A Phase 1, Open-Label, Multicenter, Drug-Drug Interaction Study of TAK-788 and Midazolam, a Sensitive CYP3A Substrate, in Patients With Advanced Non-Small Cell Lung Cancer
Phase: PHASE1
Conditions: Carcinoma, Non-Small-Cell Lung, Lung Neoplasms
Sponsor: Millennium Pharmaceuticals, Inc.




Title: A Phase 1, Open-Label, Multicenter, Drug-Drug Interaction Study of TAK-788 and 
Midazolam, a Sensitive CYP3A Substrate, in Patients With Advanced Non–Small Cell Lung 
Cancer
NCT Number: NCT04051827
Protocol Approve Date: 03 September 2020
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
view with a black/blue bar) to protect either personally identifiable information (PPD) or company 
confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal information, or 
to otherwise protect the integrity of the clinical study.

PROTOCOL
A Phase 1, Open-Label, Multicenter, Drug-Drug Interaction Study of TAK-788 and 
Midazolam, a Sensitive CYP3A Substrate, in Patients With Advanced Non–Small Cell 
Lung Cancer
Drug-Drug Interaction Study of TAK-788 and Midazolam in Patients With Advanced Non–
Small Cell Lung Cancer
Sponsor:
Millennium Pharmaceuticals, Inc.*
40 Landsdowne Street
Cambridge, MA 02139 
USA
*Please note: Millennium Pharmaceuticals is a wholly owned subsidiary of Takeda
Pharmaceutical Company Limited and thereafter, any reference to the sponsor will
use Takeda’s name.
Study Number:
TAK-788-1004
EudraCT Number:
2019-000725-44
Compound:
TAK-788 (formerly AP32788)
Date:
03 September 2020
Amendment Number:
2
Amendment History:
Date
Amendment Number
Amendment Type (for use 
in Europe only)
Region
03 September 2020
2
Substantial
Global
03 April 2020
01
Substantial
Global
14 February 2019
Initial Protocol
Not applicable
Global
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TAK-788
Study No. TAK-788-1004
Page 2 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
1.0
ADMINISTRATIVE INFORMATION
1.1
Contacts
A separate contact information list will be provided to each site.
Serious adverse event and pregnancy reporting information is presented in Section 10.0, as is 
information on reporting product complaints.
Takeda Development Center–sponsored investigators per individual country requirements will 
be provided with emergency medical contact information cards to be carried by each patient.
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 study manual.
CCI
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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TAK-788
Study No. TAK-788-1004
Page 3 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
1.2
Approval 
REPRESENTATIVES OF TAKEDA 
This study will be conducted with the highest respect for the individual participants in 
accordance with the requirements of this clinical study protocol and also in accordance with the 
following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Council for Harmonisation E6 (R2) Good Clinical Practice: Consolidated 
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws, clinical 
trial disclosure laws, and regulations.
SIGNATURES
The signature of the responsible Takeda medical officer (and other signatories, as applicable) can 
be found on the signature page.
Electronic signatures may be found on the last page of this document.
CCI
PPD
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TAK-788
Study No. TAK-788-1004
Page 4 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
1.3
Protocol Amendment 2 Summary of Changes
Protocol Amendment 2 Summary and Rationale:
This section describes the changes in reference to the protocol incorporating Amendment 2. The 
primary reasons for this amendment are to:

Update cardiac monitoring based upon recent analysis of cardiac adverse events (AEs) 
reported across TAK-788 program.

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, electronic 
informed consent (eConsent) language, accommodations to allow local disease assessments 
and remote source data verification as an alternative approach for monitoring visits.

Revised management of drug-related diarrhea and inserted a table to improve readability.

Update Appendix E Drugs That Interact With the CYP3A Family of Cytochromes-P450.

Update Appendix F Drugs With a Risk of Torsades de Pointes.
In this amendment, minor grammatical, editorial, formatting, and administrative changes not 
affecting the conduct of the study are included for clarification and administrative purposes only.
Protocol Amendment 2
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 8.6.2 Diarrhea
Added Table 8.e Management of 
Drug-Related Diarrhea.
To update for consistency across the 
TAK-788 program.
Section 8.9 Preparation, 
Reconstitution, and Dispensation
Updated text to include DTP as 
an alternative method for 
dispensing self-administered 
study drug.
To ensure continuity of TAK-788 
treatment due to coronavirus disease 
2019 (COVID-19)-related quarantines, 
cancellations of on-site visits, or 
concerns about possible COVID-19 
exposure.
Section 9.3 Study Procedures
Section 9.3.1 Informed Consent
Section 9.3.12.1 Hematology, 
Clinical Chemistry and Serology
Section 9.3.16 Disease Assessment
Section 9.3.19 Patient Dosing Diary
Section 14.1 Study-Site Monitoring 
Visits
Updated text to include 
alternative methods for 
conducting patient visits and 
collecting data.
To ensure consistent patient monitoring 
and evaluation during the COVID-19 
public health emergency.
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TAK-788
Study No. TAK-788-1004
Page 5 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
Protocol Amendment 2
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 9.3.9 ECG
Appendix A Schedule of Events

Updated text to clarify repeat 
testing and additional 
echocardiograms (ECGs)
may be performed at the 
investigator’s discretion.

Updated ECG assessments 
for Part 2 to C2D1, C4D1, 
C7D1, every 4 cycles 
following C7, and end of
treatment (EOT). 
To update ECG assessments based upon 
recent analysis of cardiac AEs reported 
across TAK-788 program.
Section 9.3.11
Echocardiogram/MUGA Scan for 
Left Ventricular Ejection Fraction
Appendix A Schedule of Events

Added text to clarify 
additional cardiology 
consultation may be done 
during treatment according 
to medical judgment.

Updated echocardiogram 
(ECHO)/multigated 
acquisition (MUGA) scan 
for Part 2 to C2D1, C4D1, 
C7D1 and EOT. 
To update ECHO/MUGA assessments
based upon recent analysis of cardiac 
AEs reported across the TAK-788 
program.
Appendix E Drugs That Interact 
With the CYP3A Family of 
Cytochrome P450 
Updated Appendix E Drugs That 
Interact With the CYP3A Family 
of Cytochromes-P450.
To update for consistency with current 
references. 
Appendix F Drugs With a Risk of 
Torsades de Pointes
Updated Appendix F Drugs With 
a Risk of Torsades de Pointes.
To update for consistency with current 
reference.
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TAK-788
Study No. TAK-788-1004
Page 6 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
INVESTIGATOR AGREEMENT 
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, 
prescribing information, and any other product information provided by the sponsor. I agree to 
conduct this study in accordance with the requirements of this protocol and also to protect the 
rights, safety, privacy, and well-being of study subjects in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Council for Harmonisation, E6 (R2) Good Clinical Practice: Consolidated 
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting serious adverse events defined in Section 10.0 of this 
protocol.

Terms outlined in the clinical study site agreement.

Responsibilities of the investigator (Appendix B).
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix C of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Province)
Location of Facility (Country)
CCI
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TAK-788
Study No. TAK-788-1004
Page 7 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
TABLE OF CONTENTS
1.0
ADMINISTRATIVE INFORMATION ...........................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
1.3
Protocol Amendment 2 Summary of Changes............................................................4
2.0
STUDY SUMMARY ....................................................................................................12
3.0
STUDY REFERENCE INFORMATION ......................................................................17
3.1
Study-Related Responsibilities.................................................................................17
3.2
Coordinating Investigator.........................................................................................17
3.3
List of Abbreviations ...............................................................................................18
3.4
Corporate Identification...........................................................................................19
4.0
INTRODUCTION.........................................................................................................20
4.1
Disease Background ................................................................................................20
4.2
TAK-788 Nonclinical Experience ............................................................................21
4.3
TAK-788 Clinical Experience..................................................................................21
4.4
Rationale for the Proposed Study.............................................................................22
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................22
5.1
Objectives................................................................................................................22
5.1.1
Primary Objective............................................................................................22
5.1.2
Secondary Objective........................................................................................22
5.1.3
5.2
Endpoints.................................................................................................................23
5.2.1
Primary Endpoints ...........................................................................................23
5.2.2
Secondary Endpoints .......................................................................................23
5.2.3
6.0
STUDY DESIGN..........................................................................................................24
6.1
Overview of Study Design.......................................................................................24
6.2
Number of Patients ..................................................................................................27
6.3
Duration of Study ....................................................................................................27
6.3.1
Duration of an Individual Patient’s Study Participation....................................27
6.3.2
End of Study/Study Completion Definition and Planned Reporting..................28
6.3.3
Timeframes for Primary and Secondary Endpoints to Support Disclosures ......28
6.3.4
Total Study Duration .......................................................................................29
6.3.5
Post-Trial Access.............................................................................................29
7.0
STUDY POPULATION................................................................................................30
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TAK-788
Study No. TAK-788-1004
Page 8 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
7.1
Inclusion Criteria .....................................................................................................30
7.2
Exclusion Criteria ....................................................................................................32
8.0
STUDY DRUG .............................................................................................................33
8.1
Study Drug Administration......................................................................................33
8.1.1
Part A Study Dosing ........................................................................................34
8.1.2
Part B Study Dosing ........................................................................................35
8.1.3
Additional Study Dosing Guidance..................................................................35
8.2
Dose Modification Guidelines..................................................................................36
8.2.1
Dose Modifications of TAK-788......................................................................36
8.2.2
Dose Modifications of Midazolam...................................................................37
8.2.3
Re-escalation of TAK-788 Dose After Dose Reduction ...................................37
8.3
Excluded Concomitant Medications and Procedures ................................................37
8.4
Permitted Concomitant Medications and Procedures................................................38
8.5
Precautions and Restrictions ....................................................................................38
8.5.1
TAK-788 .........................................................................................................38
8.5.2
Midazolam.......................................................................................................40
8.6
Management of Selected Treatment-Related Clinical Events....................................40
8.6.1
Nausea and Emesis ..........................................................................................40
8.6.2
Diarrhea...........................................................................................................40
8.6.3
Asymptomatic Lipase/Amylase Elevation........................................................42
8.6.4
Pneumonitis.....................................................................................................42
8.7
Blinding and Unblinding..........................................................................................43
8.8
Description of Investigational Agents ......................................................................43
8.9
Preparation, Reconstitution, and Dispensation..........................................................43
8.10
Packaging and Labeling...........................................................................................43
8.11
Storage, Handling, and Accountability.....................................................................43
9.0
STUDY CONDUCT......................................................................................................44
9.1
Study Personnel and Organizations..........................................................................44
9.2
Arrangements for Recruitment of Patients................................................................44
9.3
Study Procedures.....................................................................................................44
9.3.1
Informed Consent ............................................................................................45
9.3.2
Enrollment.......................................................................................................46
9.3.3
Screening.........................................................................................................46
9.3.4
Patient Demographics......................................................................................46
9.3.5
Medical/Surgical History.................................................................................46
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TAK-788
Study No. TAK-788-1004
Page 9 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
9.3.6
Patient Height and Weight ...............................................................................47
9.3.7
Vital Signs.......................................................................................................47
9.3.8
ECOG Performance Status...............................................................................47
9.3.9
ECG ................................................................................................................47
9.3.10
Physical Examination ......................................................................................47
9.3.11
Echocardiogram/MUGA Scan for Left Ventricular Ejection Fraction...............48
9.3.12
Clinical Laboratory Evaluations.......................................................................48
9.3.13
Pregnancy Test ................................................................................................49
9.3.14
AEs .................................................................................................................50
9.3.15
Concomitant Medications and Procedures........................................................50
9.3.16
Disease Assessment.........................................................................................50
9.3.17
PK Measurements............................................................................................51
9.3.18
9.3.19
Patient Dosing Diary........................................................................................51
9.3.20
End-of-Treatment Assessments........................................................................51
9.3.21
30 Days After Last Dose..................................................................................52
9.4
Completion of Study Treatment (for Individual Patients) .........................................52
9.5
Completion of Study (for Individual Patients)..........................................................52
9.6
Discontinuation of Treatment With Study Drug .......................................................52
9.7
Withdrawal of Patients From Study .........................................................................53
9.8
Study or Site Termination........................................................................................53
10.0
ADVERSE EVENTS ....................................................................................................54
10.1
Definitions...............................................................................................................54
10.1.1
Pretreatment Event Definition..........................................................................54
10.1.2
AE Definition ..................................................................................................54
10.1.3
SAE Definition................................................................................................54
10.2
Procedures for Recording and Reporting AEs and SAEs..........................................55
10.3
Monitoring of AEs and Period of Observation .........................................................56
10.4
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events.........56
10.5
Procedures for Reporting Product Complaints or Medication Errors (Including 
Overdose) ................................................................................................................57
10.6
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities...........57
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................57
12.0
DATA HANDLING AND RECORDKEEPING............................................................57
12.1
eCRFs......................................................................................................................58
12.2
Record Retention .....................................................................................................58
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TAK-788
Study No. TAK-788-1004
Page 10 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
13.0
STATISTICAL METHODS..........................................................................................59
13.1
Statistical and Analytical Plans ................................................................................59
13.1.1
Analysis Sets ...................................................................................................59
13.1.2
Analysis of Demographics and Other Baseline Characteristics.........................60
13.1.3
PK Analysis.....................................................................................................60
13.1.4
Safety Analysis................................................................................................60
13.1.5
Pharmacodynamic Analysis.............................................................................61
13.1.6
13.2
Interim Analysis and Criteria for Early Termination ................................................62
13.3
Determination of Sample Size..................................................................................62
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................62
14.1
Study-Site Monitoring Visits ...................................................................................62
14.2
Protocol Deviations..................................................................................................63
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................63
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................63
15.1
IRB and/or IEC Approval ........................................................................................64
15.2
Subject Information, Informed Consent, and Subject Authorization .........................64
15.3
Subject Confidentiality ............................................................................................66
15.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................66
15.4.1
Publication.......................................................................................................66
15.4.2
Clinical Trial Registration................................................................................66
15.4.3
Clinical Trial Results Disclosure......................................................................67
15.5
Insurance and Compensation for Injury....................................................................67
16.0
REFERENCES..............................................................................................................68
LIST OF IN-TEXT TABLES
Table 6.a
Study Design for Part A (Cycle 1: PK Cycle and Cycle 2 Day 1) .......................26
Table 6.b
Primary and Secondary Endpoints for Disclosures .............................................29
Table 8.a 
Summary of Dose Administration ......................................................................34
Table 8.b
Recommended TAK-788 Dose Reduction Levels...............................................36
Table 8.c
TAK-788 Dose Modification Recommendations for Treatment-Related AEs.....37
Table 8.d
Highly Effective Methods of Contraception and Additional Effective Barrier 
Methods.............................................................................................................39
Table 8.e
Management of Drug-Related Diarrhea..............................................................41
Table 9.a
Clinical Laboratory Tests...................................................................................49
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TAK-788
Study No. TAK-788-1004
Page 11 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
LIST OF APPENDICES
Appendix A
Schedule of Events.............................................................................................70
Appendix B
Responsibilities of the Investigator.....................................................................77
Appendix C
Investigator Consent to Use of Personal Information..........................................79
Appendix D
ECOG Scale for Performance Status ..................................................................80
Appendix E 
Drugs That Interact With the CYP3A Family of Cytochrome P450....................81
Appendix F
Drugs With a Risk of Torsades de Pointes..........................................................83
Appendix G
Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1)................86
Appendix H
Protocol History.................................................................................................89
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TAK-788
Study No. TAK-788-1004
Page 12 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
2.0
STUDY SUMMARY
Name of Sponsor: Millennium Pharmaceuticals, Inc
*Please note: Millennium Pharmaceuticals is a wholly 
owned subsidiary of Takeda Pharmaceutical Company 
Limited and thereafter, any reference to the sponsor will use 
Takeda’s name.
Compound: TAK-788
Title of Protocol: A Phase 1, Open-Label, Multicenter, 
Drug-Drug Interaction Study of TAK-788 and Midazolam, 
a Sensitive CYP3A Substrate, in Patients With Advanced 
Non–Small Cell Lung Cancer
EudraCT No.:
2019-000725-44
Study Number: TAK-788-1004
Phase: 1
Study Design:
This open-label, multicenter, drug-drug interaction study will consist of 2 parts: Part A (Cycle 1: PK Cycle) and Part 
B (Cycle 2 to Cycle 24: Treatment Cycles).
In Part A of the study, a fixed-sequence design over a single 30-day treatment cycle will be used (Cycle 1: PK Cycle 
and Cycle 2 Day1). After screening, eligible patients will be enrolled and will receive a single oral dose of 
midazolam 3 mg on Days 1 and 24 and a single IV dose of midazolam 1 mg as a 5-minute infusion on Days 2 and 
25. Patients will also receive TAK-788 160 mg QD orally on Days 3 through 30. Serial PK blood samples will be 
collected to measure plasma concentrations of midazolam and its metabolite 1-hydroxymidazolam in the absence 
and presence of TAK-788 on study Days 1, 2, 24, and 25. TAK-788 PK blood samples to assess TAK-788 plasma 
concentrations and its active metabolites AP32960 and AP32914 will be collected predose on Days 24, 25, and 26 of 
cycle 1 as well as Day 1 of cycle 2 and postdose on Cycle 1 Day 24.
Further, biomarker blood samples will be collected on Days 1 and 24 predose to measure plasma concentrations of 
4β-hydroxycholesterol and cholesterol, in addition to samples collected to assess for circulating tumor DNA as part 
of Cycle 1, 3, 5, and disease progression assessments. 
After completion of Part A, patients may continue into Part B to  continue treatment with TAK-788 (Cycle 2 to 
Cycle 24: Treatment Cycles). Any patients who are not PK-evaluable due to incomplete PK sample collections in 
Part A will be eligible to continue into Part B.
Part B of the study will consist of 28-day treatment cycles in which patients will continue to receive TAK-788 QD 
for up to 23 months (ie, Cycle 24) or until progressive disease, intolerable toxicity, or another discontinuation 
criterion is met, whichever is sooner.
TAK-788 dose may be reduced based on protocol-defined dose modification guidelines during the study. Safety and 
tolerability will be evaluated during the study by AE monitoring, clinical laboratory tests, vital signs, and physical 
examinations. The study will include a 30-day follow-up period after EOT for reporting of AEs. 
Primary Objectives:
The primary objective of this study is to characterize the effect of repeated oral administration of TAK-788 160 mg 
QD on the single oral- and IV-dose PK of midazolam. 
Secondary Objectives:
The secondary objective of this study is to assess the safety and tolerability of TAK-788 in patients with advanced 
NSCLC.
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TAK-788
Study No. TAK-788-1004
Page 13 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
Subject Population:
Approximately 26 patients ≥18 years with locally advanced or metastatic NSCLC who are refractory or who have 
relapsed to standard available therapies, will be enrolled in this study.
Number of Subjects: 
Approximately 26 patients to achieve approximately 12 PK-
evaluable patients for assessment of the effect of repeated 
doses of TAK-788 on the PK of midazolam. 
Number of Sites: 4 to 6 clinical sites; 
countries/regions are detailed in the study manual.
Dose Level(s):
Part A Cycle 1:
Day 1 and 24: oral midazolam 3 mg.
Day 2 and 25: IV midazolam 1 mg.
Days 3 to 30: oral TAK-788 160 mg QD.
Part B Cycle 2 to 24:
Oral TAK-788 160 mg (in cases of dose adjustments during 
Part A, the optimal tolerated dose from Part A (ie, 80 mg, 
120 mg, or 160 mg OD).
Route of Administration:
Part A: 
Midazolam, IV and oral.
TAK-788, oral.
Part B:
TAK-788, oral.
Duration of Treatment: Cycle 1 to Cycle 24 (patients will 
be treated with TAK-788 until they experience progressive 
disease that requires an alternate therapy in the opinion of 
the investigator, intolerable toxicity, or another 
discontinuation criterion. Treatment with TAK-788 may be 
continued after progressive disease if, in the opinion of the 
investigator, the patient continues to experience clinical 
benefit). 
Period of Evaluation: Screening (14 days prior to 
Cycle 1, Day 1) until 30 days after last day of study 
dosing. 
Main Criteria for Inclusion:
1.
Male or female patients aged ≥18 years.
2.
Histologically or cytologically confirmed locally advanced NSCLC in which the patient is not a candidate for 
definitive therapy; or, the patient has recurrent or metastatic (Stage IV) disease.
3.
Refractory or intolerant to standard available therapies.
4.
Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1.
5.
Minimum life expectancy of 3 months or more.
6.
Adequate organ function as defined by the protocol criteria.
a)
Total serum bilirubin ≤1.5 × upper limit of normal (ULN) (≤3 × ULN for patients with Gilbert syndrome 
or if liver function abnormalities are due to underlying malignancy);
b)
Alanine aminotransferase and aspartate aminotransferase ≤2.5 × ULN (or ≤5 × ULN if liver function 
abnormalities are due to underlying malignancy);
c)
Estimated creatinine clearance ≥30 mL/min (calculated by using the Cockcroft-Gault equation);
d)
Serum albumin ≥2 g/dL; 
e)
Serum lipase ≤1.5 × ULN; and
f)
Serum amylase ≤1.5 × ULN unless the increased serum amylase is due to salivary isoenzymes.
7.
Adequate bone marrow function, as defined by the protocol criteria.
a)
Absolute neutrophil count ≥1.5 × 109/L;
b)
Platelet count ≥75 × 109/L; and
c)
Hemoglobin ≥9.0 g/dL.
8.
Normal QT interval on screening ECG, defined as QTcF of ≤450 msec in males or ≤470 msec in females. (as 
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TAK-788
Study No. TAK-788-1004
Page 14 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
conducted and interpreted in accordance to local institutional practices and confirmed by PI).
9.
All toxicities from prior anticancer therapy must have resolved to ≤Grade 1 according to the NCI CTCAE 
version 5.0 [1], or have resolved to baseline, at the time of first dose of TAK-788. Note: treatment-related Grade 
2 or 3 alopecia and treatment-related Grade 2 peripheral neuropathy are allowed if deemed irreversible. 
10. Female patients who are of childbearing potential, agree to comply with protocol-defined contraception criteria 
or practice true abstinence. 
11. Male patients agree to practice effective barrier contraception during the entire study treatment period and 
through 30 days after the last dose of study drug, or agree to practice true abstinence.
12. If female, a negative serum or urine pregnancy test result during the screening period.
13. Suitable venous access for study-required blood sampling (ie, including for PK, pharmacodynamics, and 
clinical laboratory tests).
14. Willingness and ability to comply with scheduled visits and study procedures.
15. Signed and dated the informed consent indicating that the patient has been informed of all pertinent aspects of 
the study. 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. 
Main Criteria for Exclusion:
1.
Previously received TAK-788.
2.
Received a strong or moderate CYP3A inhibitor or strong or moderate CYP3A inducer within 2 weeks prior to 
the first dose of TAK-788.
3.
Received small-molecule anticancer therapy (including but not limited to cytotoxic chemotherapy and 
investigational agents) within 2 weeks prior to the first dose of TAK-788.
4.
Received antineoplastic monoclonal antibodies including check point inhibitors within 28 days of the first dose 
of TAK-788.
5.
Received radiotherapy ≤14 days prior to the first dose of TAK-788. However, patients are allowed to receive 
any of the following treatments up to 7 days prior to the first dose: (a) Stereotactic radiosurgery (SRS), 
(b) stereotactic body radiation therapy (SBRT), or (c) palliative radiation outside the chest and brain.
6.
Major surgery within 28 days prior to the first dose of TAK-788. Minor surgical procedures, such as catheter 
placement or minimally invasive biopsy, are allowed.
7.
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 another primary 
malignancy and is definitively relapse-free with at least 3 years elapsed since the diagnosis of the other primary 
malignancy.
8.
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.
9.
Current spinal cord compression (symptomatic or asymptomatic and detected by radiographic imaging) or 
leptomeningeal disease (symptomatic or asymptomatic).
10. Have uncontrolled hypertension. Patients with hypertension should be under treatment on study entry to control 
blood pressure.
11. Significant, uncontrolled, or active cardiovascular disease.
12. Treatment with medications known to be associated with the development of torsades de pointes (see Appendix 
F).
13. Current or history of interstitial lung disease, radiation pneumonitis that required steroid treatment, or drug-
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TAK-788
Study No. TAK-788-1004
Page 15 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
related pneumonitis. 
14. Ongoing or active infection including, but not limited to, the requirement for IV antibiotics, or a known history 
of human immunodeficiency virus infection. Testing is not required in the absence of history. Patients who are 
positive for hepatitis B surface antigen or anti-hepatitis C virus antibody may be eligible (see full protocol for 
further details).
15. Gastrointestinal illness or disorder that could affect oral absorption of TAK-788 or midazolam.
16. If female, the patient is lactating and breastfeeding. Female patients who are lactating will be eligible if they
discontinue breastfeeding.
17. History of, or suspected, hypersensitivity or allergy to midazolam or its excipients or TAK-788.
18. 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 study drug.
19. Admission or evidence of illicit drug use, drug abuse, or alcohol abuse. 
Main Criteria for Evaluation and Analyses:
The primary endpoints of the study include, but are not limited to the following midazolam PK parameters after oral 
or IV administration in the presence and absence of TAK-788:
Primary Endpoints

The geometric mean ratios and 90% CI of Cmax and AUC∞for midazolam administered orally with TAK-788 
and when orally administered as midazolam alone.

The geometric mean ratios and 90% CI of Cmax and AUC∞for midazolam administered intravenously with 
TAK-788 and when intravenously administered as midazolam alone.
Secondary Endpoints
The secondary endpoints of the study encompass the safety profile of TAK-788 and are as follows:

AEs.

Clinical laboratory tests (hematology and clinical chemistry).

Vital signs.
Statistical Considerations:
For the estimation of the effect of TAK-788 on oral and IV midazolam PK, the ratios of geometric mean midazolam 
AUC∞and Cmax (to be measured both with vs without TAK-788 coadministration) and the associated 2-sided 90% 
CIs will be calculated on the basis of the within-patient variance using a mixed-effects analysis of variance 
(ANOVA) fitting terms for treatment (midazolam with or without TAK-788 coadministration). The patient will be 
treated as a random effect in the model. After log transformation, AUC∞and Cmax will be separately analyzed. Point 
estimates and adjusted 90% CIs for the difference in treatment will be calculated and then exponentially back-
transformed to provide point and CI estimates for the ratios of interest.
No interim analysis is planned.
PK-Evaluable Population
Patients will be considered PK-evaluable if they meet all of the following criteria during study Part A, Cycle 1: 
1.
Received the protocol-specified dosing regimen without dose reductions prior to Day 26. 
2.
Experienced no dose interruptions within 1 week prior to Day 24.
3.
Experienced no more than 1 day of dose interruption within the first 14 days of TAK-788 treatment.
4.
Did not receive any excluded concomitant medications through the completion of PK sampling (Day 26).
5.
There is sufficient midazolam concentration-time data to permit the reliable estimation of PK parameters by 
noncompartmental analysis methods.
Assessment of the PK-evaluable population will be conducted when dosing and safety (ie, vomiting) data become 
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TAK-788
Study No. TAK-788-1004
Page 16 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
available and prior to study closure.
PK and Pharmacodynamics Analyses 
In Part A (Cycle 1: PK Cycle), oral and IV PK parameters (including but not limited to AUC∞, Cmax, and tmax) of 
midazolam and 1 hydroxymidazolam in the presence and absence of TAK-788 will be summarized using descriptive 
statistics. 
The oral bioavailability of midazolam and the 1-hydroxymidazolam to midazolam AUC ratios following IV and oral 
midazolam dosing will be descriptively summarized, in the absence and presence of TAK-788.
Plasma concentrations and PK parameters of TAK-788 and its active metabolites AP32960 and AP32914 will be 
listed by patient and summarized using descriptive statistics. 
Safety Analyses
Safety will be evaluated by the incidence of AEs, severity and type of AEs, and by changes from baseline in the 
patient’s clinical laboratory results, weight, and vital signs. Exposure to study drug and reasons for discontinuation 
will be tabulated. TEAEs that occur after administration of the first dose of any study drug and through 30 days after 
the last dose of TAK-788 will be tabulated.
Additional safety analyses may be performed to most clearly enumerate rates of toxicities and to further define the 
safety profile of TAK-788. 
Sample Size Justification: 
It is anticipated that approximately 26 patients will be enrolled in this study to obtain approximately 
12 PK-evaluable patients. The sample size calculation was based on the expected 2-sided 90% CI for the difference 
in the paired, log-transformed AUC∞mean values for midazolam in the absence and presence of TAK-788.
 
Assuming that the AUC∞ratio for midazolam in the presence versus absence of TAK-788 is 1, with a sample size of 
12, the 90% CI for the AUC∞ratio is expected to be 0.82 to 1.23 on the basis of the variance assumptions. Assuming 
that the AUC∞ratio for midazolam in the presence versus absence of TAK-788 is X, with a sample size of 12, the 
90% CI for the AUC∞ratio is expected to be 0.82X to 1.23X on the basis of the variance assumptions.
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TAK-788
Study No. TAK-788-1004
Page 17 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
3.0
STUDY REFERENCE INFORMATION
3.1
Study-Related Responsibilities
The sponsor will perform all study-related activities with the exception of those identified in the 
clinical supplier list in the study manual. The identified vendors 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 drug, 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.
CCI
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TAK-788
Study No. TAK-788-1004
Page 18 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
3.3
List of Abbreviations
AE
adverse event 
AUC
area under the plasma concentration-time curve 
AUC∞
area under the plasma concentration-time curve from time 0 to infinity
AUCt
area under the plasma concentration-time curve from time 0 to time
Cmax
maximum observed plasma concentration
CNS
central nervous system 
COVID-19
coronavirus disease 2019
eCRF
electronic case report form 
CR
complete response 
CRO
contract research organization 
CSR
clinical study report
CT
computed tomography 
CYP
cytochrome P450
DCR
disease control rate 
DLT
dose-limiting toxicity
DOR
duration of response 
DTP
direct-to-patient
ECG
electrocardiogram 
ECHO
echocardiogram
ECOG
Eastern Cooperative Oncology Group 
eConsent
electronic informed consent
EDC
electronic data capture 
EGFR
epidermal growth factor receptor 
EMA
European Medicines Agency 
EOT
end of treatment 
FDA
[United States] Food and Drug Administration 
GCP
Good Clinical Practice 
HER2
human epidermal growth factor 2 
ICF
informed consent form 
ICH
International Council for Harmonisation 
IEC
independent ethics committee 
IRB
institutional review board 
IV
intravenous 
L858R
Leu858Arg 
LVEF
left ventricular ejection fraction
MedDRA
Medical Dictionary for Regulatory Activities 
MHRA
Medicines and Healthcare products Regulatory Agency 
MRI
magnetic resonance imaging 
MUGA
multigated acquisition scan
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TAK-788
Study No. TAK-788-1004
Page 19 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events 
NSCLC
non–small cell lung cancer 
PD
progressive disease 
PFS
progression-free survival
PK
pharmacokinetics
PMDA
Pharmaceuticals and Medical Devices Agency of Japan 
PO
oral administration 
PR
partial response 
QD
once daily
RECIST
Response Evaluation Criteria in Solid Tumors 
RP2D
recommended phase 2 dose 
SAE
serious adverse event 
SBRT
stereotactic body radiation therapy 
SD
stable disease 
SRS
stereotactic radiosurgery 
SUSAR
suspected unexpected serious adverse reaction 
TEAE
treatment-emergent adverse events 
TKI
tyrosine kinase inhibitors 
tmax
time of first occurrence of maximum observed concentration 
ULN
upper limit of the normal range
UK
United Kingdom
US
United States
WHO
World Health Organization
WT
wild-type 
3.4
Corporate Identification 
Millennium
Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda 
Pharmaceutical Company Limited
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TAK-788
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Page 20 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
4.0
INTRODUCTION
4.1
Disease Background
Specific genetic alterations 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% to 
40% of patients with non–small cell lung cancer (NSCLC) [7,8]. 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 (WT) EGFR in normal tissues is associated with dose-limiting 
toxicities (DLTs), substantial clinical benefit has generally been associated with TKIs that inhibit 
specific, activated variants of EGFR more potently than they inhibit WT EGFR.
The most common activating mutations in EGFR are in-frame deletions in exon 19 and a 
Leu858Arg (L858R) substitution in exon 21, together accounting for about 90% of all 
EGFR-activating mutations [9]. Erlotinib and gefitinib (“first generation” EGFR TKIs), as well 
as afatinib (a “second generation” EGFR TKI), potently inhibit these mutants in vitro and induce 
high response rates of about 60% to 70% in patients with these mutations [10]. Although these 
TKIs are approved for use in patients with these specific mutations, their clinical efficacy is 
ultimately limited by the development of resistance, such as by mutation of the EGFR kinase 
domain gatekeeper residue (T790M), which occurs in 50% of patients [11,12]. Osimertinib has 
recently been approved in patients with common mutations as the firstline treatment option, 
following the first approval in patients with metastatic EGFR T790M mutation–positive NSCLC 
and who have progressed on or after EGFR TKI therapy [5,6].
For erlotinib and gefitinib, high response rates have largely been restricted to patients with the 
most common activating mutants; however, preliminary results with afatinib suggest that 
relatively high response rates are also achieved in patients with a second class of activating 
mutants, so-called “uncommon” mutants, such as those occurring at other amino acids in 
exons 19 and 21 (eg, G719 and L861) [13]. Afatinib was recently approved by the Food and 
Drug Administration (FDA) for a broadened indication in first-line treatment of patients with
metastatic NSCLC whose tumors have nonresistant EGFR mutations to include patients whose 
tumors harbor uncommon mutations, such as L861Q, G719X, and S768I [14].
The final class of EGFR-activating mutations, known as exon 20 insertions, account for 
approximately 9% of EGFR-mutant NSCLC [15]. Unlike mutations in exons 19 or 21, almost all 
EGFR exon 20 insertions confer in vitro and primary clinical resistance to the 4 approved EGFR 
TKIs erlotinib, gefitinib, afatinib and osimertinib [13,16,17]. Patients with NSCLC containing 
EGFR exon 20 insertions exhibit clinical characteristics similar to those carrying common EGFR 
mutations (eg, young, nonsmoker, with adenocarcinoma subtype) [18], consistent with potential 
roles as driver mutations that could confer benefit to targeted therapy. In summary, while 
erlotinib, gefitinib, afatinib, dacomitinib, and osimertinib are approved by the FDA for use in 
patients with NSCLC containing common activating mutations in EGFR (ie, exon 19 deletions 
and L858R substitutions) and afatinib was recently approved by the FDA for a broadened 
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TAK-788
Study No. TAK-788-1004
Page 21 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
indication that includes the uncommon EGFR mutations, such as L861Q, G719X, and S768I, no 
targeted therapies are approved for patients with EGFR exon 20 insertions.
Human epidermal growth factor 2 (HER2) mutations, typically consisting of in-frame insertions 
in exon 20, have also been identified as potential oncogenic drivers in 2% to 4% of patients with 
NSCLC. These patients exhibit clinical characteristics similar to patients with EGFR mutations 
[19-21]. Currently, no therapies are approved for use in patients with NSCLC who have 
HER2-activating mutations.
To address limitations of existing therapies targeting EGFR and HER2, the sponsor is developing 
TAK-788 (formerly AP32788), a novel, synthetic, orally-administered TKI.
4.2
TAK-788 Nonclinical Experience
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 WT EGFR, suggesting it may have the selectivity necessary to achieve levels of 
exposure required to inhibit all activated forms of these kinases.
Further information on the nonclinical properties of TAK-788 can be found in the current 
Investigator’s Brochure.
4.3
TAK-788 Clinical Experience
Study AP32788-15-101 is an ongoing first-in-human, open-label, multicenter study to determine 
the recommended phase 2 dose (RP2D) of TAK-788, in addition to the clinical safety,
tolerability, and antitumor activity of TAK-788. The trial is being conducted in 3 parts: a 
dose-escalation phase (3+3 design) (Part 1), followed by an expansion phase with the RP2D 
(Part 2) and a pivotal extension phase after early proof-of-concept and confirmation of the RP2D 
(Part 3). 
As of the 21 March 2018 data cut-off, a total of 57 patients have been treated with 8 different 
once-daily (QD) doses and 2 different twice daily doses evaluated. Median age of enrolled 
patients was 61 years, with 97% having received 2 or more prior anticancer therapies. The 
majority of patients (68%) had an EGFR exon 20 insertion mutation. All 6 patients (100%) in the 
160 mg QD cohort had EGFR exon 20 insertion mutations. 
Treatment-emergent adverse events (TEAEs) occurred in 96.5% of patients in the full analysis 
set and 97.0% of patients in the dose cohorts that received 80, 120, or 160 mg TDD. The TEAEs 
by System Organ Class that occurred in ≥50% of patients in the dose cohorts that received 80, 
120, or 160 mg TDD were gastrointestinal disorders (84.8%) and skin and subcutaneous tissue 
disorders (63.6%) (data on file). A total of 5 DLTs were observed in Part 1 of the study. The 
DLTs included 2 events of pneumonitits (one event was Grade 3, the other Grade 5); 1 event of 
Grade 3 diarrhoea, and 1 event whereby 25% of planned dosing was missed due to TEAEs 
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TAK-788
Study No. TAK-788-1004
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Protocol Incorporating Amendment No. 2
03 September 2020
(Grade 2 diarrhea, fatigue, and dehydration). Nine patients (15.8%) in the full analysis set died 
due to a TEAE, with 8 of the deaths occurring in patients receiving 40 mg QD or less of 
TAK-788, and were due to lung cancer related reasons. Within the 80 mg, 120 mg and 160 mg 
TDD group, 40% of patients (6 of 15) with EGFR exon 20 insertion mutations had an objective 
response; 93% (14 of 15 patients) within this group experienced disease control. In the 160 mg 
QD cohort, 2 of 3 patients (67%) with EGFR exon 20 insertion mutations had an objective 
response, with 100% experiencing disease control.
In summary, in Study AP32788-15-101, TAK-788 was generally well tolerated, and preliminary
anticancer activity was observed in patients with EGFR exon 20 insertion-positive NSCLC who 
had been previously treated.
4.4
Rationale for the Proposed Study
Data from in vitro induction studies have indicated concentration-dependent cytochrome P450 
(CYP) 3A4 induction by TAK-788 and its 2 active metabolites, AP32960 and AP32914. In 
addition, TAK-788 clinical pharmacokinetic (PK) data from the 160 mg QD regimen in the 
AP32788-15-101 study indicated autoinduction of the apparent oral clearance of TAK-788 
following multiple-dose administration, likely via induction of CYP3A. It is well known that 
CYP3A subfamily enzymes are a major determinant of first-pass and systemic drug clearance in 
humans for drugs that are mainly cleared via hepatic metabolism. Therefore, this study is 
designed to evaluate the effect of repeat-dose administration of TAK-788 on the single oral- and 
intravenous (IV)-dose PK of midazolam, a sensitive CYP3A probe substrate, to determine 
whether TAK-788, 160 mg QD, produces clinically meaningful CYP3A induction in humans, 
and, if so, to inform strategies to manage potential drug-drug interactions between TAK-788 and 
coadministered CYP3A substrates.
5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objective
The primary objective of this study is to characterize the effect of repeated oral administration of 
TAK-788 160 mg QD on the single oral- and IV-dose PK of midazolam.
5.1.2
Secondary Objective
The secondary objective of this study is to assess the safety and tolerability of TAK-788 in 
patients with advanced NSCLC.
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TAK-788
Study No. TAK-788-1004
Page 23 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
5.2
Endpoints
5.2.1
Primary Endpoints
The primary endpoints of this study are midazolam PK parameters in the presence and absence 
of TAK-788, to include the following:

The geometric mean ratios and 90% CI of Cmax and AUC∞ for midazolam administered orally
with TAK-788 and when orally administered as midazolam alone. 

The geometric mean ratios and 90% CI of Cmax and AUC∞ for midazolam administered 
intravenously with TAK-788 and when intravenously administered as midazolam alone.
5.2.2
Secondary Endpoints
The secondary endpoints of the study to assess the safety and tolerability TAK-788, are as 
follows:

Adverse events (AEs).

Clinical laboratory tests (hematology, and clinical chemistry).

Vital signs.
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TAK-788
Study No. TAK-788-1004
Page 24 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
6.0
STUDY DESIGN
6.1
Overview of Study Design
This phase 1, open-label, multicenter, drug-drug interaction study will consist of 2 parts: Part A 
(Cycle 1: PK cycle) and Part B (Cycle 2 to Cycle 24: Treatment Cycles). The patient population 
will consist of adult patients with locally advanced or metastatic NSCLC that is refractory to 
standard available therapies. It is expected that approximately 26 patients will be enrolled in the 
study.
In Part A of the study, a fixed-sequence design over a single 30-day duration including 28 days 
of treatment with TAK-788 will be used (Cycle 1: PK Cycle and Cycle 2 Day 1) (Table 6.a). 
After screening, eligible patients will be enrolled and will receive a single oral dose of 
midazolam 3 mg on Day 1 and Day 24 and a single IV dose of midazolam 1 mg as a 5-minute 
infusion on Day 2 and Day 25. Patients also will receive TAK-788 160 mg QD orally on Days 3 
through Day 30 (see Table 8.a for standard dosing, and Table 8.b and Table 8.c for dose 
adjustments). Serial PK blood samples will be collected to measure plasma concentrations of 
midazolam and its metabolite 1-hydroxymidazolam in the absence and presence of TAK-788. In 
addition, TAK-788 PK blood sample will be collected prior dosing on Cycle 1 Day 24, 25, 26 
and Cycle 2 Day 1 and post dosing on Day 24 to assess TAK-788 plasma concentrations and its 
active metabolites AP32960 and AP32914 Table 6.a. Further, biomarker blood samples will be 
collected on Days 1 and 24 prior to dosing, to measure plasma concentrations of 
4β-hydroxycholesterol and cholesterol, in addition circulating tumor DNA sampling which will 
be collected as part of assessments during Cycles 1, 3, and 5, and at the time of progressive 
disease assessments. (see Table 6.a).
PK-Evaluable Population
Patients will be considered PK-evaluable if they meet all of the following criteria during study
Part A, Cycle 1: 
1. Received the protocol-specified dosing regimen without dose reductions prior to Day 26. 
2. Experienced no dose interruptions within one week prior to Day 24.
3. Experienced no more than 1 day of dose interruption within the first 14 days of TAK-788 
treatment.
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TAK-788
Study No. TAK-788-1004
Page 25 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
4. Did not receive any excluded concomitant medications through the completion of PK 
sampling (Day 26).
Assessment of the PK-evaluable population will be conducted when dosing and safety (ie, 
vomiting) data become available and prior to study closure.
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TAK-788
Study No. TAK-788-1004
Page 26 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
CONFIDENTIAL
Table 6.a
Study Design for Part A (Cycle 1: PK Cycle and Cycle 2 Day 1)
Study Day
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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C2
D1
Midazolam
3 mg PO a
X
X
Midazolam 
1 mg IV
X
X
TAK-788
160 mg 
dosing
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PK Blood 
Samples b
X
X
X
X
X
X
X
Cholesterol 
Blood 
Samples d
X
X
C: cycle; D: day; IV: intravenous; PK: pharmacokinetic; PO: oral.
Pre- and postflushing information is provided in the pharmacy manual.
a A detailed PK blood sampling schedule for midazolam is provided in Appendix A Table A-2.
b To measure plasma concentrations of midazolam and its metabolite 1-hydroxymidazolam, blood samples will be collected predose and over 24 hours after the 
oral dose on Days 1 and 24 and predose and over 24 hours after the IV dose on Days 2 and 25. To measure trough plasma concentrations of TAK-788 and its 
active metabolites AP32960 and TAK-914, PK blood samples will be collected predose on Days 24, 25, and 26 of Cycle 1 as well as Cycle 2 Day 1. In addition, 
serial PK blood samples will be collected over 24 hours postdose on Day 24 to measure plasma concentrations of TAK-788, AP32960, and AP32914.
c A
d A cholesterol blood sample will be collected predose on Days 1 and 24 to measure plasma concentrations of 4β-hydroxycholesterol and cholesterol.
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TAK-788
Study No. TAK-788-1004
Page 27 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
After completion of Part A, patients may continue into Part B to continue treatment with
TAK-788 (Cycle 2 to Cycle 24: Treatment Cycles). Any patients who are not PK-evaluable in 
Part A may be eligible to continue into Part B.
Part B of the study will consist of 28-day treatment cycles in which patients will continue to 
receive TAK-788 until completion of Cycle 24, or until progressive disease (PD), intolerable 
toxicity, or another discontinuation criterion is met, whichever is sooner.
During each treatment cycle, the TAK-788 dose may be reduced based on dose modification 
guidelines to 120, or 80 mg QD in patients who do not tolerate the 160 mg dose (see 
Section 8.2). However, any patient who experiences dose reduction prior to Day 26 in Part A 
Cycle 1 will not be considered as a PK-evaluable patient. The study will include a 30-day
follow-up period after EOT. Safety and tolerability will be evaluated during the study by AE 
monitoring, clinical laboratory tests, vital signs, and physical examinations until 30 days after 
EOT. Toxicity will be evaluated according to National Cancer Institute Common Terminology
Criteria for Adverse Events (NCI CTCAE), version 5.0 [1].
. 
Additional details regarding the timing of study procedures are provided in the Schedule of 
Study Events (Appendix A Table A-1 for Part A and Table A-3 for Part B).
6.2
Number of Patients
Approximately 26 patients with locally advanced or metastatic NSCLC will be enrolled in this 
study from 4 to 6 clinical sites to achieve approximately 12 PK-evaluable patients for assessment 
of the effect of repeated doses of TAK-788 on the PK of midazolam. Study regions will be 
provided in the study manual.
6.3
Duration of Study
6.3.1
Duration of an Individual Patient’s Study Participation
The PK cycle in Part A will be completed after patients finish a single 30-day cycle. Following 
PK cycle in Part A, patients may enter Part B and continue daily treatment with TAK-788 in 
28-day repeated treatment cycles until completion of Cycle 24, or until PD, intolerable toxicity,
or another discontinuation criterion is met. Treatment with TAK-788 may be continued after PD 
if, in the opinion of the investigator, the patient continues to experience clinical benefit. Patients 
will have an assessment at 30 days after treatment discontinuation.
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Study No. TAK-788-1004
Page 28 of 91
Protocol Incorporating Amendment No. 2
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The maximum duration of study participation for an individual patient will be approximately 
26 months (which includes the screening period, the Part A PK cycle, a maximum of 23 cycles in 
Part B, and the 30-day follow-up period after EOT).
6.3.2
End of Study/Study Completion Definition and Planned Reporting
6.3.2.1
Study Duration
6.3.2.1.1
Primary Study Duration
The estimated time frame for primary completion of the study is 13 to 15 months, which includes 
an estimated 12- to 14-month enrollment period and the PK Cycle in Part A of the study. 
Analyses for the primary and exploratory endpoints, except antitumor activity, will be conducted 
after 12 PK-evaluable patients complete Part A of the study, at which time, the CSR will be 
developed and include an analyses of PK and safety. Assessment of the PK-evaluable population 
will be conducted when dosing and safety (ie, vomiting) data become available and prior to study 
closure.
Other Planned Analyses
A CSR addendum for exploratory efficacy and additional safety is planned when all enrolled 
patients have completed Part B of the study (approximately 2 years after enrollment of the last 
patient).
The total duration of the study is anticipated to be up to approximately 3 years, including the 
enrollment period, Part A PK cycle, Part B treatment cycles, and follow-up period.
6.3.3
Timeframes for Primary and Secondary Endpoints to Support Disclosures
Please refer to Table 6.b for disclosure information for the primary and secondary endpoints.
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TAK-788
Study No. TAK-788-1004
Page 29 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
Table 6.b
Primary and Secondary Endpoints for Disclosures
Definition
Maximum Time Frame (For an 
Individual Patient)
Primary Endpoints
Midazolam AUC∞.
Area under the concentration-time 
curve from time 0 to infinity. 
From predose up to 24 hours after the 
oral dose on Days 1 and 24 and from 
predose up to 24 hours after the IV 
dose on Days 2 and 25, for a total 
time frame of 26 days.
Midazolam Cmax.
Maximum observed concentration.
Midazolam tmax.
Time of first occurrence of Cmax.
Secondary Endpoints
AEs. 
See Section 10.1.2 and 10.1.3.
From the first dose of study drug 
through the 30-day follow-up period,
for a total time frame of up to 
approximately 25 months.
Clinical laboratory tests 
(hematology, and clinical 
chemistry).
See Table 9.a.
From the first dose of study drug 
through the 30-day follow-up period, 
for a total time frame of up to 
approximately 25 months.
Vital signs.
DBP, SBP, heart rate, respiratory rate, 
and body temperature.
From the first dose of study drug 
through the 30-day follow-up period, 
for a total time frame of up to 
approximately 25 months.
AE: adverse event; DBP: diastolic blood pressure; IV: intravenous; SBP: systolic blood pressure.
6.3.4
Total Study Duration
Part A will consist of a single 30-day PK cycle. Part B will consist of repeated 28-day treatment 
cycles for up to 23 cycles of treatment (24 cycles in total, including Part A), or until PD, 
intolerable toxicity, or another discontinuation criterion. Treatment with TAK-788 may be 
continued after PD if, in the opinion of the investigator, the patient continues to experience 
clinical benefit. The total duration of the study is anticipated to be up to approximately 3 years, 
including the enrollment period, Part A PK cycle, Part B treatment cycles, and follow-up period.
6.3.5
Post-Trial Access
The clinical study database will be closed approximately 2 years after the last patient has been 
enrolled in the study. Patients will be allowed to continue treatment 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.
Continued access to TAK-788 for patients 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. Post-trial access may be terminated in a country or 
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TAK-788
Study No. TAK-788-1004
Page 30 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
geographical region where marketing authorization has been rejected, the development of 
TAK-788 has been suspended or stopped by the sponsor, or TAK-788 can no longer be supplied.
7.0
STUDY POPULATION
Approximately 26 patients with locally advanced or metastatic NSCLC who are refractory or 
who have relapsed to standard therapies and meet all protocol-defined eligibility criteria, will be 
enrolled in this study.
7.1
Inclusion Criteria
Each patient must meet all the following inclusion criteria to be enrolled in the study:
1. Male or female patients aged ≥18 years.
2. Histologically or cytologically confirmed locally advanced NSCLC in which the patient is 
not a candidate for definitive therapy; or, the patient has recurrent, or metastatic (Stage IV) 
disease.
3. Refractory or intolerant to standard available therapies.
4. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1.
5. Minimum life expectancy of 3 months or more.
6. Adequate organ function as defined by the following criteria:
a) Total serum bilirubin ≤1.5 × upper limit of normal (ULN) (≤3 × ULN for patients with 
Gilbert syndrome or if liver function abnormalities are due to underlying malignancy);
b) Alanine aminotransferase and aspartate aminotransferase ≤2.5 × ULN (or ≤5 × ULN if 
liver function abnormalities are due to underlying malignancy);
c) Estimated creatinine clearance ≥30 mL/min (calculated by using the Cockcroft-Gault 
equation);
d) Serum albumin ≥2 g/dL; and
e) Serum lipase ≤1.5 × ULN; and
f)
Serum amylase ≤1.5 × ULN unless the increased serum amylase is due to salivary 
isoenzymes.
7. Adequate bone marrow function as defined by the following criteria:
a) Absolute neutrophil count ≥1.5 × 109/L;
b) Platelet count ≥75 × 109/L; and
c) Hemoglobin ≥9.0 g/dL.
8. Normal QT interval on screening ECG, defined as QTcF of ≤450 msec in males or 
≤470 msec in females. (as conducted and interpreted in accordance to local institutional 
practices and confirmed by PI).
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TAK-788
Study No. TAK-788-1004
Page 31 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
9. All toxicities from prior anticancer therapy must have resolved to ≤Grade 1 according to the 
NCI CTCAE version 5.0 [1], or have resolved to baseline, at the time of first dose of 
TAK-788. Note: treatment-related Grade 2 or 3 alopecia and treatment-related Grade 2 
peripheral neuropathy are allowed if deemed irreversible.
10. Female patients who:
a) Are postmenopausal for at least 1 year before the screening visit, or
b) Are surgically sterile, or
c) If they are of childbearing potential, agree to practice 1 highly effective, nonhormonal 
method of contraception and 1 additional effective (barrier) method at the same time, 
from the time of signing the informed consent through 30 days after the last dose of study
drug (see Table 8.d), or
d) Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, 
postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are 
not acceptable methods of contraception. Female and male condoms should not be used 
together).
11. Male patients, even if surgically sterilized (ie, status postvasectomy), who:
a) Agree to practice effective barrier contraception during the entire study treatment period 
and through 30 days after the last dose of study drug (Table 8.d), or
b) Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, 
postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are 
not acceptable methods of contraception. Female and male condoms should not be used 
together).
12. If female, a negative serum or urine pregnancy test result during the screening period.
13. Suitable venous access for study-required blood sampling (ie, including for PK, 
pharmacodynamics, and clinical laboratory tests).
14. Willingness and ability to comply with scheduled visits and study procedures.
15. Signed and dated the informed consent indicating that the patient has been informed of all
pertinent aspects of the study. 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.
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TAK-788
Study No. TAK-788-1004
Page 32 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
7.2
Exclusion Criteria
Patients meeting any of the following exclusion criteria are not to be enrolled in the study.
1. Previously received TAK-788.
2. Received a strong or moderate CYP3A inhibitor or strong or moderate CYP3A inducer 
within 2 weeks prior to the first dose of TAK-788.
3. Received small-molecule anticancer therapy (including but not limited to cytotoxic 
chemotherapy and investigational agents) within 2 weeks prior to the first dose of TAK-788.
4. Received antineoplastic monoclonal antibodies including check point inhibitors within 
28 days of the first dose of TAK-788.
5. Received radiotherapy ≤14 days prior to the first dose of TAK-788. However, patients are 
allowed to receive any of the following treatments up to 7 days prior to the first dose: (a) 
Stereotactic radiosurgery (SRS), (b) stereotactic body radiation therapy (SBRT), or (c) 
palliative radiation outside the chest and brain.
6. Major surgery within 28 days prior to the first dose of TAK-788. Minor surgical procedures, 
such as catheter placement or minimally invasive biopsy, are allowed.
7. 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 another primary malignancy and is definitively relapse-free with at least 
3 years elapsed since the diagnosis of the other primary malignancy.
8. 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.
9. Current spinal cord compression (symptomatic or asymptomatic and detected by
radiographic imaging) or leptomeningeal disease (symptomatic or asymptomatic).
10. Have uncontrolled hypertension. Patients with hypertension should be under treatment on 
study entry to control blood pressure.
11. Significant, uncontrolled, or active cardiovascular disease, including, but not limited to the 
following:
a) Myocardial infarction within 6 months prior to the first dose of study drug;
b) Unstable angina within 6 months prior to the first dose of study drug;
c) Congestive heart failure within 6 months prior to the first dose of study drug. Cardiac 
ejection fraction <50% by echocardiogram (ECHO) or multigated acquisition (MUGA) 
scan;
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TAK-788
Study No. TAK-788-1004
Page 33 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
d) History of clinically significant (as determined by the treating physician) atrial 
arrhythmia;
e) Any history of ventricular arrhythmia; or
f)
Cerebrovascular accident or transient ischemic attack within 6 months prior to the first 
dose of study drug.
12. Treatment with medications known to be associated with the development of torsades de 
pointes (see Appendix F).
13. Current or history of interstitial lung disease, radiation pneumonitis that required steroid 
treatment, or drug-related pneumonitis.
14. Ongoing or active infection including, but not limited to, the requirement for IV antibiotics, 
or a known history of human immunodeficiency virus infection. Testing is not required in the 
absence of history.
Patients who are positive for hepatitis B surface antigen can be enrolled if hepatitis B virus 
DNA is below 1000 copies/mL in the plasma. Patients who are positive for anti-hepatitis C 
virus antibody can be enrolled but must not have detectable hepatitis C virus RNA in the 
plasma.
15. Gastrointestinal illness or disorder that could affect oral absorption of TAK-788 or 
midazolam.
16. If female, the patient is lactating and breastfeeding. Female patients who are lactating will be 
eligible if they discontinue breastfeeding.
17. History of, or suspected, hypersensitivity or allergy to midazolam or its excipients or TAK-
788.
18. 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 study drug.
19. Admission or evidence of illicit drug use, drug abuse, or alcohol abuse.
NOTE: In accordance with local institutional practice, patients will be monitored for any
signs or symptoms associated with alcohol or illicit drug abuse. PIs should advise subject to 
avoid excessive alcohol consumption while enrolled in this study. Medical use of cannabis is 
allowed, if it is legal where the patient resides and no alternative treatment is available, on 
the basis of case by-case review and agreement by the medical monitor.
8.0
STUDY DRUG
8.1
Study Drug Administration
All protocol-specified criteria for administration of study drug must be met and documented 
before drug administration. Study drug will be administered or dispensed only to eligible patients 
under the supervision of the investigator or identified subinvestigators. A summary of
assessments and procedures are provided in Table A-1 (for Part A), and Table A-3 (for Part B), 
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TAK-788
Study No. TAK-788-1004
Page 34 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
with dose adjustments guidelines outlined in Table 8.b and Table 8.c; in addition, PK and 
biomarker assessments for Part A are provided in Table A-2. A summary of study drug 
administration is provided in this section, additional details on dosing administration and 
procedures are provided in study manual. 
On Day 1 of Part A (Cycle 1: PK Cycle), all eligible enrolled patients will report to the clinic and 
receive an oral dose of midazolam 3 mg in accordance with dose administration guidance 
outlined in Table 8.a.
Table 8.a
Summary of Dose Administration
Part A Midazolam Administration a, b
Day 1 and 24
Dose: 3 mg PO with approximately 8 ounces (240 mL) of water on an empty stomach
(defined as fasting for 2 hours prior to dosing and 2 hours after dosing; subjects may not 
consume water during the fasting period except during dose administration).
NOTE: On Day 24, TAK-788 should be administered immediately after oral midazolam 
administration. Total water intake for both midazolam and TAK-788 dosing should be 
approximately 8 ounces (240 mL) of water on an empty stomach.
Day 2 and 25 
Dose: 1 mg IV (with or without food).
NOTE: Refer to Part A TAK-788 administration for further guidance on co-administration.
Part A TAK-788 Administration a 
Day 3 to 30 
Except Day 24
Dose: 160 mg daily.
Administer with approximately 8 ounces (240 mL) of water with or without a low-fat meal 
(ie, ≤350 calories and ≤15% of calories from fat).
Days 24, 25
Dose: 160 mg daily.
TAK-788 is to be taken immediately after midazolam administration (on Day 24, immediately 
after oral administration of midazolam with total 240 mL water on an empty stomach; and 
Day 25, immediately after IV administration of midazolam with 240 mL water with or 
without a low-fat meal).
NOTE: Refer to Midazolam text for co-administration.
Part B TAK-788 Administration c
Day 1 to 28
Dose: 160 mg daily.
Administer with approximately 8 ounces (240 mL) of water with or without a low-fat meal 
(ie, ≤350 calories and ≤15% of calories from fat).
IV: intravenous; PO: oral.
a Refer to the study manuals for complete Part A dosing details.
b Refer to current Midazolam package insert for further details on the safety and clinical oversight associated with 
midazolam administration 
c Refer to the study manuals for complete Part B dosing details.
8.1.1
Part A Study Dosing
Midazolam will be administered at clinic on study Day 1, Day 2, Day 24, and Day 25 during 
Part A (Cycle 1: PK Cycle), as outlined in Table 8.a.
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TAK-788
Study No. TAK-788-1004
Page 35 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
On study Days 3 through 30, TAK-788 capsules will be self-administered orally at home at 
160 mg QD, except on Days 3, 24, 25, and 26, on which the TAK-788 160 mg dose will be 
administered in the clinic. Patients will be instructed to take each TAK-788 dose at 
approximately the same time each day, approximately 24 hours apart (ie, in the morning). 
After Day 24 predose PK samples for midazolam and TAK-788, patients will take 3 mg oral
dose of midazolam first, immediately followed by administration of the 160 mg dose of 
TAK-788 with total approximately 8 ounces (240 mL) of water (used for both midazolam and 
TAK-788). No food should be allowed for at least 2 hours prior to and 2 hours postdose of 
midazolam and TAK-788 on Day 24. 
On the morning of Day 25 of Part A, patients will return to the clinic. After collection of the 
pre-dose PK blood samples, patients will be administered an IV dose of midazolam 1 mg as a 
5-minute infusion first, immediately followed by administration of the 160 mg dose of TAK-788 
with approximately 8 ounces (240 mL) of water, with or without a low-fat meal.
On the morning of Day 26, patients will return to the clinic for collection of the predose PK 
blood sample and then will be administered the TAK-788 160 mg dose with approximately 
8 ounces (240 ml) of water with or without a low-fat meal. Patients will continue to 
self-administer TAK-788 QD with approximately 8 ounces (240 ml) of water on Days 27 
through 30 of Part A with or without a low-fat meal.
8.1.2
Part B Study Dosing 
During Part B of the study, patients continuing in the study will return to the clinic for visits on 
Day 1 of Cycle 2 and each treatment cycle thereafter. In Part B Cycle 2, patients will receive 
TAK-788 at the dose that they were receiving (and tolerating) at the end of Part A and will 
continue treatment until Cycle 24, or until the first incidence of PD, unacceptable toxicity, or 
another discontinuation criterion is met. On Day 1 of each treatment cycle, TAK-788 capsules 
will be dispensed to patients for oral QD administration on Days 1 through 28. The Day 1 
TAK-788 dose will be administered in the clinic (refer to the study manual for details regarding 
TAK-788 administration and dosing). During Part B of the study, patients will take the TAK-788 
dose with approximately 8 ounces (240 mL) of water with or without a low-fat meal.
8.1.3
Additional Study Dosing Guidance
During study Part A and B, the date and time of TAK-788 administration should be recorded in 
the patient’s dosing diary. 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). 
The patient should record any missed doses in the dosing diary. If emesis occurs after study drug 
administration, the patient should simply adhere to the dosing schedule and resume dosing at the 
next scheduled dosing time with the prescribed dosage. The timing of emesis relative to study 
drug administration should be recorded. Patients should not repeat a dose, nor attempt to make 
up missed doses by doubling a given dose.
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TAK-788
Study No. TAK-788-1004
Page 36 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
8.2
Dose Modification Guidelines
8.2.1
Dose Modifications of TAK-788
The allowable daily modified doses of TAK-788 in this study are 120 mg and 80 mg. Doses may 
be reduced, in accordance with the dose-reduction scheme shown in Table 8.b, if the patient is 
intolerant to their current dose.
Table 8.b
Recommended TAK-788 Dose Reduction Levels
Starting Dose (Part A)
First Dose Adjustment
Second Dose Adjustment
160 mg QD
120 mg QD
80 mg QD
QD: once daily.
TAK-788 dose interruption or reductions will be implemented for patients who experience 
treatment-related AEs as indicated in the following section and in Table 8.c. 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 
doses will occur only in consultation with the sponsor, as stipulated in Section 8.2.3 below. If 
toxicity requiring dose reduction occurs at the 80 mg dose, therapy should be discontinued. 
Toxicity grades will be defined by NCI CTCAE v5.0. Please note that patients who experience 
dose reduction during cycle 1 in part A of the study may be considered as PK-unevaluable 
(Section 13.1.1.1). 
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TAK-788
Study No. TAK-788-1004
Page 37 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
Table 8.c
TAK-788 Dose Modification Recommendations for Treatment-Related AEs
Toxicity Grade
Action
Non-hematologic toxicity
Grade 1
Continue therapy at same dose level.
Grade 2
Continue therapy at 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. a
Grade 3
Withhold therapy until toxicity is ≤Grade 1 or has returned to baseline, then resume 
therapy. Therapy may be resumed at the same dose or at the next lower dose level, based 
on the investigator’s judgment. a
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 same dose level.
Grade 2
Continue therapy at 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 same 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.
a For cases of pneumonitis, investigators should follow guidance in Section 8.6.4.
Further instructions for dose modification/management of nausea and emesis, diarrhea, 
asymptomatic lipase/amylase elevation, and pneumonitis can be found in Section 8.6.
8.2.2
Dose Modifications of Midazolam
Midazolam dose modification is not allowed.
8.2.3
Re-escalation of TAK-788 Dose After Dose Reduction
After dose reduction for toxicity, the dose may be re-escalated to the original dose level only 
after discussion with the sponsor. For dose re-escalation, the escalation dose must not exceed 
160 mg QD, and the patient must have recovered from the AE.
8.3
Excluded Concomitant Medications and Procedures
The following medications and procedures are prohibited during the study:

Any other systemic 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 
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TAK-788
Study No. TAK-788-1004
Page 38 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
for palliative or symptomatic control of existing lesions, with appropriate treatment 
interruption at the discretion of the investigator).

Any other investigational agent or device.

Medications that are known to be associated with the development of torsades de pointes (see 
Appendix F). Medications that prolong the QT interval, but are not known to be associated 
with torsades de pointes, should be avoided but are not prohibited.

Grapefruit or grapefruit-containing products, pomegranate-, pomelo-, or star fruit 
juice-containing products, and Seville oranges.

Medications that are moderate or strong inducers or inhibitors of the CYP3A subfamily of 
CYP enzymes in Part A Cycle 1 (see Appendix E). In Part B, only strong inducers or 
inhibitors of the CYP3A enzymes are excluded as concomitant medications.

Extensive surgery requiring in-patient care (patients may have an interruption in therapy for 
2 weeks should emergency surgery be required).

Any illicit substance. Note: Medical use of cannabis is allowed, if it is legal where the patient 
resides and no alternative treatment is available, on the basis of case-by-case review and 
agreement by the medical monitor. 
8.4
Permitted Concomitant Medications and Procedures
During the study, palliative therapy and supportive care are permitted for management of 
symptoms and underlying medical conditions that may develop during the study (to include 
steriodal dosing for palliative care). Once a patient has begun treatment, a condition may arise 
that requires the initiation of a new concomitant treatment. Patients with CNS lesions requiring 
local radiotherapy such as SRS are allowed to continue study drug after appropriate interruption, 
as determined by the investigator with sponsor agreement.
Concomitant medications 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 through the 30-day follow-up period after EOT. All concomitant medications related to 
serious or study-drug–related toxicities must be reported until the medication is no longer taken 
or until patient contact ceases.
8.5
Precautions and Restrictions
8.5.1
TAK-788
8.5.1.1
CYP3A Substrates (Including Hormonal Contraceptives)
TAK-788 potently induces CYP3A in vitro and may decrease concentrations of concomitantly 
administered CYP3A substrates. Based on emerging clinical PK data (Study AP32788-15-101), 
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 including 
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TAK-788
Study No. TAK-788-1004
Page 39 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
hormonal contraceptives, can result in decreased concentrations and loss of efficacy of these 
coadministered drugs.
Medications that are CYP3A substrates and which have narrow therapeutic index, including 
alfentanil, cyclosporine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus, 
and all statins may be concurrently administered with TAK-788 with caution. 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.
If a patient’s clinical condition requires treatment with this class of medications specified above, 
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.
8.5.1.2
Pregnancy and Breastfeeding
TAK-788 demonstrated embryofetal toxicity in rats and, similar to other EGFR inhibitors, has 
the potential to cause embryofetal 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. 
As specified in Section 7.1, female patients of childbearing potential must agree to use 1 highly 
effective (ie, results in a low failure rate when used consistently and correctly) nonhormonal 
method and 1 additional effective (barrier) method of contraception (see Table 8.d) from the time 
of signing of the informed consent and through 30 days after the last dose of study drug or must 
agree to practice true abstinence. Male patients must agree to practice effective barrier 
contraception during the entire study treatment period and through 30 days after the last dose of 
study drug, or must agree to practice true abstinence.
In Parts A and B of the study, a pregnancy test will be performed for each female patient of
childbearing potential at the time points specified in Section 9.3.13. A negative pregnancy test 
must be documented prior to administration of study drug. Please refer to Section 10.4 for 
pregnancy reporting requirements.
Table 8.d
Highly Effective Methods of Contraception and Additional Effective Barrier 
Methods
Highly Effective Nonhormonal Methods
Additional Effective Barrier Methods

Nonhormonal intrauterine device (IUD)

Bilateral tubal occlusion

Vasectomized sole sexual partner

Sexual abstinence (no sexual intercourse)

Male or female condom with or without spermicide 
(female and male condoms should not be used 
together)

Cap, diaphragm, or sponge with spermicide
Note that hormonal contraceptives are permitted to be used for purposes other than pregnancy 
prevention during the study if clinically indicated but may not be considered as a highly effective 
method of contraception.
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TAK-788
Study No. TAK-788-1004
Page 40 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
It is not known whether TAK-788 passes into the breast milk. Mothers should not breastfeed 
during study drug administration.
8.5.2
Midazolam
Midazolam is a short-acting benzodiazepine that depresses activity of the CNS and has been 
associated with respiratory depression, most often when used concomitantly with other CNS 
depressants (eg, opioids and other benzodiazepines). Therefore, all patients will be closely
monitored for respiratory and cardiac function (ie, pulse oximetry) after administration of 
midazolam on Days 1, 2, 24, and 25 of Part A of the study. Immediate availability of reversal 
agents (eg, flumazenil), resuscitative drugs, equipment for ventilation and intubation, and 
personnel trained in their use and skilled in airway management should be assured. Please refer 
to the midazolam prescribing information for full details regarding the use of midazolam.
Midazolam causes sedation. Patients should not drive, operate dangerous tools or machinery, or 
engage in any other potentially hazardous activity that requires full alertness and coordination 
after receiving midazolam on Days 1, 2, 24, and 25 of Part A of the study.
8.6
Management of Selected Treatment-Related Clinical Events
8.6.1
Nausea and Emesis
Standard antiemetics, such as prochlorperazine, may be used for the treatment of vomiting. 
Taking the study drug with food may reduce nausea. Prophylactic antiemetics may be used.
8.6.2
Diarrhea
On the basis of clinical findings and known class effect, patients should be monitored for the 
onset of diarrhea. Symptomatic care, such as site-provided loperamide where available (refer to 
the pharmacy manual for details), may be needed to manage diarrhea. Sites should follow their 
local standard of care. Table 8.e provides guidance to manage drug-related diarrhea.
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TAK-788
Study No. TAK-788-1004
Page 41 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
Table 8.e
Management of Drug-Related Diarrhea
Guidance
Action with TAK-788
No diarrhea or Cycle 1, 
Day 1

Primary prophylactic antidiarrheal medications 
may be used after discussion with the sponsor. 
Maintain fluid intake to prevent dehydration; 
monitor and replace electrolytes as appropriate, 
and adjust diet as per standard medical practice.
Continue TAK-788.
First evidence of loose 
stool, increased frequency 
of bowel movements (<4 
stools per day over 
baseline) Grade 1 

Patient should be instructed to contact the study 
doctor/team as soon as convenient.

Symptomatic care, such as loperamide, may be 
given according to the investigator’s clinical 
judgment.

Patient should be instructed to drink fluids and 
adjust their diet to avoid fried, greasy, high-fiber, 
or spicy foods.

Other medications (such as diphenoxylate 
hydrochloride with atropine sulfate) and supportive 
care may be added according to the institution’s 
standard of care.

Secondary prophylaxis in patients who have 
experienced diarrhea with TAK-788 is allowed.
Continue TAK-788.
No dose modification 
unless intolerant to TAK-
788.
Refer to Table 8.c and 
Table 8.b if TAK-788 not 
tolerated.
For increase of 4-6 stools 
per day over baseline; 
Grade 2

Patient should be instructed to contact study 
doctor/team immediately.

Should prescribe loperamide at 4 mg, then 2 mg 
every 2 to 4 hours until the patient is symptom free 
for 12 hours. 

Patient should be instructed to drink fluids and 
adjust their diet to avoid fried, greasy, high-fiber, 
or spicy foods.

Symptom directed assessment for clinical sequela 
is encouraged per standard medical practice.

Other medications (such as diphenoxylate 
hydrochloride with atropine sulfate) and supportive 
care may be added according to the institution’s 
standard of care.

Secondary prophylaxis in patients who have 
experienced diarrhea with TAK-788 is allowed.
Continue TAK-788.
No dose modification is 
necessary unless the patient 
does not tolerate TAK-788 
or the symptom recurs.
Refer to Table 8.c and 
Table 8.b if TAK-788 not 
tolerated.
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TAK-788
Study No. TAK-788-1004
Page 42 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
Table 8.e
Management of Drug-Related Diarrhea
Guidance
Action with TAK-788
For increase of >7 stools 
per day over baseline; 
Grade 3 or Grade 4 
diarrhea 

Patient should be instructed to contact study 
doctor/team immediately.

Evaluate patient for clinical sequela is 
recommended. Evaluate need for additional or 
alternative supportive care and provide any based 
on clinical judgement

Administer loperamide: initial dose of 4 mg 
(2 tablets/capsules) with the first bout of diarrhea 
followed by 2 mg (1 tablet/capsule) every 4 hours 
or after every unformed stool (maximum 16 mg 
daily) and continue loperamide at this frequency 
until diarrhea free for 12 hours. Then titrate the 
amount of loperamide used to keep diarrhea 
controlled (<4 stools/day).

Other medications (such as diphenoxylate 
hydrochloride with atropine sulfate, octreotide, IV 
fluids) and other supportive care may be added 
according to the institution’s standard of care.

Patient should be instructed to drink fluids and 
adjust their diet to avoid fried, greasy, high-fiber, 
or spicy foods; additional dietary adjustment may 
be needed based on clinical judgment.

Secondary prophylaxis in patients who have 
experienced diarrhea with TAK-788 is allowed.
Stop TAK-788 until 
recovery to Grade ≤1.
Refer to Table 8.c and 
Table 8.b if TAK-788 not 
tolerated.
8.6.3
Asymptomatic Lipase/Amylase Elevation
In the event of Grade 3 asymptomatic lipase/amylase elevation (>5.0 x 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-≤5 × ULN), continue therapy at the 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 to 
lipase/amylase levels and clinical symptoms are highly recommended.
8.6.4
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.
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TAK-788
Study No. TAK-788-1004
Page 43 of 91
Protocol Incorporating Amendment No. 2
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8.7
Blinding and Unblinding
Because this is an open-label study, there will be no study drug blinding.
8.8
Description of Investigational Agents
TAK-788 drug product will be supplied as 40 mg capsules for oral dosing. TAK-788 is 
manufactured under current Good Manufacturing Practice in accordance with approved 
procedures.
Midazolam is a short-acting benzodiazepine that is a probe substrate of CYP3A. Midazolam 
hydrochloride for oral and IV administration will be obtained from commercial sources. The 
precautions, warnings, contraindications, and AEs associated with midazolam therapy are 
included in the midazolam prescribing information.
Additional details regarding the description of TAK-788 and midazolam are provided in the 
pharmacy manual.
8.9
Preparation, Reconstitution, and Dispensation
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/ethics committees, TAK-788 can be shipped DTP from the investigation site to the 
patient’s home address via courier if needed. Additional details regarding study drug preparation 
and dispensation are provided in the pharmacy manual.
8.10
Packaging and Labeling
TAK-788 capsules will be supplied in white HDPE (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.
8.11
Storage, Handling, and Accountability
The recommended storage condition for TAK-788 is controlled room temperature. Midazolam 
hydrochloride should be stored in accordance with the product’s prescribing information. Storage 
area temperature conditions must be monitored and recorded daily. All temperature excursions 
must be reported to the sponsor for assessment and determination for continued use.
The study pharmacist or designee at the site will be responsible for handling and dispensing 
study drug, and completing associated documentary paperwork. Supplies will be 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 drug is dispensed to a patient, the following 
information must be recorded: the patient’s initials, the patient’s study number, drug product 
strength, quantity dispensed with the corresponding lot number, and the initials of the person 
dispensing the drug. These logs are to be maintained by the study pharmacist in the pharmacy 
CCI
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TAK-788
Study No. TAK-788-1004
Page 44 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
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.
All used bottles of study drug must be destroyed in an appropriate manner according to the 
standard practice at each study center. Destruction of such supplies will be documented, and a 
representative of the sponsor will verify disposition records. During the trial 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. 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 and disposition of residual 
study drug. Each site is responsible for proper and careful destruction of study drug returned by 
patients.
Periodically, throughout and at the conclusion of the study, a representative of the sponsor will 
conduct an inventory of unused study drug. At the completion of the trial, a final study drug 
accountability review will be conducted. Any discrepancies must be investigated and all unused 
study drug must be destroyed on site per the standard operating procedures of the investigative 
site.
9.0
STUDY CONDUCT
This trial will be conducted in compliance with the protocol, Good Clinical Practice (GCP), 
applicable regulatory requirements, and International Council for Harmonisation (ICH) 
guidelines.
9.1
Study Personnel and Organizations
Contact information for the project clinician, the central laboratory conducting the analysis of PK 
samples, coordinating investigator, interactive response technology provider, and contract 
research organization (CRO) team may be found in the study manual. The list of investigators is 
available in the sponsor’s investigator database.
9.2
Arrangements for Recruitment of Patients
Recruitment and enrollment strategies for this study may include recruitment from the 
investigator’s local practice or referrals from other physicians. If advertisements become part of 
the recruitment strategy, they will be reviewed by the institutional review board 
(IRB)/independent ethics committee (IEC).
9.3
Study Procedures
Timing of assessments and procedures are outlined in the Schedule of Events (SOE) 
(Appendix A Table A-1 for Part A; and, Table A-3 for Part B). Timing of PK and 
pharmacodynamic assessments in Part A is specified in Appendix A Table A-2. The EOT visit is 
to be completed only when study dosing is permanently withdrawn (ie, either Part A or Part B of 
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TAK-788
Study No. TAK-788-1004
Page 45 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
the study). Safety procedures (ie, ECG, clinical laboratory tests, and vital signs) must be 
completed prior to dose administration, as applicable; all other procedures can be performed after 
study dosing. Unless otherwise noted, tests and procedures should be performed as scheduled in 
the SOEs. 
During Part A of the study (Cycle 1: PK Cycle), study clinic visits will take place on Days 1, 2, 
3, 24, 25, and 26. Blood samples for midazolam PK characterization will be collected over the 
24-hour postdose period on Days 1, 2, 24, and 25. Blood samples for TAK-788 PK 
characterization will be collected on Days 24, 25, and 26. Patients will be closely monitored for 
respiratory and cardiac function (ie, pulse oximetry) after administration of midazolam on these 
days. Predose PK blood sample will be collected on Cycle 2 Day 1.
During Part B, study clinic visits will take place on Day 1 of each cycle for assessment of ECOG 
performance status, weight, and vital signs, and 12-lead ECGs (Cycle 2 only), physical 
examinations (PE) (symptom-directed on Day 1 of each cycle, with a full PE at EOT visit), and 
clinical laboratory tests. Predose PK blood sample will be collected on Cycle 2 Day 1. Imaging 
assessments will be conducted every 8 weeks (ie, on Day 28 [± 3 days] of every even-numbered 
cycle) up to Cycle 14, and every 12 weeks (ie, on Day 28 [± 3 days] every 3 cycles) thereafter. 
Part B, Day 1 assessments must be completed prior to study dosing, with the exception of AE 
assessments, which will be conducted both prior to and after study dosing. Treatment delays 
should not impact imaging schedule. Please refer to Appendix A Table A-1 for Part A and 
Table A-3 for Part B for timing of assessments. The timing of PK and pharmacodynamic 
assessments in Part A is specified in Appendix A Table A-2. Additional details are provided as 
necessary in the sections that follow.
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. Remote visits and telemedicine are not permitted during the first cycle. Such 
instances will be documented in the study records.
9.3.1
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. 
Patients will be given an informed consent for review and signature; patients consenting via the 
eConsent, where this is available, will electronically sign consent forms (paper consents will be 
used if required by local regulations). eConsent provides the same information as that provided 
in written consent, but the electronic format may include multimedia components. It is important 
to note that eConsent is not meant to replace the important discussion between the participant 
CCI
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TAK-788
Study No. TAK-788-1004
Page 46 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
and site staff. As with traditional consenting, the site will continue to own the consenting 
process. The requirements of informed consent are described in Section 15.2
9.3.2
Enrollment 
Patients will be considered enrolled after initial study dose has been administered; and, 
considered registered, prior to enrollment, after successful entry into the study interactive 
response technology (IRT) system. All screening procedures, as outlined in Table A-1 must be 
completed, and eligibility confirmed by the PI, prior to enrollment. Those patients not meeting 
eligibility criteria, are deemed screen-failures and noted as such (with reason for screen-failure) 
in source documentation.
9.3.3
Screening
Informed consent may be signed anytime prior to performance of any study-related procedure 
not part of standard medical care. However, the procedure performed under standard of care 
must meet the protocol requirements if used for screening. Screening assessments must be 
performed no more than 14 days before randomization. The allowable window for the disease 
assessment is 21 days before randomization. However, whenever feasible, baseline imaging 
should be performed as close as possible to randomization.
Patients who have signed informed consent and subsequently fail to meet the inclusion and/or 
exclusion criteria are defined as screen failures. Patients who screen fail may later be re-screened 
with prior sponsor approval. Any patient who is re-screened after screen failure must, in addition 
to the failed test, repeat only those screening tests that have fallen outside the specified screening 
period, as outlined in the SOE. Once the investigator determines that screening will not continue 
for a patient and the patient will not be enrolled in the study, the screen failure should be 
documented on the Eligibility Criteria eCRF. 
All AEs and SAEs must be reported during the screening period until the patient has been 
determined to be a screen failure.
9.3.4
Patient Demographics
Patient demographic characteristics will be collected at screening and will include, age, sex, race, 
and ethnicity (optional depending on country).
9.3.5
Medical/Surgical History
A complete medical history will be taken at screening. Information to be documented includes 
relevant past illnesses, smoking history, ongoing medical conditions, and surgical procedures 
(not related to the primary diagnosis).
9.3.5.1
Diagnosis and Disease History 
The initial cancer diagnosis and the current cancer stage at the time of screening, along with 
tumor histology, mutation status and all sites of disease, should be recorded. 
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TAK-788
Study No. TAK-788-1004
Page 47 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
9.3.5.2
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, neoadjuvant, adjuvant, for advanced/metastatic disease), 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.
9.3.6
Patient Height and Weight
The patient’s height will be measured during screening (within 14 days before the first dose of 
study drug).
The patient’s weight will be measured on Day 1 of each cycle and at EOT (Parts A and B).
9.3.7
Vital Signs
Vital signs will be measured at each visit before dose administration of study drug(s) in Parts A 
and B, after 3 to 5 minutes in the supine position, and will include measurements of diastolic and 
systolic blood pressure, respiratory rate, heart rate, pulse oximetry, and body temperature. Any 
change in a vital sign measurement 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.
9.3.8
ECOG Performance Status
ECOG performance status will be assessed and recorded at screening on Day 1 of each cycle, 
and at EOT. Please refer to Appendix D for the ECOG scale.
9.3.9
ECG
A 12-lead ECG will be performed prior to dosing at timepoints specified in the SOE 
(Appendix A). Repeat testing during screening and throughout the study is permitted. In addition 
to the prespecified time points, additional ECGs may be performed at the investigator’s 
discretion to ensure patient safety. ECG is also considered at any time the study patients 
complain of a lightheadedness, near syncope, or syncope with or without palpitations. The ECGs 
will be performed at the study sites, to be conducted and interpreted in accordance to local 
institutional practices and confirmed by the PI. Any change in ECG measurement 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.
9.3.10
Physical Examination
A physical examination will be completed in accordance with the study site’s standard of care at 
the times specified in Appendix A Table A-1 for Part A; and, Table A-3 for Part B. Additional 
symptom-directed evaluations may be performed.
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TAK-788
Study No. TAK-788-1004
Page 48 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
A complete physical examination must be performed at screening, the extent of which should be 
consistent with the patient’s medical history and underlying disease. Subsequent physical 
examinations may be directed to relevant findings.
The EOT physical examination should be a complete physical examination. The physical 
examination at the end of the 30-day follow-up period may be directed to any relevant findings.
9.3.11
Echocardiogram/MUGA Scan for Left Ventricular Ejection Fraction 
Conduct cardiac monitoring, including assessment of left ventricular ejection fraction (LVEF) at 
specified timepoints in the SOE (Appendix A). Cardiac monitoring and cardiology consultation 
may be done during treatment at other times according to medical judgment. Assess LVEF in 
patients who develop relevant cardiac signs or symptoms during treatment [22] 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 
10.2.
9.3.12
Clinical Laboratory Evaluations
Hematology, serum chemistry, and serology assessments will be performed locally, with
reference ranges provided in the electronic data capture (EDC) system. Clinical laboratory
evaluations will be performed according to the SOE throughout the study.
Instructions for handling and shipping clinical laboratory samples are provided in the study
laboratory manual.
9.3.12.1
Hematology, Clinical Chemistry and Serology 
Clinical laboratory tests that will be performed are listed in Table 9.a. Blood samples for 
hematology and clinical chemistry tests will be collected as specified in Appendix A Table A-1
for Part A and Table A-3 for Part B. In extenuating circumstances, such as the COVID-19 public 
health emergency, patients may use alternative site/location for the collection of clinical 
laboratory test if approved by the sponsor or designee. Such instances will be documented in the 
study records.
HBV and HCV testing will be performed at screening. As appropriate and according to local
guidelines for the management of HBV infection, HBV screening may include the following: 
HBsAg, hepatitis B surface antibody, and hepatitis B core antibody. Patients who are HBsAg 
positive will also be tested for HBV DNA. HBsAg-positive patients are allowed to enroll if HBV 
DNA is below 1000 copies/mL in the plasma with HBV DNA monitoring every 12 weeks. 
Initiation of antiviral treatment should follow local practice if HBV DNA >1000 copies is 
detected in the plasma during the study. HCV screening will include HCVAb. Patients who test 
positive for HCVAb will also be tested for HCV RNA at screening.
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TAK-788
Study No. TAK-788-1004
Page 49 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
Table 9.a
Clinical Laboratory Tests
Hematology
Serum Chemistry

Hemoglobin.

WBC count with 5-part differential 
(lymphocytes, monocytes, 
neutrophils, eosinophils, basophils).

Platelet count.

Albumin.

Total protein.

Alkaline phosphatase (ALP).

Alanine transaminase (ALT/serum glutamic pyruvic transaminase 
[SGPT]).

Aspartate transaminase (AST/serum glutamic oxaloacetic 
transaminase [SGOT]).

Amylase.

Bilirubin (total and direct/indirect).

Blood urea nitrogen (BUN).

Calcium.

Creatinine.

Chloride.

Glucose.

Lipase.

Phosphorous.

Magnesium.

Potassium.

Sodium.

Bicarbonate or total carbon dioxide.
ALP: alkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase; BUN: blood urea 
nitrogen; LDH: lactate dehydrogenase; SGOT: serum glutamic oxaloacetic transaminase; SGPT: serum glutamic 
pyruvic transaminase; WBC: white blood cell.
Any change in clinical laboratory values 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.
9.3.13
Pregnancy Test
A serum or urine pregnancy test will be performed for women of childbearing potential during 
screening and within 1 day before the first dose of study drug on Cycle 1 Day 1.
The test results must be negative and available before the first dose of study drug is 
administered. Pregnancy testing must be conducted every 4 weeks thereafter and at EOT 
Additional pregnancy testing may be required or recommended according to local guidelines and 
regulations.
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TAK-788
Study No. TAK-788-1004
Page 50 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
Pregnancy tests will not be performed for women who are not of childbearing potential (status 
posthysterectomy, postbilateral oophorectomy, or postmenopausal [defined as amenorrhea for at 
least 12 months]).
9.3.14
AEs
Monitoring of AEs, serious and nonserious, will be conducted throughout the study as specified 
in Appendix A Table A-1 for Part A; and Table A-3 for Part B.
Please refer to Section 10.0 for details regarding definitions, documentation, and reporting of 
AEs and serious adverse events (SAEs).
9.3.15
Concomitant Medications and Procedures
Concomitant medications and procedures will be recorded in the electronic case report form 
(eCRF) from the date the informed consent is signed through the 30-day follow-up period 
following EOT. Please refer to Section 8.3 for a description of excluded concomitant 
medications and procedures, and Section 8.4 for a description of permitted concomitant 
medications and procedures during the study.
9.3.16
Disease Assessment
Patients will undergo CT and MRI scanning with contrast, (unless contrast media is 
contraindicated) to monitor and assess disease progression using RECIST version 1.1 (see 
Appendix G).
At screening, disease assessment must include imaging of the chest, abdomen, pelvis, and brain 
using appropriate radiological procedures (computed tomography [CT] scans or 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.
When possible, the same qualified physician will interpret results to reduce variability.
Radiographic images will be maintained at the site, and test results and physicians’ findings will 
be filed in patient source documents.
Disease assessment by CT or MRI scan will be performed at screening (ie, as close as possible to 
Day 1 of Cycle 1, but no more than 21 days before the first dose of TAK-788 on Day 1 of
Cycle 1), and at 8-week intervals thereafter (ie, on Day 28 [±3 days] of every even-numbered 
cycle) through 14 cycles after the initial dose of TAK-788, and every 3 cycles thereafter until PD 
(Appendix A Table A-1 for Part A; and, Table A-3 for Part B). Treatment delays should not 
impact imaging schedule.
More frequent imaging is recommended at any time, if clinically indicated; confirmation of 
complete response (CR) or partial response (PR) may be performed at least 4 weeks after the 
initial response. In extenuating circumstances during the COVID-19 public health emergency, 
patients may use alternative site for imaging if approved by the sponsor or designee.
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TAK-788
Study No. TAK-788-1004
Page 51 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
In the event of antitumor response, the sponsor may request electronic images for those patients
who demonstrate tumor reduction.
9.3.17
PK Measurements
Serial blood samples for the determination of plasma concentrations of midazolam and its 
metabolite 1-hydroxymidazolam will be collected during Part A (Cycle 1: PK Cycle), on Days 1, 
2, 3 (ie, Day 2: 24 hours), 24, 25, and 26 (ie, Day 25: 24 hours), as described in Appendix A
Table A-2. Additional blood samples for the determination of plasma concentrations of TAK-
788 and its active metabolites AP32960 and AP32914 will be collected on Days 24, 25, and 26 
of Cycle 1 as well as Day 1 of Cycle 2 (predose), with additional serial blood samples to be 
collected on Day 24 (postdose), as described in Appendix A Table A-2. The exact date and time 
of each PK sample collection should be recorded.
Plasma concentrations of midazolam, 1-hydroxymidazolam and, TAK-788, AP32960, and 
AP32914 will be measured using validated liquid chromatography-tandem mass spectrometry
assays. Details regarding the preparation, handling, and shipping of the PK samples are provided 
in the study manual.
9.3.19
Patient Dosing Diary
A patient dosing diary will be completed during Part A and Part B of the study. Patients are to 
bring unused TAK-788 and the dosing diary with them to each clinic visit. The study center staff 
will check the diary and the patient’s supply of TAK-788 to assess adherence to the treatment 
regimen. In case of extenuating circumstances that prevent a patient from attending the study site 
(eg, the COVID-19 pandemic), TAK-788 drug packs and dosing diaries should be returned at the 
next available on-site clinic visit.
Please refer to the study manual for complete instructions.
9.3.20
End-of-Treatment Assessments
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 
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TAK-788
Study No. TAK-788-1004
Page 52 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
later. Physical examinations, laboratory tests (hematology, chemistry), 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. Disease assessment does not need to be 
repeated if obtained within 28 days of last dose.
9.3.21
30 Days After Last Dose
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), 
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 both the End-of-Treatment and 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.
9.4
Completion of Study Treatment (for Individual Patients)
Patients will be considered to have completed study treatment at the last dose of TAK-788 or 
when the investigator and patient decide that the patient will receive no further TAK-788, 
whichever occurs later. 
9.5
Completion of Study (for Individual Patients)
A patient will be considered to have completed the study at the completion of 30 days after last 
day follow-up visit or at completion of a total of 24 cycles of treatment. Subjects not continuing 
on study beyond Part A, must complete End of Treatment visit and 30 days after last dose visit.
9.6
Discontinuation of Treatment With Study Drug 
Study drug must be permanently discontinued for patients meeting any of the following criteria:

Patient meets the discontinuation rules for pneumonitis.

Pregnancy.

Entry into another therapeutic clinical study or start of new anticancer therapy. 
Treatment with study drug may also be discontinued for any of the following reasons:

AE.

Protocol deviation.

Clinical progressive disease. 

Documented Progression of disease based on RECIST v1.1.

Note: Treatment of patients with TAK-788 may be continued, despite progression by 
RECIST v1.1 (see Appendix G), at the discretion of the investigator, if there is still evidence 
of clinical benefit. Takeda should be informed if this decision is made.
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TAK-788
Study No. TAK-788-1004
Page 53 of 91
Protocol Incorporating Amendment No. 2
03 September 2020

Study terminated by sponsor.

Withdrawal by subject.

Lost to follow-up.

Other.
The primary reason for study drug discontinuation will be recorded in the eCRF.
Treatment with study drug may also be discontinued due to AE or as a result of patient decision 
and/or PI judgement (noting AE, or other as causality for discontinuation in study CRF, as 
applicable). 
Once study drug has been discontinued, all study procedures outlined for the EOT visit will be 
completed as specified in Appendix A Table A-1 for Part A; and Table A-3 for Part B. The 
patient will be followed for 30 days after the EOT visit for drug safety.
In the case of study termination by the sponsor, eligible patients may continue TAK-788 as 
described in Section 6.3.5.
9.7
Withdrawal of Patients From Study
A patient may choose to be withdrawn from the study at any time. 
Patients will be considered a study withdrawal for any of the following reasons:

Lost to follow-up.

Study terminated by sponsor.

Withdrawal by subject.

Death. 

PD. 

Initiation of new anticancer therapies. 

Other (outcomes of study withdrawal, not defined by categories provided).
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.
9.8
Study or Site Termination
If the sponsor, investigator, medical monitor, or regulatory agencies discover conditions during 
the study that indicate that the study or site should be terminated, this action may be taken after 
appropriate consultation between the sponsor and the investigator (in the case of site 
termination). Conditions that may warrant termination of the study include, but are not limited 
to:

The discovery of a serious, unexpected, or unacceptable risk to subjects enrolled in the study.
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Study No. TAK-788-1004
Page 54 of 91
Protocol Incorporating Amendment No. 2
03 September 2020

The decision on the part of the sponsor to suspend or discontinue testing, evaluation, or 
development of the study drug.

Submission of knowingly false information from the research facility to the sponsor, medical 
monitor, or regulatory authorities.

Insufficient adherence to protocol requirements.
10.0
ADVERSE EVENTS
10.1
Definitions
10.1.1
Pretreatment Event Definition
A pretreatment event is any untoward medical occurrence in a patient or subject who has signed 
informed consent to participate in a study but before administration of any study medication; it 
does not necessarily have to have a causal relationship with study participation.
10.1.2
AE Definition
AE means any untoward medical occurrence in a patient or subject administered a 
pharmaceutical product; the untoward medical occurrence does not necessarily have a causal
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product whether or not it is related to the medicinal product. 
This includes any newly occurring event or a previous condition that has increased in severity or 
frequency since the administration of study drug.
An abnormal laboratory value will not be assessed as an AE unless that value leads to 
discontinuation or delay in treatment, dose modification, therapeutic intervention, or is 
considered by the investigator to be a clinically significant change from baseline.
10.1.3
SAE Definition
SAE means any untoward medical occurrence that at any dose:

Results in death.

Is life-threatening (refers to an AE in which the patient was at risk of death at the time of the 
event. It does not refer to an event which hypothetically might have caused death if it were 
more severe).

Requires inpatient hospitalization or prolongation of an existing hospitalization (see 
clarification in the paragraph in Section 10.2 on planned hospitalizations).

Results in persistent or significant disability or incapacity. (Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions).

Is a congenital anomaly/birth defect.
CCI
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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TAK-788
Study No. TAK-788-1004
Page 55 of 91
Protocol Incorporating Amendment No. 2
03 September 2020

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.
In this study, intensity for each AE, including any laboratory abnormality, will be determined 
using the NCI CTCAE, version 5.0, dated 27 November 2017 [1]. 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 must be reported (see Section 10.3 for the period of observation) 
by the investigator to the Takeda Global Pharmacovigilance department or designee within 
24 hours of becoming aware of the event. This will be done by transmitting an EDC SAE report. 
If transmission of an EDC SAE report is not feasible, then a facsimile of the completed Takeda 
paper-based SAE form will be sent. In case of fax, site personnel need to confirm successful 
transmission of all pages and include an e-mail address on the fax cover sheet so that an 
acknowledgment of receipt can be returned via e-mail within 1 business day. A sample of the 
paper-based SAE form and processing directions are in the study manual. Information in the 
SAE report or form must be consistent with the data provided on the eCRF. 
If information not available at the time of the first report becomes available at a later date, then 
the investigator will transmit a follow-up EDC SAE report (or a paper-based SAE form if an 
CCI
Non-Commercial Use Only and Subject to the Applicable Terms of Use
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TAK-788
Study No. TAK-788-1004
Page 56 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
EDC SAE report is not feasible) or provide other documentation immediately within 24 hours of 
receipt. Copies of any relevant data from the hospital notes (eg, ECGs, laboratory tests, discharge 
summary, postmortem results) should be sent to the addressee, if requested.
All SAEs should be followed up until resolution or permanent outcome of the event. The 
timelines and procedure for follow-up reports are the same as those for the initial report.
Planned hospital admissions or surgical procedures for an illness or disease that existed before 
the patient was enrolled in the 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 laboratory abnormality, will be determined 
using the NCI CTCAE, version 5.0, dated 27 November 2017 [1]. The criteria are provided in 
the study manual. Selected asymptomatic laboratory values may also constitute AEs as defined 
by the NCI CTCAE.
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 informed consent through 30 days after 
administration of the last dose of study drug and recorded in the eCRFs.

SAEs will be reported to the Takeda Global Pharmacovigilance department or designee from
the signing of informed consent through 30 days after administration of the last dose of study
drug and recorded in the eCRF. After this period, only related SAEs must be reported to the 
Takeda Global Pharmacovigilance department or designee. SAEs should be monitored until 
they are resolved or are clearly determined to be due to a patient’s stable or chronic condition 
or intercurrent illness(es).
10.4
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events
If a woman becomes pregnant or suspects that she is pregnant while participating in this study, 
she must inform the investigator immediately and permanently discontinue study drug. The 
sponsor must also be contacted immediately by sending a completed pregnancy form to the 
Takeda Global Pharmacovigilance department or designee. 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 sending a completed pregnancy
form to the Takeda Global Pharmacovigilance department or designee. Every effort should be 
made to follow the pregnancy for the final pregnancy outcome.
CCI
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TAK-788
Study No. TAK-788-1004
Page 57 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
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 email 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.
Product
Call Center
Phone Number
Email
Fax
TAK-788
Product complaints and medication errors in and of themselves are not AEs. If a product 
complaint or a medication error results in an SAE, the SAE should be reported. 
10.6
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, including the European 
Medicines Agency (EMA), investigators, and IRBs and IECs, as applicable, in accordance with 
national regulations in the countries where the study is conducted. Relative to the first awareness 
of the event by/or further provision to the sponsor or sponsor’s designee, SUSARs will be 
submitted to the regulatory authorities as 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. The investigational site 
also will forward a copy of all expedited reports to his or her IRB or IEC in accordance with 
national regulations.
11.0
STUDY-SPECIFIC COMMITTEES
No steering committee, data safety monitoring committee, or clinical endpoint committee will be 
used in this study.
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 
CCI
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TAK-788
Study No. TAK-788-1004
Page 58 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
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 informed consent form (ICF).
The sponsor or its designee will supply investigative sites with access to eCRFs and will make 
arrangements to train appropriate site staff in the use of the eCRF. These forms are used to 
transmit the information collected in the performance of this study to the sponsor, CRO partners, 
and regulatory authorities. Investigative sites must complete eCRFs in English.
After completion of the entry process, computer logic checks will be run to identify items such 
as inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designee) 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 the 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 designee) will be permitted to review the subject’s medical 
and hospital records pertinent to the study to ensure accuracy of the eCRFs. The completed 
eCRFs are the sole property of the sponsor and should not be made available in any form to third 
parties, except for authorized representatives of appropriate governmental health or regulatory
authorities, without written permission of the sponsor.
12.2
Record Retention
The investigator agrees to keep the records stipulated in Section 12.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all
participating subjects, medical records, temporary media such as thermal-sensitive paper, source 
worksheets, all original signed and dated ICFs, subject authorization forms regarding the use of 
personal health information (if separate from the ICFs), electronic copies of eCRFs including the 
audit trail, and detailed records of drug disposition to enable evaluations or audits from 
regulatory authorities and the sponsor (or designees). Any source documentation printed on 
degradable thermal-sensitive paper should be photocopied by the site and filed with the original 
in the subject’s chart to ensure long-term legibility. Furthermore, ICH E6 (R2) Section 4.9.5 
requires the investigator to retain essential documents specified in ICH E6 (R2) (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 (R2) 
CCI
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TAK-788
Study No. TAK-788-1004
Page 59 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
Section 4.9.5 states that the study records should be retained until an amount of time specified by
applicable regulatory requirements or for a time specified in the clinical study site agreement 
between the investigator and sponsor.
Please refer to the clinical study site agreement for the sponsor’s requirements for record 
retention. The investigator should contact and receive written approval from the sponsor before 
disposing of any such documents.
13.0
STATISTICAL METHODS
13.1
Statistical and Analytical Plans
A statistical analysis plan will be prepared and finalized before database lock. This document 
will provide further details regarding the definition of analysis variables and analysis 
methodology to address all study objectives.
A data review will be conducted before database lock. This review will assess the accuracy and 
completeness of the study database, patient evaluability, and appropriateness of the planned 
statistical methods.
PK and safety analyses will be conducted after all patients complete Cycle 1 (Part A) of the 
study.
13.1.1
Analysis Sets
13.1.1.1
PK-Evaluable Population
PK-Evaluable Population
Patients will be considered PK-evaluable if they meet all of the following criteria during study
Part A, Cycle 1: 
1. Received the protocol-specified dosing regimen without dose reductions prior to Day 26. 
2. Experienced no dose interruptions within 1 week prior to Day 24.
3. Experienced no more than 1 day of dose interruption within the first 14 days of TAK-788 
treatment.
4. Did not receive any excluded concomitant medications through the completion of PK 
sampling (Day 26).
The PK-evaluable population will be used for all PK analyses. Assessment of the PK-evaluable 
population will be conducted when dosing and safety (ie, vomiting) data become available and 
prior to study closure.
13.1.1.2
Safety Population
The safety population is defined as all patients who received at least 1 dose of any study drug 
(TAK-788 or midazolam). The safety population will be used for all safety analyses.
CCI
keda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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TAK-788
Study No. TAK-788-1004
Page 60 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
13.1.2
Analysis of Demographics and Other Baseline Characteristics
Demographic and other baseline characteristics will be summarized, including sex, age, race, 
weight, height, and other variables as appropriate.
13.1.3
PK Analysis
In Part A (Cycle 1: PK Cycle), individual and mean plasma concentration data for midazolam 
and its metabolite 1-hydroxymidazolam after oral dosing of midazolam on Days 1 and 24 and IV 
dosing of midazolam on Days 2 and 25 will be plotted over time and listed by patient in the 
absence and presence of TAK-788. Plasma PK parameters of midazolam and 
1-hydroxymidazolam for individual patients after oral and IV dosing of midazolam in the 
absence and presence of TAK-788 will be derived using noncompartmental analysis methods. 
Plasma concentrations and PK parameters (including but not limited to AUC∞, Cmax, and tmax) of
midazolam and 1-hydroxymidazolam in the presence and absence of TAK-788 will be 
summarized using descriptive statistics.
For the estimation of the effect of TAK-788 on the PK of oral- and IV-dose midazolam, the 
ratios of geometric mean midazolam AUC∞(or area under the plasma concentration-time curve 
from time 0 to time [AUCt]) and Cmax (in the absence and presence of TAK-788) and the 
associated 2-sided 90% CIs will be calculated on the basis of the within-patient variance using a 
mixed-effects analysis of variance (ANOVA) model fitting terms for treatment (midazolam in 
the absence and presence of TAK-788). The patient will be treated as a random effect in the 
model. After log transformation, AUC∞and Cmax will be separately analyzed. Point estimates 
and adjusted 90% CIs for the difference in treatment will be calculated and then exponentially
back transformed to provide point and CI estimates for the ratios of interest.
The oral bioavailability of midazolam and the 1-hydroxymidazolam to midazolam AUC ratios 
following IV and oral midazolam dosing will be descriptively summarized, in the absence and 
presence of TAK-788.
Plasma concentrations of TAK-788 and its active metabolites AP32960 and AP32914 will be
listed by patient and summarized using descriptive statistics. Individual and mean plasma 
concentrations of TAK-788, AP32960, and AP32914 will be plotted over time. Plasma PK 
parameters for TAK-788, AP32960, and AP32914 for individual patients will be derived using 
noncompartmental analysis methods and listed by patient and summarized using descriptive 
statistics.
13.1.4
Safety Analysis
Safety will be evaluated by the incidence of AEs, severity and type of AEs, and by changes from 
baseline in the patient’s clinical laboratory results, weight, and vital signs. Exposure to study
drug and reasons for discontinuation will be tabulated.
TEAEs that occur after administration of the first dose of any study drug and through 30 days 
after the last dose of TAK-788 will be tabulated.
CCI
Non-Commercial Use Only and Subject to the Applicable Terms of Use
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TAK-788
Study No. TAK-788-1004
Page 61 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
AEs will be tabulated using the MedDRA and will include, but are not limited to, the following 
subsets:

TEAEs.

Drug-related TEAEs.

Grade 3 or higher TEAEs.

Grade 3 or higher drug-related TEAEs.

Most commonly reported TEAEs (ie, those events occurring in ≥10% of all patients).

TEAEs resulting in study drug dose reduction.

TEAEs resulting in study drug dose modification (as defined as dose interruption, dose 
reduction, or permanent discontinuation).

SAEs.
A listing of TEAEs resulting in study drug discontinuation will be provided.
Actual values (and/or change from baseline) in clinical laboratory variables, weight, and vital
signs will be summarized by scheduled time point using descriptive statistics. Mean or median 
key laboratory variables over time will be plotted. Shift tables for clinical laboratory variables 
will be generated to show changes in NCI CTCAE, version 5.0 grade from the baseline value to 
the worst postbaseline value.
All concomitant medications collected from screening through the study period will be classified 
to generic terms according to the WHO Drug Dictionary.
Additional safety analyses may be performed to most clearly enumerate rates of toxicities and to 
further define the safety profile of TAK-788.
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TAK-788
Study No. TAK-788-1004
Page 62 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
13.2
Interim Analysis and Criteria for Early Termination
No interim analysis is planned for this study.
13.3
Determination of Sample Size
It is anticipated that approximately 26 patients will be enrolled in this study to obtain 
approximately 12 PK-evaluable patients. The sample size calculation was based on the expected 
2-sided 90% CI for the difference in the paired, log-transformed AUC∞mean values for 
midazolam in the absence and presence of TAK-788. 
Assuming that the AUC∞ratio for midazolam in the presence versus absence of TAK-788 is 1, 
with a sample size of 12, the 90% CI for the AUC∞ratio is expected to be 0.82 to 1.23 on the 
basis of the variance assumptions. Assuming that the AUC∞ratio for midazolam in the presence 
versus absence of TAK-788 is X, with a sample size of 12, the 90% CI for the AUC∞ratio is 
expected to be 0.82X to 1.23X on the basis of the variance assumptions.
14.0
QUALITY CONTROL AND QUALITY ASSURANCE
14.1
Study-Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and institution guarantee access to source documents by the sponsor or its 
designee (CRO) and by the IRB or IEC.
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/IEC.
All aspects of the study and its documentation will be subject to review by the sponsor or 
designee (as long as blinding is not jeopardized) including, but not limited to, the investigator’s 
binder, study medication, subject medical records, informed consent documentation, 
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TAK-788
Study No. TAK-788-1004
Page 63 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
documentation of subject authorization to use personal health information (if separate from the 
ICFs), and review of eCRFs and associated source documents. It is important that the 
investigator and other study personnel are available during the monitoring visits and that 
sufficient time is devoted to the process.
14.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will 
require deviation from protocol-specified procedures, the investigator should consult with the 
sponsor or designee (and IRB or IEC, as required) to determine the appropriate course of action. 
There will be no exemptions (a prospectively approved deviation) from the inclusion or 
exclusion criteria.
The site should document all protocol deviations in the subject’s source documents. In the event 
of a significant deviation, the site should notify the sponsor or its designee (and IRB or IEC, as 
required). Significant deviations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the subject, or confound interpretation of the primary 
study assessment.
The sponsor will assess any protocol deviation; if it is likely to affect to a significant degree the 
safety and rights of a subject or the reliability and robustness of the data generated, it may be 
reported to regulatory authorities as a serious breach of GCP and the protocol.
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] 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 should be notified immediately. The investigator and institution 
guarantee access for quality assurance auditors to all study documents as described in 
Section 14.1.
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.
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TAK-788
Study No. TAK-788-1004
Page 64 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
The principles of Helsinki are addressed through the protocol and through appendices containing 
requirements for informed consent and investigator responsibilities.
15.1
IRB and/or IEC Approval
IRBs and IECs must be constituted according to the applicable state and federal/local 
requirements of each participating region. The sponsor or designee will require documentation 
noting all names and titles of members who make up the respective IRB or IEC. If any member 
of the IRB or IEC has direct participation in this study, written notification regarding his or her 
abstinence from voting must also be obtained. Those American sites unwilling to provide names 
and titles of all members because of privacy and conflict of interest concerns should instead 
provide a Federalwide Assurance number or comparable number assigned by the US Department 
of Health and Human Services.
The sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the investigator’s brochure, a copy of
the ICF, and, if applicable, subject recruitment materials and advertisements and other 
documents required by all applicable laws and regulations must be submitted to a central or local 
IRB or IEC for approval. The IRB’s or IEC’s written approval of the protocol and subject 
informed consent must be obtained and submitted to the sponsor or designee before 
commencement of the study, ie, before shipment of the sponsor-supplied drug or study-specific 
screening activity. The IRB or IEC approval must refer to the study by 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 or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the ICF, recruitment
materials intended for viewing by subjects, local safety reporting requirements, reports and 
updates regarding the ongoing review of the study at intervals specified by the respective IRB or 
IEC, and submission of the investigator’s final status report to IRB or IEC. All IRB and IEC 
approvals and relevant documentation for these items must be provided to the sponsor (or 
designee).
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and sponsor.
15.2
Subject Information, Informed Consent, and Subject Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The ICF, subject authorization form (if applicable), and subject 
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TAK-788
Study No. TAK-788-1004
Page 65 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
information sheet (if applicable) describe the planned and permitted uses, transfers, and 
disclosures of the subject’s personal and personal health information for purposes of conducting 
the study. The ICF and the subject information sheet (if applicable) further explain the nature of
the study, its objectives, and potential risks and benefits, and the date informed consent is given. 
The ICF will detail the requirements of the participant and the fact that he or she is free to 
withdraw at any time without giving a reason and without prejudice to his or her further medical 
care.
The investigator is responsible for the preparation, content, and IRB or IEC approval of the ICF 
and, if applicable, the subject authorization form. The ICF, subject authorization form (if 
applicable), and subject information sheet (if applicable) must be approved by both the IRB or 
IEC and the sponsor before use.
The ICF, subject authorization form (if applicable), and subject information sheet (if applicable) 
must be written in a language fully comprehensible to the prospective subject. It is the 
responsibility of the investigator to explain the detailed elements of the ICF, subject 
authorization form (if applicable), and subject information sheet (if applicable) to the subject. 
Information should be given in both oral and written form whenever possible and in the manner 
deemed appropriate by the IRB or IEC. If the subject is not capable of rendering adequate 
written informed consent, then the subject’s legally acceptable representative may provide such 
consent for the subject in accordance with applicable laws and regulations.
The subject, or the subject’s legally acceptable representative, must be given ample opportunity
to (1) inquire about details of the study and (2) decide whether to participate in the study. If the 
subject, or the subject’s legally acceptable representative, determines that he or she will 
participate in the study, then the ICF and subject authorization form (if applicable) must be 
signed and dated by the subject, or the subject’s legally acceptable representative, at the time of 
consent and before the subject enters into the study. The subject or the subject’s legally 
acceptable representative should be instructed to sign using their legal names, not nicknames, 
using a ballpoint pen with either blue or black ink. The investigator must also sign and date the 
ICF and subject authorization (if applicable) at the time of consent and before the subject enters 
into the study; however, the sponsor may allow a designee of the investigator to sign to the 
extent permitted by applicable law.
Once signed, the original ICF, subject authorization form (if applicable), and subject information 
sheet (if applicable) will be stored in the investigator’s site file. The investigator must document 
the date the subject signs the informed consent in the subject’s medical record. Copies of the 
signed ICF, the signed subject authorization form (if applicable), and subject information sheet 
(if applicable) shall be given to the subject.
All revised ICFs must be reviewed and signed by relevant subjects or the relevant subject’s 
legally acceptable representative in the same manner as the original informed consent. The date 
the revised consent was obtained should be recorded in the subject’s medical record, and the 
subject should receive a copy of the revised ICF.
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TAK-788
Study No. TAK-788-1004
Page 66 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
15.3
Subject Confidentiality
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will be linked to the 
sponsor’s clinical study database or documentation only via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or 
date of birth, and subject initials may be used to verify the subject and accuracy of the subject’s 
unique identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the 
sponsor requires the investigator to permit its monitor or designee’s monitor, representatives
from any regulatory authority (eg, US FDA, UK MHRA, Japan PMDA), the sponsor’s 
designated auditors, and the appropriate IRBs and IECs to review the subject’s original medical 
records (source data or documents) including, but not limited to, laboratory test result reports, 
ECG reports, admission and discharge summaries for hospital admissions occurring during a 
subject’s study participation, and autopsy reports. Access to a subject’s original medical records 
requires the specific authorization of the subject as part of the informed consent process (see 
Section 15.2).
Copies of any subject source documents that are provided to the sponsor must have certain 
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
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 
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TAK-788
Study No. TAK-788-1004
Page 67 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
publicly accessible websites on or before start of study, as defined by Takeda policy/standards. 
Takeda contact information, along with investigator’s city, state (for Americas investigators), 
country, and recruiting status will be registered and available for public viewing. 
As needed, Takeda and investigator/site contact information may be made public to support 
participant access to trials via registries. In certain situations/registries, Takeda may assist 
participants or potential participants in finding a clinical trial by helping them locate trial sites 
closest to their homes by providing the investigator name, address, and phone number via 
email/phone or other methods preferred by callers requesting trial information. Once subjects 
receive investigator contact information, they may call the site requesting enrollment into the 
trial. The investigative sites are encouraged to handle the trial inquiries according to their 
established subject screening process. If the caller asks additional questions beyond the topic of 
trial enrollment, they should be referred to the sponsor. 
Any investigator who objects to Takeda providing this information to callers must provide 
Takeda with a written notice requesting that their information not be listed on the registry site. 
15.4.3
Clinical Trial Results Disclosure
Takeda will post the results of clinical trials on ClinicalTrials.gov (clinicaltrialsregister.eu, if 
applicable), and other publicly accessible websites (including the Takeda corporate site) and 
registries, as required by Takeda policy/standards, applicable laws, and/or regulations.
The sponsor is committed to responsible sharing of clinical data with the goal of advancing 
medical science and improving patient care. Qualified independent researchers will be permitted 
to use data collected from patients during the study to conduct additional scientific research, 
which may be unrelated to the study drug or the patient’s disease. The data provided to external 
researchers will not include information that identifies patients personally.
15.5
Insurance and Compensation for Injury
Each subject in the study must be insured in accordance with the regulations applicable to the 
site where the subject is participating. If a local underwriter is required, then the sponsor or 
sponsor’s designee will obtain clinical study insurance against the risk of injury to clinical study
subjects. Please 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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Study No. TAK-788-1004
Page 68 of 91
Protocol Incorporating Amendment No. 2
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16.0
REFERENCES
1. Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0. U.S. Department 
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Interactions Through Cytochrome P450 3A (CYP3A) for the Selective ALK Inhibitor 
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3. Stroh M, Talaty J, Sandhu P, McCrea J, Patnaik A, Tolcher A, et al. Lack of meaningful 
effect of ridaforolimus on the pharmacokinetics of midazolam in cancer patients: model 
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4. Han TH, Gopal AK, Ramchandren R, Goy A, Chen R, Matous JV, et al. CYP3A-mediated 
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5. Gibbons JA, de Vries M, Krauwinkel W, Ohtsu Y, Noukens J, van der Walt JS, et al. 
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6. Clinical Pharmacology and Biopharmaceutics Review: Crizotinib, Application No. 
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7. Kris M, Johnson B, Berry L, Kwiatkowski D, Iafrate A, Wistuba I, et al. Using multiplexed 
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8. Yatabe Y, Kerr KM, Utomo A, Rajadurai P, Tran VK, Du X, et al. EGFR mutation testing 
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9. Murray S, Dahabreh I, Linardou H, Manoloukos M, Bafaloukos D, Kosmidis P. Somatic 
mutations of the tyrosine kinase domain of epidermal growth factor receptor and tyrosine 
kinase inhibitor response to TKIs in non-small cell lung cancer: an analytical database. J 
Thorac Oncol 2008;3(8):832-9.
10. Hirsh V. Next-Generation Covalent Irreversible Kinase Inhibitors in NSCLC: Focus on 
Afatinib. BioDrugs 2015;29(3):167-83.
11. Suda K, Murakami I, Katayama T, Tomizawa K, Osada H, Sekido Y, et al. Reciprocal and 
complementary role of MET amplification and EGFR T790M mutation in acquired 
resistance to kinase inhibitors in lung cancer. Clin Cancer Res 2010;16(22):5489-98.
12. Yun CH, Mengwasser KE, Toms AV, Woo MS, Greulich H, Wong KK, et al. The T790M 
mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc Natl 
Acad Sci U S A 2008;105(6):2070-5.
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the tyro
N
ro
yry
N
yry
ibitor re
Fo
ibitor re
Oncol 2
da: 
Oncol 2
h V. N
ked
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A
T
Afat
Ta
fatinib
Tak
inib
1.
y
1. Sud
y of
Sud
c
y
c

TAK-788
Study No. TAK-788-1004
Page 69 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
13. 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.
14. Gilotrif (afatinib). Prescribing Information. Ridgefield, Connecticut: Boehringer Ingelheim 
Pharmaceuticals, Inc., 2018.
15. 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.
16. 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.
17. 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.
18. 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.
19. 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.
20. 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.
21. 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.
22. Yu AF, Yin A, Steingart RM. Cost Effectiveness of Cardiotoxicity Monitoring. American 
College of Cardiology 2017.
23. Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and 
response criteria of the Eastern Cooperative Oncology Group. American Journal of Clinical 
Oncology 1982;5(6):649-55.
24. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New 
response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J 
Cancer 2009;45(2):228-47.
CCI
mercial Use Only and Subject to the Applicable Terms of Use
elheim 
Term
elheim 
Natura
able
Natura
n 20 inse
lica
n 20 inse
al. Epide
he Ap
al. Epide
mas: C
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mas: Cl
t al. Lun
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with poo
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with poo
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and
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Only
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erty
24.

TAK-788
Study No. TAK-788-1004
Page 70 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
CONFIDENTIAL
Appendix A
Schedule of Events
Table A-1
Schedule of Events for Part A (Cycle 1, 30-Day PK Cycle)
Subjects not continuing on study beyond Part A, must complete an EOT visit and 30 day follow up visit as described in Table A-3.
Assessment
Screening a
≤14 days to Day 1
Cycle 1
Day 1
Day 2
Day 3
Day 24
Day 25
Day 26
Informed consent a
X
Inclusion/exclusion criteria
X
Demographics
X
Medical history
X
Prior anticancer therapy
X
Height
X
Weight
X
X
Vital signs b
X
X
X
X
X
X
X
ECOG performance status
X
X
12-lead ECG c
X
X
X
X
X
X
Echocardiogram/MUGA for LVEF d
X
Physical examination e
X
X
X
Clinical laboratory tests f
X
X
Serology g
X
Pregnancy test h
X
X
Adverse events (including SAEs)
Recorded from the signing of the informed consent form through 30 days after the last dose of study drug.
Concomitant medications and procedures
Recorded from the signing of the informed consent form through 30 days after the last dose of study drug.
Imaging assessments i
X
Blood samples for PK
X
X
X
X
X
X
Blood samples for pharmacodynamics and 
other biomarkers j
X
X
Midazolam 3 mg single PO dose
X
X
Midazolam 1 mg single IV dose
X
X
Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
Te
o
A
ow up v
App
w up v
Cycle 
the
Cycle 
e
Day
o t
Day
th
to
ec
bjbjbjbjbj
Su
d 
a
y
nly
X
e O
X
O
se
U
X
a
X
U
ia
X
r
X
erc
m
mm
om
X
n
X
C
R
n
R
on
N
or
F
a: F
s
k
s and 
ed
and 
da
y of Ta
se
f T
se
Ta
dose
of
dose
f T
Property o
y o

TAK-788
Study No. TAK-788-1004
Page 71 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
CONFIDENTIAL
Assessment
Screening a
≤14 days to Day 1
Cycle 1
Day 1
Day 2
Day 3
Day 24
Day 25
Day 26
TAK-788 QD administration k
X (Days 3-30)
Dispensation of TAK-788 and patient diary
X
Assessment of patient dosing diary
X
X
X
CT: computed tomography; β-hCG: β-human chorionic gonadotropin; ECG: electrocardiogram; ECOG: Eastern Cooperative Oncology Group; EOT: end of treatment; IV: 
intravenous; LVEF: left ventricular ejection fraction; MUGA: multigated acquisition; PK: pharmacokinetics.
NOTE: Variations of visit schedule during cycle 1 for PK evaluation will be evaluated and approved by the sponsor on a case by case basis. 
a Informed consent may be signed anytime prior to randomization and must be signed before performance of any study-related procedure not part of standard medical care. 
Screening assessments must be performed no more than 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. 
b Vital signs will be measured at each visit before dose administration of TAK-788 study drug(s) in Parts A and B, after 3 to 5 minutes in the supine position, and will include 
measurements of diastolic and systolic blood pressure, respiratory rate, heart rate, pulse oximetry, and body temperature.
c Procedures to be performed before dosing.
d Echocardiogram/MUGA scan must be performed at screening for LVEF and may be performed at other times according to medical judgement.
e A complete physical examination is to be performed during screening. Symptom-directed physical examinations are to be performed afterwards.
f Clinical laboratory tests (hematology, and clinical chemistry) to be performed on Day 1 (with -2 day window for C1D1) of each cycle before dosing. See Table 9.a for the list of 
tests to be performed.
g HBV screening may include the following: HBsAg, hepatitis B surface antibody, and hepatitis B core antibody, in accordance with local institutional practices. Patients who test 
positive for HBsAg will also be tested for HBV DNA at screening. HCV screening will include HCVAb. Patients who test positive for HCVAb will also be tested for HCV RNA 
at screening (see Section 9.3.12.1).
h For all women of childbearing potential, urine or serum β-hCG test is to be performed within 1 day before first dose of study drug. Refer to Section 9.3.13 for additional 
information.
i Imaging baseline disease assessments during screening should be conducted ≤21 Days prior to Cycle 1 Day 1, yet as close to as possible to Day 1. Assessments will consist of 
CT/MRI scans of the chest, abdomen, brain, and pelvis for all patients. Imaging of the brain (contrast-enhanced MRI is preferred) is required at screening for all patients, and will 
be repeated postbaseline for patients with CNS metastases at baseline. (see Section 9.3.16).
j Biomarker blood samples are to be collected at predose on Days 1 and 24 to measure plasma concentrations of 4β-hydroxycholesterol and cholesterol; Day 1 predose sample will 
include assessment for expression of circulating tumor DNA. 
k TAK-788 160 mg QD is to be administered from Day 3 through Day30 in Part A and continues to subsequent cylces. TAK-788 dose may be reduced based on dose modification 
guidelines to 120 or 80 mg in patients who do not tolerate the 160 mg dose.
he Applicable Terms of Use
Te
e
ab
ab
ab
ab
X (Day
plic
X (Day
lic
pp
X
e
X
A
Property of Takeda: For Non-Commercial Use Only and Subject to the
perative O
the
perative O
onsor on a
ct t
onsor on a
of any stu
bjec
of any stu
or the dise
Subj
or the dise
in Parts A
nd S
in Parts A
try, and b
and
try, and b
performed
Only
performed
directed p
e O
directed p
on Day 1
Use
on Day 1
antibody
cia
antibody
CV screen
erc
CV screen
G test is to
mm
G test is to
should be
n-C
should be
s for all p
Non
s for all p
tastases at
No
tastases at
t predose 
For 
t predose 
ting tumo
Fo
ting tumo
ered from
da: 
ered from
who do
keda
who do
he

TAK-788
Study No. TAK-788-1004
Page 72 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
CONFIDENTIAL
Table A-2
PK and Pharmacodynamic Blood Sampling Schedule
Blood Sampling Time
Cycle 1
Cycle 2
Day 1
Day 2
Day 24
Day 25
Day 1
Oral
Midazolam
PK a
PD b
IV
Midazolam
PK a
Oral
Midazolam
PK a
TAK-788
PK c
PD g
IV
Midazolam
PK a
TAK-788
PK c
TAK-788
PK c
Predose (within 1 hour before dosing) f
X
X
X
X
X
X
X
X
0.25 hours postdose (±3 minutes)
X
X
0.5 hours postdose (±5 minutes)
X
X
0.75 hour postdose (±10 minutes)
X
X
1 hour postdose (±15 minutes)
X
X
X
1.5 hours postdose (±15 minutes)
X
X
2 hours postdose (±15 minutes)
X
X
X
4 hours postdose (±30 minutes)
X
X
X
6 hours postdose (±1 hour)
X
X
X
8 hours postdose (±1 hour)
X
X
X
Predose (within 1 hour before dosing) d
X
X
Immediately EOI (+3 minutes) e
X
X
10 minutes EOI (±3 minutes)
X
X
20 minutes EOI (±3 minutes)
X
X
30 minutes EOI (±5 minutes)
X
X
1 hour EOI (±15 minutes)
X
X
2 hours EOI (±15 minutes)
X
X
4 hours EOI (±30 minutes)
X
X
6 hours EOI (±1 hour)
X
X
8 hours EOI (±1 hour)
X
X
24 hours EOI (±1 hours) f
X f
X f
X
EOI: end of infusion; IV: intravenous; PD: pharmacodynamics; PK: pharmacokinetics.
a Blood samples for the measurement of concentrations of midazolam and its metabolite 1-hydroxymidazolam in plasma.
b Blood samples for the measurement of concentrations of 4β-hydroxycholesterol and cholesterol in plasma and other biomarkers.
c Blood samples for the measurement of concentrations of TAK-788 and its metabolites AP32960 and AP32914 in plasma.
n-Commercial Use Only and Subject to the Applicable Terms of Use
Te
lic
App
p
8
P
e A
 th
ect t
X
ct
X
t t
ec
S bj
S
d S
d Su
S
d 
and
X
d
ly an
X
y a
X
an
Only
X
y
X
ly 
On
On
e O
 
e O
e O
e
Us
cial 
X
al
X
l U
ercia
X
cia
e
me
mer
er
me
m
om
C
Takeda: For Non-C
n C
n
No
or
F
a
da
da
da:
da
us; PD: p
aked
us; PD: p
Property of T
ement of 
Ta
ement of 
asuremen
of T
asuremen
measurem
ty o
measurem
ed

TAK-788
Study No. TAK-788-1004
Page 73 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
CONFIDENTIAL
Table A-2
PK and Pharmacodynamic Blood Sampling Schedule
Blood Sampling Time
Cycle 1
Cycle 2
Day 1
Day 2
Day 24
Day 25
Day 1
Oral
Midazolam
PK a
PD b
IV
Midazolam
PK a
Oral
Midazolam
PK a
TAK-788
PK c
PD g
IV
Midazolam
PK a
TAK-788
PK c
TAK-788
PK c
d Blood samples also serve as the 24-hour postdose blood samples for oral midazolam.
e It is critical that this blood sample is drawn immediately at the end of infusion with as little delay as possible.
f Blood sample to be collected before TAK-788 dosing. Days 2 and 25 24-hour PK samples will be collected predose on Days 3 and 26, respectively.
g Blood samples for the measurement of concentrations of 4b-hydroxycholesterol and cholesterol in plasma only.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
Te
lic
App
p
8
P
e A
 th
sible.
bje
sible.
lected pre
Sub
lected pre
n plasma 
d S
n plasma 
t t

TAK-788
Study No. TAK-788-1004
Page 74 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
CONFIDENTIAL
Table A-3
Schedule of Events for Part B (Repeat 28-Day Treatment Cycles)
Assessment
Treatment Cycles a
EOT
30 Days 
After EOT 
Follow-up
Cycle 2
(±3 days)
Cycle 3
(±3 days)
Every 4 
Weeks
Every 8 
Weeks
Every 12 
Weeks, After 
14 Cycles
Day 1
(±3 days) b
Day 1
(±3 days) b
Day 1
(±3 days) b
Day 1
(±3 days) b
Day 1
(±3 days) b
Weight
X
X
X
Vital signs c
X
X
X
X
ECOG performance status
X
X
X
12-lead ECG d
X
C4D1, 
C7D1, and 
every 
4 cycles 
following C7
X
Echocardiogram/MUGA for LVEF e
X
C4D1 and 
C7D1 only
X
Physical examination f
X
X
X
X
Clinical laboratory tests g
X
X
X
X
Serology h
X
Pregnancy test i
X
X
X
Adverse events (including SAEs)
Recorded from the signing of the informed consent form through 30 days after the last dose of study drug.
Concomitant medications and procedures
Recorded from the signing of the informed consent form through 30 days after the last dose of study drug.
Imaging assessments j
X k
X k
X k
X k
TAK-788 QD administration l
X (Day 1-28 every treatment cycle)
Assessment of patient dosing diary
X
X
X
X
PK 
X (predose)
ommercial Use Only and Subject to the Applicable Terms of Use
Te
lic
ks
ks
Ev
p
Ev
W
A
W
App
e
Day 1
t to
Day 1
(±3 days)
ect 
(±3 days)
to
je
Sub
S
d S
C4D1, 
y an
C4D1, 
C7D1, a
nly 
C7D1, a
ev
n
ev
4
O
4
f
an
e O
U
rc
m
a: For Non-Comm
mm
om
X
n
X
C
Reco
No
Reco
on
R
N
R
N
Fo
f Takeda: F
a: 
iary
ak
iary
ed
Tak
Property of T
f T

TAK-788
Study No. TAK-788-1004
Page 75 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
CONFIDENTIAL
Table A-3
Schedule of Events for Part B (Repeat 28-Day Treatment Cycles)
Assessment
Treatment Cycles a
EOT
30 Days 
After EOT 
Follow-up
Cycle 2
(±3 days)
Cycle 3
(±3 days)
Every 4 
Weeks
Every 8 
Weeks
Every 12 
Weeks, After 
14 Cycles
Day 1
(±3 days) b
Day 1
(±3 days) b
Day 1
(±3 days) b
Day 1
(±3 days) b
Day 1
(±3 days) b
Biomarker m
X (C3 and 
C5 only)
X (at disease 
progression)
AE: adverse event; CT: computed tomography; C: Cycle; ECG: electrocardiogram; ECOG: Eastern Cooperative Oncology Group; EOT: end of treatment; β-hCG: β-human 
chorionic gonadotropin; LVEF: left ventricular ejection fraction; MRI: magnetic resonance imaging; MUGA: multigated acquisition; QD, once daily; SAE: serious adverse event.
a Treatment cycles are 28 days in duration and are to continue until disease progression, intolerable toxicity, or another discontinuation criterion is met.
b Assessments outlined for Day 1 must be performed prior to study dosing, with the exception of adverse event assessments which must be performed both prior to and after study 
dosing.
c Vital signs are to be measured just before dosing on Day 1 of each cycle; as needed throughout the study; and at EOT.
d ECGs will occur at C2D1, C4D1, C7D1, and every 4 cycles following C7 and continue throughout the treatment period and EOT.
e Echocardiogram/MUGA scan must be performed on C2D1, C4D1, C7D1, and EOT for LVEF and may be performed at other times according to medical judgment.
f Symptom-directed physical examinations will be performed on Day 1 of each cycle and at the 30-day follow-up visit. A complete physical examination is to be conducted at 
screening and EOT. 
g Clinical laboratory tests (hematology, and clinical chemistry) are to be performed on Day 1 of each cycle before dosing and at EOT. See Table 9.a for the list of tests to be 
performed.
h HBV screening may include the following: HBsAg, hepatitis B surface antibody, and hepatitis B core antibody, in accordance with local institutional practices. Patients who test 
positive for HBsAg will also be tested for HBV DNA at screening. HCV screening will include HCVAb. Patients who test positive for HCVAb will also be tested for HCV RNA 
at screening (see Section 9.3.12.1).
i For all women of childbearing potential, a urine or serum β-hCG pregnancy test is to be performed within 1 day before first dose of study drug (Cycle 1 Day 1, Part A). The test 
results must be negative and available before the first dose of study drug is administered. Pregnancy testing must be conducted every 4 weeks (±3 days) thereafter and at EOT. 
Refer to Section 9.3.13 for additional information. 
j CT/MRI is to be performed every 8 weeks, at the end of every even-numbered cycle (ie, 2, 4, 6, etc) up to Cycle 14, and every 12 weeks (ie, every 3 cycles) thereafter and at EOT. 
Imaging assessments will consist of CT scans of the chest, abdomen, and pelvis for all patients. Imaging of the brain (contrast-enhanced MRI is preferred) is required at screening 
for all patients, and will be repeated postbaseline for patients with CNS metastases at baseline (see Section 9.3.16).
k Imaging is to be performed at 8-week intervals in part B (ie, on Day 28 [±3 days] of every even-numbered cycle) through 14 cycles after the initial dose of TAK-788, and every 3 
cycles thereafter until PD and at EOT. If there is PD during study treatment, imaging assessment need not be repeated at EOT. Imaging assessments will consist of CT scans of the 
chest, abdomen, and pelvis for all patients. Imaging of the brain (contrast-enhanced MRI is preferred) is required at screening for all patients, and will be repeated postbaseline for 
of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
Te
lic
ks
ks
Ev
p
Ev
W
A
W
App
e
Day 1
t to
Day 1
(±3 days)
ect 
(±3 days)
to
je
S
rn Cooper
nd S
rn Cooper
aging; MU
and
aging; MU
olerable to
ly a
olerable to
eption of 
Only
eption of 
ded throu
Use 
ded throu
nd continu
l Us
nd continu
, and EO
ial 
and EO
of each c
erci
of each c
re to be p
mm
re to be p
atitis B su
-Co
atitis B su
at screenin
on-
at screenin
e or serum
or N
e or serum
the first d
For
the first d
mation.
a: F
mation.
eeks, at th
eda
eeks, at th
f CT scans
ked
f CT scans
ted postba
Tak
ted postba
at 8
f T
at 8
Property o
-
f T
-week
f Ta
week
and at EO
of 
and at EO
lvis for al
ty o
lvis for al
S

TAK-788
Study No. TAK-788-1004
Page 76 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
CONFIDENTIAL
Table A-3
Schedule of Events for Part B (Repeat 28-Day Treatment Cycles)
Assessment
Treatment Cycles a
EOT
30 Days 
After EOT 
Follow-up
Cycle 2
(±3 days)
Cycle 3
(±3 days)
Every 4 
Weeks
Every 8 
Weeks
Every 12 
Weeks, After 
14 Cycles
Day 1
(±3 days) b
Day 1
(±3 days) b
Day 1
(±3 days) b
Day 1
(±3 days) b
Day 1
(±3 days) b
patients with CNS metastases at baseline (see Section 9.3.16). Disease assessment at EOT does not need to be repeated if obtained within 28 days of last dose
l TAK-788 160 mg QD is to be administered once per day from Day 1 through Day 28 of each treatment cycle. TAK-788 dose may be reduced based on dose modification 
guidelines to 120 or 80 mg in patients who do not tolerate the 160 mg dose. 
m Biomarker assessment will include circulating DNA to be evaluated at Cycle 3, and Cycle 5, as well as at the time of disease progression.
to the Applicable Terms of Use
Te
lic
ks
ks
Ev
p
Ev
W
A
W
App
e
ct to 
Day 1
t to
Day 1
jec
(±3 days)
ect 
(±3 days)
to
nd Subje
to be repe
ubje
to be repe
ent cycle. 
Sub
ent cycle. 
Property of Takeda: For Non-Commercial Use Only an
as well as
and
as well as
je

TAK-788
Study No. TAK-788-1004
Page 77 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
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 responsibilities imposed on investigators by the FDA are 
summarized in the Statement of Investigator (Form FDA 1572), which must be completed and 
signed before the investigator may participate in this study.
The investigator agrees to assume the following responsibilities by signing a Form FDA 1572:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff who will assist in the protocol.
3. If the investigator/institution retains the services of any individual or party to perform trial-
related duties and functions, the investigator/institution should ensure that this individual or 
party is qualified to perform those trial-related duties and functions and should implement 
procedures to ensure the integrity of the trial-related duties and functions performed and any 
data generated.
4. Ensure that study-related procedures, including study-specific (nonroutine/nonstandard 
panel) screening assessments, are NOT performed on potential subjects before the receipt of 
written approval from relevant governing bodies/authorities.
5. Ensure that all colleagues and employees assisting in the conduct of the study are informed 
of these obligations.
6. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform 
to 21 CFR Part 56, ICH, and local regulatory requirements.
7. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and 
approval of the protocol. Promptly report to the IRB/IEC all changes in research activity and 
all anticipated risks to subjects. Make at least yearly reports on the progress of the study to 
the IRB/IEC, and issue a final report within 3 months of study completion.
8. Ensure that requirements for informed consent, as outlined in 21 CFR Part 50, ICH, and local 
regulations, are met.
9. Obtain valid informed consent from each subject who participates in the study, and document 
the date of consent in the subject’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each ICF should contain a subject authorization section 
that describes the uses and disclosures of a subject’s personal information (including personal 
health information) that will take place in connection with the study. If an ICF does not 
include such a subject authorization, then the investigator must obtain a separate subject 
authorization form from each subject or the subject’s legally acceptable representative.
10. Prepare and maintain adequate case histories of all persons entered into the study, including 
eCRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
2 years following notification by the sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
CCI
Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
and 
rm
and 
FDA
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in

TAK-788
Study No. TAK-788-1004
Page 78 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
contact and receive written approval from the sponsor before disposing of any such 
documents.
11. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
12. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor.
13. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours.
CCI
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
iaial
o
l
upplied 
Ter
upplied 
tify the 
cab
tify the 

TAK-788
Study No. TAK-788-1004
Page 79 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
Appendix C
Investigator Consent to Use of Personal Information
Takeda will collect and retain personal information of the investigator, including his or her name, 
address, and other identifying personal information. In addition, the investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
UK, US, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
The investigator’s personal information may be retained, processed, and transferred by Takeda 
and these other parties for research purposes including the following:

Assessment of the suitability of the investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may 
contain the same chemical compound present in the study medication.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of study records.

Posting investigator site contact information, study details, and results on publicly accessible 
clinical trial registries, databases, and websites.
The investigator’s personal information may be transferred to other countries that do not have 
data protection laws that offer the same level of protection as data protection laws in the 
investigator’s own country.
The investigator acknowledges and consents to the use of his or her personal information by 
Takeda and other parties for the purposes described above.
CCI
f Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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TAK-788
Study No. TAK-788-1004
Page 80 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
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 [23].
CCI
pplicable Terms of Use
of
ble to 
rms
ble to 
out any w
e T
out any w
hair mor
cab
hair mor
Property of Takeda: For Non-Commercial Use Only and Subject to the Ap
tally con
App
tally con
o t

TAK-788
Study No. TAK-788-1004
Page 81 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
Appendix E
Drugs That Interact With the CYP3A Family of Cytochrome P450 
Drugs listed in Table A-4 below are moderate inducers or inhibitors or strong inducers or 
inhibitors of the CYP3A family and are prohibited as concomitant medications with TAK-788, 
with the exception of nonsystemic use.
Table A-4
Schedule of Events for Drugs Inducing or Inhibiting CYP3A Metabolism 
That Prohibited Concomitant Medications With TAK-788
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
clarithromycin
cobicistat
danoprevir and ritonavir
elvitegravir and ritonavir
grapefruit juice
idelalisib
indinavir and ritonavir
itraconazole
ketoconazole
lopinavir and ritonavir
CCI
akeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
8,
ms
8,
bolism
e Te
bolism
ab
pli
t t
jec
O
Us
YP3A In
ked
YP3A In
ed
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previr
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of T
rithromy
cobicista
y o
cobicista
danop
erty
danop
elv
er
elv
Prope
ak
pe

TAK-788
Study No. TAK-788-1004
Page 82 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
nefazodone
nelfinavir
paritaprevir and ritonavir and (ombitasvir and/or dasabuvir)
posaconazole
ritonavir
saquinavir and ritonavir
telaprevir
telithromycin
tipranavir and ritonavir
troleandomycin
voriconazole
CYP: cytochrome P450.
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 with any queries. 
a fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-
inducers#table3-3 (accessed 25 August 2020).
b fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-
inducers#table3-2 (accessed 25 August 2020).
CCI
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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pp

TAK-788
Study No. TAK-788-1004
Page 83 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
Appendix F
Drugs With a Risk of Torsades de Pointes
The website crediblemeds.org/everyone/composite-list-all-qtdrugs/ 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 Table A-5 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.
Table A-5
Drugs With 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 / 
thrombocythemia
Arsenic trioxide
Trisenox
Anticancer / leukemia
Astemizole
Hismanal
Antihistamine / allergic rhinitis
Azithromycin
Zithromax, Zmax
Antibiotic / bacterial infection
Bepridil 
Vascor
Antianginal / angina pectoris (heart 
pain)
Cesium chloride
Energy Catalyst
Toxin/ alternative therapy cancer
Chloroquine
Aralen
Antimalarial / malaria 
Chlorpromazine
Thorazine, Largactil, Megaphen
Antipsychotic, antiemetic / 
schizophrenia, nausea, many others
Chlorprothixene
Truxal
Antipsychotic / schizophrenia
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
CCI
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
ith
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e
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pe
p

TAK-788
Study No. TAK-788-1004
Page 84 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
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, 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
Antifungal / 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
Hydroxychloroquine
Plaquenil, Quineprox
Antimalarial, anti-inflammatory / 
malaria, SLE, rheumatoid arthritis
Ibogaine
None
Psychedelic / narcotic addiction, 
unproven
Ibutilide
Corvert
Antiarrhythmic / abnormal heart 
rhythm
Levofloxacin
Levaquin, Tavanic
Antibiotic / bacterial infection
Levomepromazine 
(methotrimeprazine)
Nosinan, Nozinan, Levoprome
Antipsychotic / schizophrenia
Levomethadyl acetate
Orlaam
Opiate agonist / narcotic dependence
Levosulpiride
Lesuride, Levazeo, Enliva 
Antipsychotic / schizophrenia
Mesoridazine
Serentil
Antipsychotic / schizophrenia
Methadone
Dolophine, Symoron, Amidone, 
Methadose, Physeptone, Heptadon
Opiate agonist / pain, narcotic 
dependence
Moxifloxacin
Avelox, Avalox, Avelon
Antibiotic / bacterial infection
Nifekalant
Shinbit
Antiarrhythmic / arrhythmia
CCI
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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TAK-788
Study No. TAK-788-1004
Page 85 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
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
Vasoconstrictor / septic shock
Terodiline
Micturin, Mictrol
Muscle relaxant / bladder spasm
Thioridazine
Mellaril, Novoridazine, Thioril 
Antipsychotic / schizophrenia
Vandetanib
Caprelsa
Anticancer / cancer (thyroid)
Source: crediblemeds.org/everyone/composite-list-all-qtdrugs/ [Accessed 25 August 2020].
GI: gastrointestinal; SLE: systemic lupus erythematosus; SSRI: selective serotonin reuptake inhibitor.
Drugs generally accepted by the CredibleMeds QTDrug List Advisory Board to have a known risk of causing 
torsades de pointes.
CCI
d Subject to the Applicable Terms of Use
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s o
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TAK-788
Study No. TAK-788-1004
Page 86 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
Appendix G
Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1)
Note: These criteria are adapted from Eisenhauer et al [24].
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 LD (longest diameters) of non-nodal lesions (axial plane).

Add short axis diameters of nodes.

This is the SLD (sum of the longest diameters).
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.
CCI
ommercial Use Only and Subject to the Applicable Terms of Use
t lesion w
licab
t lesion w
classifi
d S
classifi
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and
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Com
target
w lesio
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w lesion
these as
or N
these as

TAK-788
Study No. TAK-788-1004
Page 87 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
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. (2 
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).
SLD: sum of the longest diameters.
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.
CCI
keda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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TAK-788
Study No. TAK-788-1004
Page 88 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
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.
CCI
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TAK-788
Study No. TAK-788-1004
Page 89 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
Appendix H
Protocol History
Date
Amendment Number
Amendment Type (for use 
in Europe only)
Region
03 September 2020
2
Substantial
Global
03 April 2020
01
Substantial
Global
14 February 2019
Initial Protocol
Not applicable
Global
Protocol Amendment 01 Summary and Rationale:
This document describes the changes in reference to the protocol incorporating Amendment 01. 
The primary reasons for this amendment are to:

Provide clarification for some of the protocol language.

Increase the number of planned patients to 26.

Provide clarification of screening windows and rescreening.

Provide clarification of inclusion and exclusion requirements.

Provide updated information for potential effect of TAK-788 to cause embryofetal harm and 
relevant restrictions for patient reproductive behavior.

Provide clarification for management of diarrhea and pneumonitis.

Provide safety monitoring of left ventricular ejection fraction (LVEF).

Provide instructions for Acknowledgement of Receipt when a serious adverse event (SAE) is 
submitted to Takeda or designee by facsimile (fax).
In this amendment, minor grammatical, editorial, formatting, and administrative changes not 
affecting the conduct of the study are included for clarification and administrative purposes only.
Protocol Amendment
Summary of Changes Since the Last Version of the Approved Protocol
Amendment Number
01
Amendment Date
03 April 2020
Global
Description of Each Change and Rationale 
Sections Affected by Change
Description 
Rationale 
Location
1. Added separate inclusion 
criterion (No 6.f) for serum amylase 
(≤1.5 × upper limit of normal 
[ULN] unless the increased serum 
amylase is due to salivary
isoenzymes).
Clarification 
Section 2.0 Study Summary
Section 7.1 Inclusion Criteria
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TAK-788
Study No. TAK-788-1004
Page 90 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
Protocol Amendment
Summary of Changes Since the Last Version of the Approved Protocol
Amendment Number
01
Amendment Date
03 April 2020
Global
2. Added clarification of exclusion 
criterion for central nervous system 
(CNS) metastases (No 8) for 
previously treated, untreated, or 
progressing CNS lesions.
Clarification
Section 2.0 Study Summary
Section 7.2 Exclusion Criteria
3. Added clarification of exclusion 
criterion for congestive heart failure 
(No 11.c) to include cardiac ejection 
fraction <50% by echocardiogram 
(ECHO) or multiple gated 
acquisition scan (MUGA).
Clarification
Section 7.2 Exclusion Criteria
4. Increased the number of planned 
patients to 26 and added that 
assessment of the PK-evaluable 
population will be conducted when 
dosing and safety (ie, vomiting) data 
become available and prior to study 
closure.
To adjust for non-evaluable 
subjects that may result from 
dosing and safety (ie, vomiting) 
issues.
Section 2.0 Study Summary
Section 6.1 Overview of Study Design
Section 6.2 Number of Patients
Section 6.3.2.1 Study Duration
Section 7.0 Study Population
Section 13.1.1.1 PK-Evaluable 
Population
Section 13.3 Determination of Sample 
Size
5. Added clarification that fasting 
for 2 hours prior to and 2 hours after 
oral midazolam dosing included 
consumption of water except during 
dose administration.
Clarification
Section 8.1 Study Drug Administration 
(Table 8.a)
6. Added potential effect of TAK-
788 to cause embryofetal harm 
(based on embryofetal toxicity study 
in rats).
To provide updated safety 
information
Section 8.5.1.2 Pregnancy and 
Breastfeeding
7. Added clarification for 
management of diarrhea.
Clarification
Section 8.6.2 Diarrhea
8. Added clarification for 
management of pneumonitis.
Clarification
Section 8.6.4 Pneumonitis
9. Added new section for screening 
that describes the time windows 
relative to randomization, 
rescreening, and collection of AEs 
during screening.
Clarification
Section 9.3.3 Screening
Schedule of Events Table Part A, 
footnote “a”
10. Added instructions for 
investigators to record clinically 
significant changes in vital sign 
measurements in the electronic case 
report form (eCRF) as an AE. 
Clarification
Section 9.3.7 Vital Signs
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TAK-788
Study No. TAK-788-1004
Page 91 of 91
Protocol Incorporating Amendment No. 2
03 September 2020
Protocol Amendment
Summary of Changes Since the Last Version of the Approved Protocol
Amendment Number
01
Amendment Date
03 April 2020
Global
11. Added instructions for 
investigators to record clinically 
significant changes in 
electrocardiogram (ECG) 
measurements in the eCRF as an 
AE.
Clarification
Section 9.3.9 ECG
12. Added cardiac monitoring of left 
ventricular ejection fraction (LVEF) 
by echocardiogram/Multigated 
Acquisition (MUGA) Scan.
To provide monitoring of LVEF
Section 9.3.11 Echocardiogram/ MUGA 
Scan for Left Ventricular Ejection 
Fraction.
Appendix A Schedule of Events Tables 
Part A and Part B, including footnote 
“d”
13. Added instructions for 
investigators to record clinically 
significant changes in clinical 
laboratory evaluations in the eCRF 
as an AE.
Clarification
Section 9.3.12.1 Hematology, Clinical 
Chemistry and Serology
14. Added language for 
acknowledgement of receipt when a 
serious adverse event (SAE) is 
submitted to Takeda or designee by 
facsimile.
Clarification
Section 10.2 Procedures for Reporting 
AEs and SAEs
15. Minor editorial revisions were 
made for clarification throughout 
the document.
Administrative
Throughout the protocol
CCI
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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ELECTRONIC SIGNATURES
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm ‘UTC’) 
090101d680e4f4d2
Amendment 2 to A Phase 1, Open-Label, Multicenter, Drug-Drug Interaction Study of TAK-788 and Midazolam,
a Sensitive CYP3A Substrate, in Patients With Advanced Non–Small Cell Lung Cancer
Clinical Approval
04-Sep-2020 12:31 UTC
Biostatistics Approval
04-Sep-2020 12:58 UTC
Clinical Pharmacology Approval
04-Sep-2020 13:10 UTC
CCI
PPD
Terms of Use
e Te
ate 
T
ate 
ble T
HH:mm ‘U
ble 
HH:mm ‘U
Ter
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable
ble
31 UTC
able
31 UTC
020 12:58
ppli
020 12:58
-Sep-2020
he A
-Sep-2020