 
0.05 
0.10 
0.13 
0.15 
0.20 
120 mg 
0.10 
0.15 
0.20 
0.25 
0.32 
160 mg 
0.20 
0.23 
0.28 
0.40 
0.45 
Abbreviation: P(DLT), probability of a DLT at each DL. 
(a) Starting dose.
The trend of the dose-DLT relationship becomes steeper and MTD is reached earlier from 
Scenario 1 to Scenario 5. The following table shows the operating characteristic results. 
Operating Characteristics for BLRM Dose Escalation Rule 
Scenario 
Probability of recommending a: 
Average proportion of patients 
receiving a:  
Average number of 
patients 
Low 
Dose 
Target 
Dose 
High 
Dose 
No 
MTD 
Low 
Dose 
Target 
Dose 
High 
Dose 
Per 
study 
Experiencing 
DLT per study 
1 
98.7% (a) 
NA 
NA 
1.3% 
100% 
NA 
NA 
17.2 
2.1 
2 
25.9% 
71.0% 
NA 
3.1% 
57.3% 
42.7% 
NA 
17.8 
2.8 
3 
34.5% 
58.1% 
NA 
7.4% 
61.5% 
38.5% 
NA 
18.7 
3.8 
4 
3.4% 
49.2% 
28.6% 
18.8% 
24.3% 
45.6% 
30.1% 
20.0 
5.1 
5 
8.9% 
46.0% 
15.2% 
29.9% 
28.3% 
49.8% 
21.9% 
20.9 
6.3 
Abbreviations: DLT=dose limiting toxicity, MTD=maximum tolerated dose, 
low dose=true DLT rate is [0, 0.21), target dose=true DLT rate is [0.21, 0.33), high dose=true DLT rate is [0.33, 1.00], no 
MTD=MTD rule is not met and determination will be based on clinical judgement. 
(a) Probability of 76.9% to claim 160 mg as MTD.
In Scenario 1 where all true DLT rates are below 0.33, the probabilities of recommending the 
highest dose level (160 mg) is 76.9%. In Scenario 1, the average number of DLT evaluable 
patients required is approximately 17.2 with 2.1 DLTs expected on average. In Scenario 2, there 
is 25.9% chance of recommending a lower dose as MTD, 71.0% chance of successfully 
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recommending target dose levels. The average number of patients required is approximately 
17.8, with approximately 2.8 DLTs expected on average. In Scenario 3, with faster increase of 
DLT rate over doses, there is a 58.1% probability of recommending target dose levels. The 
average number of patients required is approximately 18.7 with 3.8 DLTs expected on average. 
In Scenario 4, there is 49.2% chance of claiming the target doses as MTD. The average number 
of patients required is approximately 20.0 with 5.1 DLTs expected on average. In Scenario 5, 
there is 46.0% chance of claiming the target doses as MTD. The average number of patients 
required is approximately 20.9 with 6.3 DLTs expected on average. 
The average sample sizes across different scenarios range from 17.2 to 20.9. Based on this, a 
total sample size of approximately 21 DLT evaluable patients is determined. Assuming a 15% 
drop out rate and potentially up to 5 patients will be enrolled for any cohort to further confirm 
the safety, the total sample size for this study will be approximately 28-33. 
The accuracy of the BLRM recommendation relies on the true DLT rate, thus the safety, PK and 
efficacy data evaluation are combined to support the dose escalation. As an example, a 
hypothetical dose escalation step is shown in the following table to illustrate how BLRM guides 
dose escalation. 
Hypothetical Dose Escalation Step 
Step 
Dose (mg) 
#patients 
(evaluable) 
#DLTs 
Next Recommended Dose (mg) 
1 
40 
3 
0 
120 
2 
40 
3 
0 
120 
4 
1 
160 
3 
40 
3 
0 
120 
4 
1 
160 
5 
2 
120 
4 
40 
3 
0 
120 
8 
2 
120 
160 
5 
2 
(Claim 120 mg as MTD) 
Abbreviation: MTD, maximum tolerated dose. 
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Protocol Incorporating Amendment No.06 
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Appendix H Detailed Description of Amendments to Text 
This document describes changes in reference from Protocol Incorporating Amendment No. 05 
to Protocol Incorporating Amendment No. 06. 
The previous descriptions in Amendment No. 05 are identified using italicized underscore, and 
the amended descriptions (Amendment 06) are shown with bold letter and underline. Note that, 
editorial changes are not listed. 
Page 1, Cover Page 
Existing Text (Amendment 05) 
Date: 27 July 2020 
Amendment Number: 05 
Date 
Amendment Number 
Region 
17 October 2018 
Initial Protocol 
All sites 
22 November 2018 
Amendment No. 01 
All sites 
20 December 2019 
Amendment No. 02 
All sites 
27 January 2020 
Amendment No. 03 
All sites 
25 June 2020 
Amendment No. 04 
All sites 
27 July 2020 
Amendment No. 05 
All sites 
Revised Text (Amendment 06) 
Date: 12 January 2022 
Amendment Number: 06 
Date 
Amendment Number 
Region 
17 October 2018 
Initial Protocol 
All sites 
22 November 2018 
Amendment No. 01 
All sites 
20 December 2019 
Amendment No. 02 
All sites 
27 January 2020 
Amendment No. 03 
All sites 
25 June 2020 
Amendment No. 04 
All sites 
27 July 2020 
Amendment No. 05 
All sites 
12 January 2022 
Amendment No. 06 
All sites 
Rationale for Amendment 
To amend the protocol. 
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Page 3, Section 1.2 Approval (SIGNATURES) 
Existing Text (Amendment 05) 
 
 
 
 
 
 
 
Revised Text (Amendment 06) 
 
 
 
 
 
 
Rationale for Amendment 
Change of the person in charge 
Page 40, Section 8.1 Study Drug Administration (Phase 2 Part) 
Existing Text (Amendment 05) 
Phase 2 Part 
TAK-788 drug product will be administered orally. TAK-788 will be self-administered by the 
patient. The dose will be 160 mg orally administered once daily. Each 28-day dosing period is 
referred to as 1 cycle. Patients will take the prescribed dose with water with or without a low-fat 
meal (ie, ≤350 kcal and ≤15% of calories from fat). Patients who forget to take their scheduled 
dose of study drug should be instructed not to make up the missed dose (if >6 hours after 
 
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scheduled time of administration). Missed doses should be recorded in an appropriate source 
record (eg, clinic chart), patient diary, and study drug administration eCRF. 
Revised Text (Amendment 06) 
Phase 2 Part 
TAK-788 drug product will be administered orally. TAK-788 will be self-administered by the 
patient. The dose will be 160 mg orally administered once daily. Each 28-day dosing period is 
referred to as 1 cycle. Patients will take the prescribed dose with water with or without a low-fat 
meal (ie, ≤350 kcal and ≤15% of calories from fat). Patients who forget to take their scheduled 
dose of study drug should be instructed not to make up the missed dose (if >6 hours after 
scheduled time of administration). Missed doses should be recorded in an appropriate source 
record (eg, clinic chart), patient diary, and study drug administration eCRF. 
In case of extenuating circumstances that prevent a patient from attending the study site 
(eg, the COVID-19 pandemic), drug packs and patient diaries should be returned at the 
next available on-site clinic visit. 
Rationale for Amendment 
To ensure patient monitoring and evaluation during the coronavirus disease 2019 (COVID-19) 
public health emergency. 
Page 43, Section 8.4.1.1 Management of Selected Treatment-Related Adverse Events 
Existing Text (Amendment 05) 
Diarrhea 
Based on pre-clinical findings and known class effect, patients should be monitored for the onset 
of diarrhea. Symptomatic care, such as loperamide, may be given at first evidence of loose stool, 
increased frequency of bowel movement, or at grade 1 diarrhea, according to the investigator’s 
clinical judgment. For grade 2 diarrhea, administer loperamide at 4 mg, then 2 mg every 2 to 
4 hours until the patient is symptom-free for 12 hours. No dose modification is necessary unless 
the patient does not tolerate TAK-788 or the symptom recurs. For grade ≥3 diarrhea despite 
loperamide, treatment will be withheld until recovery to grade ≤1 diarrhea. Secondary 
prophylaxis in patients who have experienced diarrhea with TAK-788 treatment is allowed. 
Other medications (such as diphenoxylate hydrochloride with atropine sulfate) and supportive 
care may be added according to the institution’s standard of care. Primary prophylactic 
antidiarrheal medications may be used after discussion with the sponsor. 
Revised Text (Amendment 06) 
Diarrhea 
Based on pre-clinical findings and known class effect, patients should be monitored for the onset 
of diarrhea. Symptomatic care, such as loperamide, may be given at first evidence of loose stool, 
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increased frequency of bowel movement, or at grade 1 diarrhea, according to the investigator’s 
clinical judgment (not to exceed total dose of 16 mg over 24 hours). For grade 2 diarrhea, 
administer loperamide at 4 mg, then 2 mg every 2 to 4 hours until the patient is symptom-free for 
12 hours (not to exceed total dose of 16 mg over 24 hours). No dose modification is necessary 
unless the patient does not tolerate TAK-788 or the symptom recurs. For grade ≥3 diarrhea 
despite loperamide, treatment will be withheld until recovery to grade ≤1 diarrhea. Secondary 
prophylaxis in patients who have experienced diarrhea with TAK-788 treatment is allowed. 
Other medications (such as diphenoxylate hydrochloride with atropine sulfate) and supportive 
care may be added according to the institution’s standard of care. Primary prophylactic 
antidiarrheal medications may be used after discussion with the sponsor. 
Rationale for Amendment 
For consistency across the TAK-788 program. 
Page 43, Section 8.4.1.1 Management of Selected Treatment-Related Adverse Events 
Existing Text (Amendment 05) 
N/A 
Revised Text (Amendment 06) 
Cardiac Events: QTc Interval Prolongation and Heart Failure 
TAK-788 dose modification guidelines, outlined in Table 8.c, should be closely followed for 
patients who experience QTc interval prolongation or heart failure deemed related to 
TAK-788 dosing. TAK-788 dose reduction levels should follow the schedule outlined in 
Table 8.b. 
 
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Table 8.c 
TAK-788 Dose Modification for TEAEs of QTc Interval Prolongation and 
Heart Failure 
Toxicity Grade 
Parameters 
TAK-788 Dose Modification 
QTc Interval Prolongation 
Grade 2 
QTc Interval of 481 to 500 msec. 
First Occurrence: 
• Withhold TAK-788 dosing until QTc
interval recovers to a ≤Grade 1 or
baseline.
• Once recovered, resume TAK-788 at
the most recent dose.
Recurrence: 
• Withhold TAK-788 until ≤ Grade 1 or
baseline.
• Once recovered, resume TAK-788
dosing at the next lower dose level or
permanently discontinue dosing,
based on clinical judgement.
Grade 3 
≥501 msec 
or 
Increases of >60 msec from baseline. 
First Occurrence: 
• Withhold TAK-788 until ≤ Grade 1 or
baseline.
• Once recovered, resume TAK-788
dosing at the next lower dose level, or
permanently discontinue TAK-788
dosing, based on clinical judgement.
Recurrence: 
• Permanently discontinue TAK-788
dosing.
Grade 4 
Torsades de Pointes; polymorphic 
ventricular tachycardia; 
signs/symptoms of serious arrhythmias. 
Permanently discontinue TAK-788 
dosing. 
Decreased Ejection Fraction 
Grade 2: 
Ejection fraction - 
asymptomatic.  
Resting ejection fraction 50% to 40% 
or 
Decrease from baseline 10% to 19%.  
• Withhold TAK-788 until recovered to
baseline.
• If the patient recovers to baseline
within 2 weeks of dose interruption,
resume TAK-788 at the most recent
dose level or the next lower dose level,
in accordance with clinical
judgement.
• If the patient does not resume to
baseline within 2 weeks of dose
interruption, permanently
discontinue TAK-788 dosing.
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Toxicity Grade 
Parameters 
TAK-788 Dose Modification 
≥Grade 3:  
Ejection fraction - 
asymptomatic. 
Resting ejection fraction ≤39% 
or 
≥ 20% decrease from baseline. 
Permanently discontinue TAK-788 
dosing. 
Heart Failure 
Any Grade  
Heart failure - symptomatic 
Permanently discontinue TAK-788 
dosing. 
QTc: corrected QT interval; TEAE: treatment-emergent adverse event. 
Rationale for Amendment 
To align the current protocol with newly available safety information, and to ensure consistency 
in dose modifications guidelines across the TAK-788 program. 
Page 50, Section 8.7.3 Concomitant Medications with QTc Interval Prolongation Potential 
Existing Text (Amendment 05) 
N/A 
Revised Text (Amendment 06) 
8.7.3 Concomitant Medications with QTc Interval Prolongation Potential 
Investigators should provide close oversight of patients when co-dosing TAK-788 with 
concomitant medications with known QTc inteval prolongation. Additional ECGs, as 
clinically indicated should be conducted in accordance with the investigator’s judgement. 
Dose modification for patients exhibiting QTc interval prolongation is outlined in Section 
8.3.1.5. Restricted concomitant medications with a known risk of Torsades de Pointes are 
provided in Appendix F. 
Rationale for Amendment 
To provide additional precautionary guidance for investigators regarding the concomitant dosing 
of medications with QTc interval prolongation potential. 
Page 52, Section 8.13 Storage, Handling, and Accountability 
Existing Text (Amendment 05) 
The recommended storage condition for TAK-788 drug product is at a temperature 
thermostatically maintained at the usual customary working environment of 1°C to 30°C, as 
experienced in pharmacies, hospitals, and warehouses. 
The study pharmacist or designee at the site will be responsible for handling and dispensing 
study drug and completing associated documentary paperwork. Supplies are shipped to the 
 
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investigative site at appropriate intervals, depending on patient accrual. The site must use an 
appropriate dispensing log/accountability form provided by the sponsor, or an acceptable 
substitute approved by the sponsor. Each time study medication is dispensed to a patient, the 
following information must be recorded: the patient identification number, drug product strength, 
quantity dispensed with the corresponding lot number, and the signs of the person dispensing the 
drug. These logs are to be maintained by the study pharmacist in the pharmacy throughout the 
duration of the study and will be periodically verified by a representative of the sponsor. 
The investigator is responsible for ensuring that the study drug provided to the patient and 
returned from the patient are accounted for and noted in source documentation. 
Revised Text (Amendment 06) 
The recommended storage condition for TAK-788 drug product is at a temperature 
thermostatically maintained at the usual customary working environment of 1°C to 30°C, as 
experienced in pharmacies, hospitals, and warehouses. 
The study pharmacist or designee at the site will be responsible for handling and dispensing 
study drug and completing associated documentary paperwork. Supplies are shipped to the 
investigative site at appropriate intervals, depending on patient accrual. The site must use an 
appropriate dispensing log/accountability form provided by the sponsor, or an acceptable 
substitute approved by the sponsor. Each time study medication is dispensed to a patient, the 
following information must be recorded: the patient identification number, drug product strength, 
quantity dispensed with the corresponding lot number, and the signs of the person dispensing the 
drug. These logs are to be maintained by the study pharmacist in the pharmacy throughout the 
duration of the study and will be periodically verified by a representative of the sponsor. 
Disruption to site visits due to the COVID-19 pandemic may require the site to use an 
alternative method for dispensing TAK-788 to ensure continuity of treatment. If allowed by 
country regulation/IRB, TAK-788 can be shipped DTP from the investigation site to the 
patient’s home address via courier if needed. 
The investigator is responsible for ensuring that the study drug provided to the patient and 
returned from the patient are accounted for and noted in source documentation. 
Rationale for Amendment 
To ensure continuity of TAK-788 treatment due to COVID-19 related quarantines, cancellations 
of on-site visits, or concerns about possible COVID-19 exposure. 
Page 54, Section 9.4 Study Procedures 
Existing Text (Amendment 05) 
The study procedures to be performed at screening and throughout the entire study are listed in 
the schedule of events (Appendix A), which is meant to provide a convenient display of the 
timing and scope of required assessments expected at each visit, but does not provide a 
 
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comprehensive description of each assessment. Additional details are provided as necessary in 
the sections that follow. 
The ICF may be signed more than 21 days before C1D1. Screening assessments must be 
performed within 14 days before C1D1, with the exception of tumor imaging assessment, for 
which the allowable window is 21 days before C1D1. 
Investigators must be familiar with the details of this section and use it in conjunction with the 
table to adequately carry out the required study assessments. All study assessments should occur 
within ±3 days of the scheduled study day unless otherwise noted in the schedule of events 
descriptions or table. A cycle is defined as 28 days. 
In Phase 1, patients will be hospitalized during DLT evaluation in Cycle 1. If a patient needs to 
be discharged temporarily during the period, the investigator must obtain an approval from the 
sponsor. The investigator must document the confirmation record for stabilization of the 
patient’s symptoms per the available data in an appropriate source record (eg, medical records) 
before the patient’s temporary discharge. 
Revised Text (Amendment 06) 
The study procedures to be performed at screening and throughout the entire study are listed in 
the schedule of events (Appendix A), which is meant to provide a convenient display of the 
timing and scope of required assessments expected at each visit, but does not provide a 
comprehensive description of each assessment. Additional details are provided as necessary in 
the sections that follow. 
The ICF may be signed more than 21 days before C1D1. Screening assessments must be 
performed within 14 days before C1D1, with the exception of tumor imaging assessment, for 
which the allowable window is 21 days before C1D1. 
Investigators must be familiar with the details of this section and use it in conjunction with the 
table to adequately carry out the required study assessments. All study assessments should occur 
within ±3 days of the scheduled study day unless otherwise noted in the schedule of events 
descriptions or table. A cycle is defined as 28 days. 
In Phase 1, patients will be hospitalized during DLT evaluation in Cycle 1. If a patient needs to 
be discharged temporarily during the period, the investigator must obtain an approval from the 
sponsor. The investigator must document the confirmation record for stabilization of the 
patient’s symptoms per the available data in an appropriate source record (eg, medical records) 
before the patient’s temporary discharge. 
Sites will make every effort to see patients in the clinic for assessments. In unavoidable 
circumstances, such as the COVID-19 public health emergency, exceptions can be made for 
alternative methods for conducting patient visits/assessments and ideally should be 
approved by the sponsor or designee. These methods may include remote visits being 
conducted by phone (eg, collection of AEs and monitoring) or video conferencing 
(Telehealth or Telemedicine, physician/patient preferred methodology), or alternative 
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site/location (eg, collection of safety assessments). Remote visits and telemedicine must 
comply with national and local laws and regulations. Such instances will be documented in 
the study records. 
Rationale for Amendment 
To ensure patient monitoring and evaluation during the coronavirus disease 2019 (COVID-19) 
public health emergency. 
Page 59, Section 9.4.18 Disease Assessment 
Existing Text (Amendment 05) 
At screening, disease assessment must include imaging of the chest, abdomen, pelvis, and brain 
using appropriate radiological procedures (computed tomography [CT] scans or magnetic 
resonance imaging [MRI] with contrast, unless contrast media is contraindicated). Imaging of the 
brain (contrast-enhanced MRI is preferred) is required at screening for all patients, and will be 
repeated post-baseline for patients with CNS metastases at baseline. 
Patients must have at least 1 measurable lesion per RECIST v1.1 (see Appendix C). Previously 
irradiated lesions may not be used for target lesions, unless there is unambiguous radiological 
progression after radiotherapy. For Phase 1 part, brain lesions may be used as target lesions 
provided they are ≥10 mm and have not been: 1) previously treated with whole brain radiation 
therapy (WBRT) within 3 months, or 2) previously treated by SRS or surgical resection. 
Abbreviated 
Revised text (Amendment 06) 
At screening, disease assessment must include imaging of the chest, abdomen, pelvis, and brain 
using appropriate radiological procedures (computed tomography [CT] scans or magnetic 
resonance imaging [MRI] with contrast, unless contrast media is contraindicated). Imaging of the 
brain (contrast-enhanced MRI is preferred) is required at screening for all patients, and will be 
repeated post-baseline for patients with CNS metastases at baseline. 
Patients must have at least 1 measurable lesion per RECIST v1.1 (see Appendix C). Previously 
irradiated lesions may not be used for target lesions, unless there is unambiguous radiological 
progression after radiotherapy. For Phase 1 part, brain lesions may be used as target lesions 
provided they are ≥10 mm and have not been: 1) previously treated with whole brain radiation 
therapy (WBRT) within 3 months, or 2) previously treated by SRS or surgical resection. 
Local site investigator/radiology assessment based on RECIST version 1.1 will be used to 
determine subject eligibility. In extenuating circumstances during the COVID-19 public 
health emergency, patients may use alternative site for imaging if approved by the sponsor 
or designee. 
Abbreviated 
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Rationale for Amendment 
To ensure patient monitoring and evaluation during the coronavirus disease 2019 (COVID-19) 
public health emergency. 
Page 80, Section 14.1 Study-Site Monitoring Visits 
Existing Text (Amendment 05) 
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and institution guarantee access to source documents by the sponsor or its 
designee (CRO) and by the IRB. 
All aspects of the study and its documentation will be subject to review by the sponsor or 
designee including, but not limited to, the investigator’s binder, study medication, subject 
medical records, informed consent documentation, 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. 
Revised text (Amendment 06) 
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and institution guarantee access to source documents by the sponsor or its 
designee (CRO) and by the IRB. 
All aspects of the study and its documentation will be subject to review by the sponsor or 
designee including, but not limited to, the investigator’s binder, study medication, subject 
medical records, informed consent documentation, 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. 
In the event a monitor cannot visit the site in a timely manner due to the COVID-19 
pandemic, alternative monitoring approaches such as remote source data verification or 
telephone contact may be used to ensure data quality and integrity and maintain patient 
safety. Alternative monitoring approaches should be used only where allowed by applicable 
local regulations and permitted by the IRB. 
Rationale for Amendment 
To ensure patient monitoring and evaluation during the coronavirus disease 2019 (COVID-19) 
public health emergency. 
 
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Page 102, Appendix F Drugs with a Risk of Torsades de Pointes 
Existing Text (Amendment 05) 
The website crediblemeds.org/everyone/composite-list-all-qtdrugs/[Accessed: 7 June 2019] lists 
4 categories of QT-prolonging drugs and may be used as a guide for this protocol. Categories 
include “Drugs with Known TdP Risk”, “Drugs with Possible TdP Risk”, “Drugs with 
Conditional TdP Risk”, and “Drugs to be Avoided by Congenital Long QT Patients”. The 
investigative site should register (under the “For Healthcare Providers” tab) to access these 
categories. If the investigative site does not wish to register, a composite list, including all 
categories, is available. 
Drugs with a known risk of Torsades de Pointes are listed in the table below, and are the only 
category of QT-prolonging drugs that are prohibited in this study. 
Note: The website and table are only to be used as a guideline and are not comprehensive. It is 
the investigator’s responsibility to ensure that any drugs under consideration have not been 
newly identified as causing Torsades de Pointes. 
Drugs Generally Accepted by the CredibleMeds QTDrug List Advisory Board to have a 
Known Risk of Causing Torsades de Pointes; Prohibited in this Study 
Generic Name 
Brand Name 
Class/Clinical Use 
Aclarubicin 
Aclacin, Aclacinomycine, Aclacinon, 
Aclaplastin, Jaclacin 
Anticancer 
Amiodarone 
Cordarone, Pacerone, Nexterone 
Antiarrhythmic/abnormal heart rhythm 
Anagrelide 
Agrylin, Xagrid 
Phosphodiesterase 3 inhibitor/ 
thrombocytemia 
Arsenic trioxide 
Trisenox 
Anticancer/leukemia 
Astemizole 
Hismanal 
Antihistamine/allergic rhinitis 
Azithromycin 
Zithromax, Zmax 
Antibiotic/bacterial infection 
Bepridil 
Vascor 
Antianginal/angina pectoris (heart pain) 
Chloroquine 
Aralen 
Antimalarial/malaria 
Chlorpromazine 
Thorazine, Largactil, Megaphen 
Antipsychotic, Antiemetic/schizophrenia, 
nausea, many others 
Cilostazol 
Pletal 
Phosphodiesterase 3 inhibitor/ 
intermittent claudication 
Ciprofloxacin 
Cipro, Cipro-XR, Neofloxin 
Antibiotic/bacterial infection 
Cisapride 
Propulsid 
GI stimulant/increase GI motility 
Citalopram 
Celexa, Cipramil 
Antidepressant, SSRI/depression 
Clarithromycin 
Biaxin, Prevpac 
Antibiotic/bacterial infection 
Cocaine 
Cocaine 
Local anesthetic/anesthesia (topical) 
Disopyramide 
Norpace 
Antiarrhythmic/abnormal heart rhythm 
Dofetilide 
Tikosyn 
Antiarrhythmic/abnormal heart rhythm 
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Generic Name 
Brand Name 
Class/Clinical Use 
Domperidone 
Motilium, Motillium, Motinorm Costi, 
Nomit 
Antinausea/nausea, vomiting 
Donepezil 
Aricept 
Cholinesterase inhibitor/dementia 
(Alzheimer’s Disease) 
Dronedarone 
Multaq 
Antiarrhythmic/abnormal heart rhythm 
Droperidol 
Inapsine, Droleptan, Dridol, Xomolix 
Antipsychotic, Antiemetic/anesthesia 
(adjunct), nausea 
Erythromycin 
E.E.S., Robimycin, EMycin, Erymax, Ery-
Tab, Eryc Ranbaxy, Erypar, Eryped, 
Erythrocin Stearate Filmtab, Erythrocot, 
E-Base, Erythroped, Ilosone, MY-E,
Pediamycin, Zineryt, Abboticin, 
Abboticin-ES, Erycin, PCE Dispertab, 
Stiemycine, Acnasol, Tiloryth 
Antibiotic/bacterial infection, increase GI 
motility 
Escitalopram 
Cipralex, Lexapro, Nexito, Anxiset-E, 
Exodus, Esto, Seroplex, Elicea, Lexamil, 
Lexam, Entact, Losita, Reposil, 
Animaxen, Esitalo, Lexamil 
Antidepressant, SSRI/depression (major), 
anxiety disorder 
Flecainide 
Tambocor, Almarytm, Apocard, Ecrinal, 
Flécaine 
Antiarrhythmic/abnormal heart rhythm 
Fluconazole 
Diflucan, Trican 
Anti-fungal/fungal infection 
Gatifloxacin 
Tequin 
Antibiotic/bacterial infection 
Grepafloxacin 
Raxar 
Antibiotic/bacterial infection 
Halofantrine 
Halfan 
Antimalarial/malaria 
Haloperidol 
Haldol, Aloperidin, Bioperidolo, 
Brotopon, Dozic, Duraperidol, Einalon S, 
Eukystol, Halosten, Keselan, Linton, 
Peluces, Serenace, Serenase, Sigaperidol 
Antipsychotic/schizophrenia, agitation 
Hydroquinidine, 
dihydroquinidine 
Serecor 
Antiarrhythmic/arrhythmia 
Ibogaine 
None 
Psychedelic/narcotic addition, unproven 
Ibutilide 
Corvert 
Antiarrhythmic/abnormal heart rhythm 
Levofloxacin 
Levaquin, Tavanic 
Antibiotic/bacterial infection 
Levomepromazine 
Nosinan, Nozinan, Levoprome 
Antipsychotic/schizophrenia 
Levomethadyl acetate 
Orlaam 
Opiate agonist/narcotic dependence 
Levosulpiride 
Lesuride, Levazeo, Enliva (with 
rabeprazole) 
Antipsychotic/schizophrenia 
Mesoridazine 
Serentil 
Antipsychotic/schizophrenia 
Methadone 
Dolophine, Symoron, Amidone, 
Methadose, Physeptone, Heptadone 
Opiate agonist/pain, narcotic dependence 
Moxifloxacin 
Avelox, Avalox, Avelon 
Antibiotic/bacterial infection 
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Generic Name 
Brand Name 
Class/Clinical Use 
Ondansetron 
Zofran, Anset, Ondemet, Zuplenz, 
Emetron, Ondavell, Emeset, Ondisolv, 
Setronax 
Antiemetic/nausea, vomiting 
Oxaliplatin 
Eloxatin 
Antineoplastic agent/cancer 
Papaverine HCl (Intra-
coronary) 
None 
Vasodilator, Coronary/diagnostic 
adjunct 
Pentamidine 
Pentam 
Antifungal/fungal infection (pneumocystis 
pneumonia) 
Pimozide 
Orap 
Antipsychotic/Tourette's Disorder 
Probucol 
Lorelco 
Antilipemic/hypercholesterolemia 
Procainamide 
Pronestyl, Procan 
Antiarrhythmic/abnormal heart rhythm 
Propofol 
Diprivan, Propoven 
Anesthetic, general/anesthesia 
Quinidine 
Quinaglute, Duraquin, Quinact, 
Quinidex, Cin-Quin, Quinora 
Antiarrhythmic/abnormal heart rhythm 
Roxithromycin 
Rulide, Xthrocin, Roxl-150, Roxo, Surlid, 
Rulide, Biaxsig, Roxar, Roximycinv, 
Roxomycin, Rulid, Tirabicin, Coroxin 
Antibiotic/bacterial infection 
Sevoflurane 
Ultane, Sojourn 
Anesthetic, general/anesthesia 
Sotalol 
Betapace, Sotalex, Sotacor 
Antiarrhythmic/abnormal heart rhythm 
Sparfloxacin 
Zagam 
Antibiotic/bacterial infection 
Sulpiride 
Dogmatil, Dolmatil, Eglonyl, Espiride, 
Modal, Sulpor 
Antipsychotic, atypical/schizophrenia 
Sultopride 
Barnetil, Barnotil, Topral 
Antipsychotic, atypical/schizophrenia 
Terfenadine 
Seldane 
Antihistamine/allergic rhinitis 
Terlipressin 
Teripress, Glypressin, Terlipin, 
Remestyp, Tresil, Teriss, and others 
Vasoconsrictor/septic shock 
Terodiline 
Micturin, Mictrol (not bethanechol) 
Muscle relaxant/bladder spasm 
Thioridazine 
Mellaril, Novoridazine, Thioril 
Antipsychotic/schizophrenia 
Vandetanib 
Caprelsa 
Anticancer/cancer (thyroid) 
Revised Text (Amendment 06) 
The website crediblemeds.org/everyone [Accessed: 19 November 2021] lists 4 categories of 
QT-prolonging drugs and may be used as a guide for this protocol. Categories include “Drugs 
with Known TdP Risk”, “Drugs with Possible TdP Risk”, “Drugs with Conditional TdP Risk”, 
and “Drugs to be Avoided by Congenital Long QT Patients”. The investigative site should 
register (under the “For Healthcare Providers” tab) to access these categories.  
Drugs with a known risk of Torsades de Pointes are listed in the table below, and are the only 
category of QT-prolonging drugs that are prohibited in this study. 
Note: The website and table are only to be used as a guideline and are not comprehensive. It is 
the investigator’s responsibility to ensure that any drugs under consideration have not been 
newly identified as causing Torsades de Pointes. 
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TAK-788 
Study No. TAK-788-1003 
Page 128 of 128 
Protocol Incorporating Amendment No.06 
12 January 2022 
Generic Name 
Brand Name 
General Indication a 
Source a 
Cilostazol 
Pletal 
Reduction of symptoms related to 
intermittent claudication. 
Pletal (cilostazol) 
PI 
Droperidol 
Inapsine, Droleptan, 
Dridol, Xomolix 
Inaspsine, Droleptan, Xomolix: 
reduction of PONV. 
Dridol: treatment of 
hypoparathyroidism, refractory 
rickets, and familial 
hypophosphatemia. 
Dridol (droperidol 
for injection) PI 
Levomepromazine 
Nosinan, Nozinan, 
Levoprome 
Supportive treatment for 
terminally ill patients for (1) 
intractable nausea and vomiting, 
(2) management of pain,(3)
restlessness, and distress. 
Levomepromazine 
(Levomepromazine 
Maleate) PI 
Levomethadyl 
acetate 
Orlaam 
For the management of opiate 
dependencies. 
Orlaam 
(levomethadyl 
acetate 
hydrochloride) PI 
Levosulpiride 
Lesuride, Levazeo, 
Enliva (with 
rabeprazole) 
Treatment of various psychiatric 
and GI disorders in accordance 
with the approved label. 
Levosulpiride PI 
Methadone 
Dolophine, Symoron, 
Amidone, Methadose, 
Physeptone, Heptadone 
(1)Treatment of severe pain, (2)
supportive treatment in the 
detoxification of opioid addiction. 
Dolophine 
hydrochloride 
(methadone 
hydrochloride) PI 
Papaverine HCl 
(Intra-coronary) 
None 
For treatment of (1) erectile 
dysfunction, (2) arrhythmias due 
to MI. Prophylaxis for peripheral 
atrial catheter patency. 
Papaverine HCL 
PI 
Probucol 
Lorelco 
Treatment for lowering 
cholesterol. 
Lorelco (probucol) 
PI 
Terlipressin 
Teripress, Glypressin, 
Terlipin, Remestyp, 
Tresil, Teriss, and others 
Treatment of bleeding oesophageal 
varices. 
Teripress 
(teripressin) PI 
Terodiline 
Micturin, Mictrol (not 
bethanechol) 
Muscle relaxant/bladder spasm 
Not available 
Ibogaine 
None 
Not available 
AFIB: atrial fibrillation; AFL: atrial flutter; APL: acute promyelocytic leukemia; EES: erythromycin 
ethylsuccinate; GERD: gastroesophageal reflux disease; GI: gastrointestinal; IBS: irritable bowel syndrome; 
MI: myocardial infarction; PJP: pneumocystis jiroveci pneumonia; PONV: post-operative nausea and 
vomiting; PSVT: paroxysmal supraventricular tachycardia; VF: ventricular fibrillation; VT: ventricular 
tachycardia. 
a Refer to the most current package insert/summary of product characteristics as relevant to the specific 
prescribing agent and region for the approved indication and safety-related dosing guidance. 
Rationale for Amendment 
For consistency across the TAK-788 program. 
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