Clinical trial NCT03370302
Conditions: Advanced Nonhematological Neoplasms
Keywords: Drug therapy
Sponsor: Calithera Biosciences, Inc
Start date: 2018-01-17; Completion date: 2019-08-28
Enrollment: 28 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the safety and tolerability, recommended phase 2 dose (RP2D), and to characterize PK of TAK-228 administered once daily or once weekly to East Asian participants with advanced nonhematological malignancies.

Detailed description:
The drug being tested in this study is called TAK-228. TAK-228 is being tested to treat East Asian participants with advanced nonhematological malignancies for whom standard anticancer treatment is not available or is no longer effective. This study will assess the safety, tolerability, PK and will determine the RP2Ds of TAK-228.

The study will enroll approximately 46 participants, including at least 6 Japanese participants at RP2D dose level. Participants will be assigned to one of the following treatment arms:

* TAK-228 Once Daily
* TAK-228 Once Weekly

This multi-center trial will be conducted in South Korea, Taiwan, and Japan. The overall time to participate in this study is up to 12 months, unless in the opinion of the investigator and sponsor the participant would derive benefit from continued therapy beyond 12 months. Participants will be followed for 30 days after last dose of study drug for a follow-up assessment.

Arms: arm 1: TAK-228, milled capsule, orally, once daily, on an empty stomach in a 28-day treatment cycle for up to 12 months or until disease progression or unacceptable toxicity or withdrawal of consent with a starting dose of 2 milligram (mg) in Cohort 1. Dose escalation will follow a standard 3+3 schema. If 2 mg, once daily, is safe and tolerable, then the dose will be escalated to 4 mg, once daily, until RP2D is determined. arm 2: TAK-228, milled capsule, orally, once weekly, on an empty stomach in Cycle 1 of a 28-day treatment cycle and following a light meal from Cycle 2 for up to 12 months or until disease progression or unacceptable toxicity or withdrawal of consent with a starting dose of 20 mg in Cohort 1. Dose escalation will follow a standard 3+3 schema. If 20 mg, once weekly, is safe and tolerable, then the dose will be escalated to 30 mg, once weekly, until RP2D is determined.
Interventions: intervention 1: TAK-228
Intervention descriptions: intervention 1: TAK-228 Capsules.

Protocol documents:
Prot_000.pdf: 



Title: A Phase 1, Open-label Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of 
TAK-228 (a Catalytic TORC1/2 Inhibitor) as Single Agent in Adult East Asian Patients with 
Advanced Nonhematological Malignancies
NCT Number: NCT03370302
Protocol Approve Date: 8 February 2018
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
view with a black/blue bar) to protect either personally identifiable information (PPD) or company 
confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal information, or 
to otherwise protect the integrity of the clinical study.


PROTOCOL
A Phase 1, Open-label Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of 
TAK-228 (a Catalytic TORC1/2 Inhibitor) as Single Agent in Adult East Asian Patients with 
Advanced Nonhematological Malignancies
A Phase 1 Study of TAK-228 in East Asian Patients with Advanced Nonhematological 
Malignancies
Sponsor:
Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda 
Pharmaceutical Company Limited
40 Landsdowne Street
Cambridge, MA USA 02139
Telephone: +1 (617) 679-7000
Please note: Millennium Pharmaceuticals, Inc, a wholly owned 
subsidiary of Takeda Pharmaceutical Company Limited, may be 
referred to in this protocol as “Millennium,” “Sponsor,” or “Takeda”.
Study Number:
C31008
IND Number:
Not Applicable
EudraCT Number:
Not Applicable 
Compound:
TAK-228
Date:
8 February 2018
Amendment Number:
02
Amendment History:
Date
Amendment Number
Region
2 August 2017
Initial Protocol
Global
25 October 2017
01
Global
8 February 2018
02
Global
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1.0
ADMINISTRATIVE
1.1
Contacts
A separate contact information list will be provided to each site.
Serious adverse event and pregnancy reporting information is presented in Section 10.0, as is 
information on reporting product complaints.
Takeda-sponsored investigators per individual country requirements will be provided with 
emergency medical contact information cards to be carried by each subject.
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site. Information on service providers is given in Section 3.1 and relevant guidelines 
provided to the site.
Contact Type/Role
Contact
Serious adverse event and 
pregnancy reporting
See Section 10.2.
Responsible Medical Officer 
(carries overall responsibility for 
the conduct of the study)
PPD
Property of Takeda: For non-commercial use on
on
ject to the applicable Terms of Use
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1.2
Approval
REPRESENTATIVES OF TAKEDA
This study will be conducted with the highest respect for the individual participants in accordance 
with the requirements of this clinical study protocol and also in accordance with the following:
!
The ethical principles that have their origin in the Declaration of Helsinki.
!
International Conference on Harmonisation (ICH) E6 Good Clinical Practice (GCP): 
Consolidated Guideline.
!
All applicable laws and regulations, including, without limitation, data privacy laws, clinical 
trial disclosure laws, and regulations.
SIGNATURES
The signature of the responsible Takeda medical officer (and other signatories, as applicable) can 
be found on the signature page.
Electronic Signatures may be found on the last page of this document.
PPD
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dance
dance
wing:
wing:
(GCP)
(GCP
ta privac
priva
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INVESTIGATOR AGREEMENT
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, and any 
other product information provided by the sponsor. I agree to conduct this study in accordance 
with the requirements of this protocol and also to protect the rights, safety, privacy, and well-being 
of study subjects in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Conference on Harmonisation, E6 Good Clinical Practice: Consolidated 
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting serious adverse events defined in Section 10.2 of this 
protocol.

Terms outlined in the Clinical Study Site Agreement.

Responsibilities of the Investigator (Appendix B).
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix C of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Provence)
Location of Facility (Country)
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1.3
Protocol Amendment 02 Summary of Changes
This document describes the changes in reference to the Protocol Incorporating Amendment No. 
02.
The primary purpose of this amendment is to incorporate regulatory feedback from the Korean 
Ministry of Food and Drug Safety (MFDS).
Justification: The changes are being made to the protocol based upon feedback received from the 
MFDS. In addition, minor revisions (including grammatical and editorial changes) are included 
for clarification purposes. Full details on changes of text are given in Appendix I. The following is 
a summary of the changes made in the amendment:
1. Section 8.2: Removed the note for the relationship to be consistent with Section 10.2.
2. Section 9.4.2: Added smoking history.
3. Section 9.8: Added pregnancy to the discontinuation criteria for clarification.
4. Section 9.8: Revised the text for “replacement subject” for clarification.
5. Section 13.1.4: Added pharmacokinetic (PK) analysis plan for the samples obtained in Cycle 2 
for QW arm.
6. Appendix A, Schedule of Events: Added additional ECG collection timepoints to collect 
additional data to verify and confirm that treatment with TAK-228 is not associated with an 
increased risk of cardiac events.
7. Appendix A: Revised Footnote a in Table A to clarify overnight fasting is not required for PK 
sampling on Cycle 1 Day 22.
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TABLE OF CONTENTS
1.0
ADMINISTRATIVE.......................................................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
1.3
Protocol Amendment 02 Summary of Changes ..........................................................5
2.0
STUDY SUMMARY ....................................................................................................11
3.0
STUDY REFERENCE INFORMATION ......................................................................16
3.1
Study-Related Responsibilities.................................................................................16
3.2
Coordinating Investigator.........................................................................................16
3.3
List of Abbreviations ...............................................................................................17
3.4
Corporate Identification...........................................................................................19
4.0
INTRODUCTION.........................................................................................................20
4.1
Background .............................................................................................................20
4.2
Nonclinical Experience............................................................................................20
4.3
Clinical Experience..................................................................................................21
4.4
Potential Risks and Benefits.....................................................................................22
4.5
Rationale for the Proposed Study.............................................................................23
4.5.1
Rationale for Dose and Schedule Selection ........................................................23
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................26
5.1
Objectives................................................................................................................26
5.1.1
Primary Objectives.............................................................................................26
5.1.2
Secondary Objectives.........................................................................................26
5.1.3
Exploratory Objectives.......................................................................................26
5.2
Endpoints.................................................................................................................26
5.2.1
Primary Endpoints .............................................................................................26
5.2.2
Secondary Endpoints..........................................................................................26
5.2.3
Exploratory Endpoints .......................................................................................27
6.0
STUDY DESIGN..........................................................................................................28
6.1
Overview of Study Design.......................................................................................28
6.2
Number of Patients ..................................................................................................29
6.3
Duration of Study ....................................................................................................30
6.3.1
Duration of an Individual Patient’s Study Participation ......................................30
6.3.2
End of Study/Study Completion Definition and Planned Reporting....................30
6.3.3
Timeframes for Primary and Secondary Endpoints to Support Disclosures.........30
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6.3.4
Total Study Duration..........................................................................................31
7.0
STUDY POPULATION................................................................................................32
7.1
Inclusion Criteria .....................................................................................................32
7.2
Exclusion Criteria ....................................................................................................33
8.0
STUDY DRUG .............................................................................................................36
8.1
Study Drug Administration......................................................................................36
8.2
Definitions of Dose Limiting Toxicity .....................................................................36
8.3
Dose Escalation Rules..............................................................................................38
8.4
Dose Modification Guidelines..................................................................................41
8.4.1
Intrapatient Dose Escalation...............................................................................41
8.4.2
Criteria for Beginning or Delaying a Subsequent Treatment Cycle.....................41
8.4.3
Criteria for Dose Interruption During a Cycle.....................................................41
8.4.4
Criteria for Dose Reduction................................................................................41
8.4.5
Criteria for Discontinuation................................................................................42
8.5
Excluded Concomitant Medications and Procedures ................................................42
8.6
Permitted Concomitant Medications and Procedures................................................43
8.7
Precautions and Restrictions ....................................................................................43
8.7.1
Pregnancy and Contraception.............................................................................43
8.7.2
Patients With Prior Exposure to HBV or HCV...................................................44
8.7.3
Overdose............................................................................................................45
8.8
Management of Clinical Events ...............................................................................45
8.8.1
Management of Hyperglycemia .........................................................................45
8.8.2
Management of Hyperlipidemia .........................................................................46
8.8.3
Management of Oral Mucositis ..........................................................................47
8.8.4
Management of Rash .........................................................................................48
8.8.5
Management of Nausea/Vomiting ......................................................................49
8.8.6
Management of AST/ALT Elevations ................................................................50
8.8.7
Management of Non-Infectious Pneumonitis......................................................51
8.8.8
Management of Other Nonhematologic Toxicities .............................................52
8.9
Blinding and Unblinding..........................................................................................53
8.10
Description of Investigational Agents ......................................................................53
8.11
Preparation, Reconstitution, and Dispensation..........................................................54
8.12
Packaging and Labeling...........................................................................................54
8.13
Storage, Handling, and Accountability.....................................................................54
8.14
Other Protocol-Specified Materials ..........................................................................55
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9.0
STUDY CONDUCT......................................................................................................56
9.1
Study Personnel and Organizations..........................................................................56
9.2
Arrangements for Recruitment of Patients................................................................56
9.3
Treatment Group Assignments.................................................................................56
9.4
Study Procedures.....................................................................................................56
9.4.1
Informed Consent...............................................................................................56
9.4.2
Patient Demographics ........................................................................................56
9.4.3
Medical History .................................................................................................56
9.4.4
Physical Examination.........................................................................................57
9.4.5
Patient Height and Weight .................................................................................57
9.4.6
Vital Signs .........................................................................................................57
9.4.7
Pregnancy Test...................................................................................................57
9.4.8
Eastern Cooperative Oncology Group Performance Status .................................57
9.4.9
Electrocardiogram..............................................................................................57
9.4.10 Concomitant Medications and Procedures..........................................................58
9.4.11 Adverse Events ..................................................................................................58
9.4.12 Enrollment .........................................................................................................58
9.4.13 Clinical Laboratory Evaluations .........................................................................58
9.4.14 Fasting Lipid Profile ..........................................................................................59
9.4.15 Fasting Serum Glucose ......................................................................................60
9.4.16 Hepatitis Testing................................................................................................60
9.4.17 In-Home Daily Fasting Glucose Monitoring.......................................................60
9.4.18 DNA Measurements...........................................................................................61
9.4.19 Disease Assessment ...........................................................................................61
9.4.20 Pharmacokinetic Measurements.........................................................................62
9.5
Documentation of Subjects Failure ..........................................................................62
9.6
Completion of Study Treatment (for Individual Patients) .........................................62
9.7
Completion of Study (for Individual Patients)..........................................................63
9.8
Discontinuation of Treatment With Study Drug and Patient Replacement................63
9.9
Study Compliance....................................................................................................64
10.0
ADVERSE EVENTS ....................................................................................................65
10.1
Definitions...............................................................................................................65
10.1.1 Pretreatment Event Definition............................................................................65
10.1.2 Adverse Event Definition...................................................................................65
10.1.3 Serious Adverse Event Definition ......................................................................65
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10.2
Procedures for Recording and Reporting Adverse Events and Serious 
Adverse Events........................................................................................................66
10.3
Monitoring of Adverse Events and Period of Observation........................................67
10.4
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events.........67
10.5
Procedures for Reporting Product Complaints or Medication Errors (Including 
Overdose) ................................................................................................................68
10.6
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities...........68
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................69
12.0
DATA HANDLING AND RECORDKEEPING............................................................70
12.1
eCRFs......................................................................................................................70
12.2
Record Retention .....................................................................................................70
13.0
STATISTICAL METHODS..........................................................................................72
13.1
Statistical and Analytical Plans ................................................................................72
13.1.1 Analysis Sets......................................................................................................72
13.1.2 Analysis of Demographics and Other Baseline Characteristics ...........................72
13.1.3 Efficacy Analysis...............................................................................................72
13.1.4 Pharmacokinetic Analysis ..................................................................................72
13.1.5 Safety Analysis ..................................................................................................73
13.2
Interim Analysis and Criteria for Early Termination ................................................73
13.3
Determination of Sample Size..................................................................................74
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................75
14.1
Study-Site Monitoring Visits ...................................................................................75
14.2
Protocol Deviations..................................................................................................75
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................76
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................77
15.1
IRB and/or IEC Approval ........................................................................................77
15.2
Subject Information, Informed Consent, and Subject Authorization .........................78
15.3
Subject Confidentiality ............................................................................................79
15.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................79
15.4.1 Publication.........................................................................................................79
15.4.2 Clinical Trial Registration..................................................................................80
15.4.3 Clinical Trial Results Disclosure ........................................................................80
15.5
Insurance and Compensation for Injury....................................................................80
16.0
REFERENCES..............................................................................................................81
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LIST OF IN-TEXT TABLES
Table 4.a
Dose Limiting Toxicities Observed with Weekly TAK-228 in Study 
MLN0128-1004 .................................................................................................24
Table 6.a
Primary and Secondary Endpoints for Disclosures .............................................31
Table 8.a
Nutritional Information for a Light Meal............................................................36
Table 8.b
Planned Dose Levels..........................................................................................38
Table 8.c
Management of Hyperglycemia .........................................................................46
Table 8.d
Management of Hyperlipidemia .........................................................................47
Table 8.e
Management of Oral Mucositis ..........................................................................48
Table 8.f
Management of Rash .........................................................................................49
Table 8.g
Management of Nausea/Vomiting ......................................................................50
Table 8.h
Management of AST/ALT Elevations ................................................................51
Table 8.i
Management of Non-Infectious Pneumonitis......................................................52
Table 8.j
Management of Other Nonhematologic Toxicities (Including Asthenia, 
Weakness, and Fatigue)......................................................................................53
Table 9.a
Hematology, Chemistry, and Coagulation Tests .................................................59
Table 9.b
Urinalysis Tests .................................................................................................59
Table 9.c
Fasting Lipid Profile ..........................................................................................59
LIST OF IN-TEXT FIGURES
Figure 6.a
Study Overview Diagram...................................................................................29
Figure 8.a
QD Arm Dose Escalation Algorithm..................................................................39
Figure 8.b
QW Arm Dose Escalation Algorithm .................................................................40
LIST OF APPENDICES
Appendix A
Schedule of Events.............................................................................................82
Appendix B
Responsibilities of the Investigator.....................................................................86
Appendix C
Investigator Consent to Use of Personal Information..........................................88
Appendix D
ECOG Scale for Performance Status ..................................................................89
Appendix E
Cockcroft-Gault Equation ..................................................................................90
Appendix F
New York Heart Association Classification of Cardiac Disease..........................91
Appendix G
Methods of Contraception Considered to be Effective........................................92
Appendix H
List of Relevant Cytochrome P450 Inhibitors and Inducers ................................93
Appendix I
Detailed Description of Amendments to Text.....................................................94
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2.0
STUDY SUMMARY
Name of Sponsor(s):
Millennium Pharmaceuticals, Inc.
Compound:
TAK-228
Title of Protocol: A Phase 1, Open-label Study to Evaluate 
the Safety, Tolerability, and Pharmacokinetics of TAK-228 
(a catalytic TORC1/2 inhibitor) as Single Agent in Adult 
East Asian Patients with Advanced Nonhematological 
Malignancies
IND No.:
Not Applicable
EudraCT No.:
Not Applicable
Study Number: C31008
Phase: 1
Study Design:
This study is a multicenter, open-label, phase 1 trial of TAK-228 administered orally as a single agent in adult East
Asian patients with advanced nonhematological malignancies for whom standard anticancer treatment is not available 
or is no longer effective.
The study will consist of 2 arms to evaluate the safety and tolerability, characterize the pharmacokinetics (PK), and 
determine the recommended phase 2 doses (RP2Ds) of single-agent TAK-228 to be used for 2 schedules (daily and 
weekly) in East Asian patients.
1. QD (daily dosing schedule) arm: milled TAK-228 will be administered on an empty stomach (nothing to eat or 
drink for at least 2 hours before and 1 hour after dosing), once daily, in repeated 28-day treatment cycles.
2. QW (weekly dosing schedule) arm: milled TAK-228 will be administered on an empty stomach in Cycle 1 and 
following a light meal in Cycle 2 and the subsequent cycles, weekly (ie, on Days 1, 8, 15, and 22), in repeated 
28-day treatment cycles.
The 2 arms will enroll in parallel. Patient assignment to a specific schedule will be decided jointly by the investigator 
and sponsor with the aim of maximizing enrollment efficiency in the study.
During dose escalation, 2 planned dose levels of TAK-228 will be tested in each arm (2 mg and 4 mg in the QD arm; 
20 mg and 30 mg in the QW arm) following standard 3+3 dose escalation rules. Dosing will increase to 4 mg in the QD 
arm or 30 mg in the QW arm, provided that the safety and tolerability of the starting dose have been demonstrated.
If a dose is deemed safe in any cohort based on 3+3 rules, then the cohort may be expanded to as many as 12 patients 
in total to further confirm safety, investigate the PK and determine the RP2D. At least 1 Japanese patient will be 
enrolled in each group of 3 patients during dose escalation. The total number of Japanese patients dosed at the RP2D 
level will be at least 6. On the basis of the geographic distribution of patients enrolled or any emerging safety or PK 
data, additional patients may be added, as needed, to further characterize the safety, tolerability, or PK in patients from 
a particular East Asian geographic region.
As Western population based RP2D have been defined as 4 mg for the QD schedule and 30 mg for the QW schedule, 
the dose escalation schemas in the current study are designed to confirm Cycle 1 based RP2D in East Asian patients or 
determine an alternative appropriate lower dose. Escalation beyond 4 mg QD or 30 mg QW is not expected to be 
necessary in this study. However, if TAK-228 exposures are unexpectedly lower than anticipated in the East Asian 
populations, and no dose limiting toxicity (DLT) have occurred in the dose escalation parts, the TAK-228 dose may be 
escalated further after discussion between the investigators and the sponsor based on the available PK and safety data.
If ≥2 of 6 patients experience a DLT at the starting dose level (ie, 2 mg in the QD arm or 20 mg in the QW arm), 
depending on the overall safety profile, the types of adverse events (AEs)/DLTs observed, and following the 
examination of the preliminary PK results in relation to the PK data in the Western population, a decision will be made 
either to evaluate a lower dose or to terminate the study, following discussion between the investigators and the 
sponsor.
For either treatment arm, more conservative dose escalation, evaluation of intermediate doses, and expansion of an 
existing or previously tested dose level are all permissible following discussions and agreement between the 
investigators and the sponsor, if such measures are needed for patient safety or for a better understanding of the 
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dose-toxicity and dose-exposure relationships of TAK-228.
Blood samples will be collected at prespecified time points in Cycle 1 Days 1, 2, 8, 15, 16, and 22 to characterize the 
PK of TAK-228 when given daily (QD) or weekly (QW). Blood samples will also be collected at prespecified time 
points during Cycle 2 Days 1 and 15 to characterize the PK of TAK-228 when given QW with light meals.
 
Radiological tumor evaluations will be used to evaluate disease response according to Response Evaluation Criteria in 
Solid Tumors (RECIST) guidelines (Version 1.1).
Toxicity will be evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI CTCAE) version 4.03.
Primary Objectives:
•
To evaluate safety and tolerability and to determine RP2D of TAK-228 administered daily (QD arm) or weekly 
(QW arm) to East Asian patients with advanced nonhematological malignancies
•
To characterize PK of TAK-228 in East Asian patients with advanced nonhematological malignancies
Secondary Objectives:
•
To evaluate preliminary anti-tumor activity of TAK-228
Subject Population: Adult East Asian patients with advanced nonhematologic malignancies for whom standard 
treatment is not available or is no longer effective.
Planned Number of Subjects:
Approximately 46 patients (23 patients each for QD and 
QW arms)
Planned Number of Sites:
Approximately 4 sites in East Asian countries
Dose Level(s):
QD arm: TAK-228 will be administered once daily, in 
repeated 28-day treatment cycles at 2 planned doses (2 mg, 
4 mg).
QW arm: TAK-228 will be administered weekly (on Days 
1, 8, 15, and 22), in repeated 28-day treatment cycles at 2 
planned dose (20 mg, 30 mg).
Route of Administration:
Oral 
Duration of Treatment:
Patients will receive TAK-228 treatment until they 
experience disease progression, unacceptable toxicity, or 
withdraw consent.
Period of Evaluation:
Patients will be followed for 30 days after the last dose 
of TAK-228.
Main Criteria for Inclusion:
1. Patients of the primary East Asian ethnicity (ie, Japanese, Korean, or Chinese) aged 18 years or older (if local 
regulation requires a minimum age for informed consent of more than 18 years, then patients must be the minimum 
age or older per the local regulation) when written study informed consent is obtained.
2. Patients with advanced nonhematologic malignancies, with the exception of primary brain tumor, and have failed 
or are not eligible for standard of care therapy. History of brain metastasis may be allowed if all of the following 
criteria are met:
•
Brain metastases have been treated.
•
There is no evidence of progression or hemorrhage after treatment.
•
Steroid has been discontinued for ≥4 weeks before the first dose of study drug.
•
There is no ongoing requirement for steroids or anti-epileptic drugs.
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Property of Takeda: For non-co
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3. Received not more than 4 prior lines of systemic cytotoxic chemotherapy for advanced or metastatic disease.
4. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1.
5. Screening clinical laboratory values as specified below:
•
Bone marrow reserve consistent with absolute neutrophil count (ANC) ≥2000/mm3, platelet count
≥125,000/mm3, and hemoglobin ≥10 g/dL without transfusion in the last 4 weeks.
Note: Prophylactic transfusions of blood products or any prophylactic use of hematopoietic growth factors 
(such as erythropoietin, thrombopoietin, granulocyte colony stimulating factor [G-CSF], and granulocyte 
macrophage colony stimulating factor [GM-CSF]) is not permitted during the screening period.
•
Hepatic: Total bilirubin ≤1.5 × upper limit of normal (ULN), alanine aminotransferase (ALT)/aspartate 
aminotransferase (AST) ≤2.5 × ULN (≤5 × ULN if their elevation can be reasonably ascribed to the presence of 
hepatocellular carcinoma, biliary tract cancer, or metastatic disease in liver).
•
Adequate renal function, defined as meeting any 1 of the following criteria:
- Serum creatinine <1.5 × ULN.
- Creatinine clearance based on the Cockcroft-Gault estimate ≥40 mL/min.
- Creatinine clearance based on urine collection (12- or 24-hour) ≥40 mL/min.
•
Metabolic: Glycosylated hemoglobin (HbA1c) ≤7%, fasting serum glucose ≤130 mg/dL, and fasting 
triglycerides ≤300 mg/dL.
6. Female patients who:
•
Are postmenopausal (natural amenorrhea, not caused by other medical reasons) for at least 1 year before the 
screening visit, OR
•
Are surgically sterile, OR
•
If they are of childbearing potential, agree to practice 1 highly effective method of contraception and 1 
additional effective (barrier) method at the same time, from the time of signing the informed consent through 
90 days after the last dose of study drug, OR
•
Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. 
(Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods], condoms only, 
withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception.)
Male patients, even if surgically sterilized (ie, status postvasectomy), who:
•
Agree to practice effective barrier contraception during the entire study treatment period and through 120 days 
after the last dose of study drug, OR
•
Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. 
(Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods for the female partner], 
condoms only, withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of 
contraception.)
7. Ability to swallow oral medications.
8. Voluntary written consent obtained 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:
Patients meeting any of the following exclusion criteria are not to be enrolled in the study:
1. Diagnosis of primary brain tumor.
2. Untreated brain metastasis or history of leptomeningeal disease or spinal cord compression.
3. Failed to recover from the reversible effects of prior anticancer therapies with the exception of alopecia, and 
after-effects associated with prior tyrosine kinase inhibitor therapy, such as hair depigmentation, hypothyroidism, 
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and/or splinter hemorrhage.
4. Received prior cancer therapy or other investigational therapy within 2 weeks before the first dose of study drug. 
For prior therapies with a half-life longer than 3 days, the interval must be at least 28 days before the first dose of 
study drug.
5. Initiation of hematopoietic growth factors within 1 week before the first dose of study drug.
6. Requirement of systemic corticosteroid treatment within 7 days before receiving the first dose of TAK-228. 
Inhalers and low-dose glucocorticoids for replacement therapy are allowed.
7. Manifestations of malabsorption caused by prior gastrointestinal surgery, gastrointestinal disease, or for some 
other reason that may alter the absorption of TAK-228. In addition, patients with enteric stomata are also excluded.
8. Poorly controlled diabetes mellitus defined as HbA1c >7%; patients with a history of transient glucose intolerance 
caused by corticosteroid administration are allowed if all other eligibility criteria are met.
9. Other clinically significant comorbidities, such as uncontrolled pulmonary disease (eg, severe chronic obstructive 
pulmonary disease with hypoxemia, interstitial lung disease, radiation induced lung injury), active central nervous 
system disease, active infection, or any other condition that could compromise the patient’s safety and 
participation in the study per protocol.
10. Known human immunodeficiency virus infection.
11. Known hepatitis B surface antigen (HBsAg) positive, or known or suspected active hepatitis C virus (HCV) 
infection. 
Note: Patients who have isolated positive hepatitis B core antibody (HBcAb) and/or hepatitis B surface antibody 
(HBsAb) may be enrolled but must have an undetectable hepatitis B virus (HBV) viral load. Patients who have 
positive hepatitis C virus antibody (HCVAb) may be enrolled but must have an undetectable HCV viral load.
12. Female patients who are lactating and breastfeeding or have a positive serum pregnancy test during the Screening 
period or a positive urine pregnancy test on Cycle 1 Day 1 before the first dose of the study drug.
(Note: Female patients who are lactating will be excluded, even if they discontinue breastfeeding.)
13. History of any of the following within the last 6 months before the first dose of study drug:
•
Ischemic myocardial event, including angina requiring therapy and artery revascularization procedures.
•
Ischemic cerebrovascular event, including transient ischemic attack and artery revascularization procedures.
•
Requirement for inotropic support (excluding digoxin) or serious (uncontrolled) cardiac arrhythmia (including 
atrial flutter/fibrillation, ventricular fibrillation, or ventricular tachycardia).
•
Placement of a pacemaker for control of rhythm.
•
New York Heart Association Class III or IV heart failure.
•
Pulmonary embolism.
14. Significant active cardiovascular or pulmonary disease before the first dose of study drug, including:
•
Uncontrolled hypertension (ie, systolic blood pressure >180 mmHg; diastolic blood pressure >95 mmHg).
•
Pulmonary hypertension.
•
Uncontrolled asthma or oxygen saturation <90% by pulse oximetry on room air.
•
Significant valvular disease; severe regurgitation or stenosis by imaging independent of symptom control with 
medical intervention; or history of valve replacement.
•
Medically significant (symptomatic) bradycardia.
•
History of arrhythmia requiring an implantable cardiac defibrillator.
•
Baseline prolongation of the rate-corrected QT interval (QTc [eg, repeated demonstration of QTc interval
>480 ms, or history of congenital long QT syndrome, or torsades de pointes]).
15. Diagnosed or treated for another malignancy within 2 years before the first dose or previously diagnosed with 
another malignancy and have any evidence of residual disease. Patients with nonmelanoma skin cancer or 
carcinoma in situ of any type are not excluded if they have undergone complete resection.
16. Requirement of daily or chronic use of proton pump inhibitors (PPIs) and/or the use of a PPI within 7 days before 
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receiving the first dose of TAK-228. Use of PPIs is prohibited during the study.
Main Criteria for Evaluation and Analyses:
Primary:
•
The number and percentage of patients with Treatment-emergent AEs (TEAEs).
•
The number and percentage of patients with Grade 3 or higher TEAEs.
•
The number and percentage of patients with serious TEAEs.
•
Number of patients with DLTs during Cycle 1.
•
The number and percentage of patients with TEAEs leading to study drug discontinuation.
•
TAK-228 Cmax, tmax, and AUC on Cycle 1 Days 1 and 15.
Secondary:
•
Clinical benefit rate defined as the proportion of patients with a best overall response of complete response 
(CR), partial response (PR) or stable disease (SD) (SD of any duration).
Exploratory:
Statistical Considerations:
Statistical analyses will be primarily descriptive in nature. Analyses for safety and binary response endpoints will be 
descriptive using percentages. No formal statistical hypothesis testing will be performed. A formal statistical analysis 
plan will be developed and finalized before database lock.
Sample Size Justification:
For each arm, dose escalation will be conducted according to a standard 3+3 dose escalation schema. There are 2 
planned dose cohorts in each of 2 arms (QD arm and QW arm) in this study. For each arm, 9 to 12 DLT-evaluable 
patients will be needed for the dose escalation portion. In addition, for each arm, additional 6 patients will be needed 
for safety expansion. Assuming a 20% dropout rate, approximately 23 patients will be needed for each arm to have 18 
DLT-evaluable patients; the total sample size for this study will be 46.
CCI
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3.0
STUDY REFERENCE INFORMATION
3.1
Study-Related Responsibilities 
The sponsor will perform all study-related activities with the exception of those identified in the 
Clinical Study Supplier List or equivalent. The identified vendors in the template for specific 
study-related activities will perform these activities in full or in partnership with the sponsor.
3.2
Coordinating Investigator
Takeda will select a Signatory Coordinating Investigator from the investigators who participate in 
the study. Selection criteria for this investigator will include significant knowledge of the study 
protocol, the study medication, their expertise in the therapeutic area and the conduct of clinical 
research as well as study participation. The Signatory Coordinating Investigator will be required to 
review and sign the clinical study report and by doing so agrees that it accurately describes the 
results of the study.
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3.3
List of Abbreviations
Abbreviation
Term
5-HT3
5-hydroxytryptamine 3 serotonin receptor
ACVR1
activin A receptor, type 1
AE
adverse event
AKT
serine/threonine-specific protein kinase (also known as protein kinase B)
ALT
alanine aminotransferase
ANC
absolute neutrophil count
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AUC
area under the plasma concentration-time curve
BMPR1B
bone morphogenetic protein receptor type-1B
CK1
casein kinase 1
CL/F
apparent clearance after extravascular administration
Cmax
maximum observed concentration
CR
complete response
CRO
contract research organization
CSF1R
colony stimulating factor 1 receptor
CSNK1D
casein kinase 1 isoform delta
CSNK1E
casein kinase 1 isoform epsilon
CSR
clinical study report
Ctrough
observed concentration at the end of a dosing interval
CT
computed tomography
CYP
cytochrome P450
DDR1
discoidin domain receptor 1
DNA
deoxyribonucleic acid
DNA-PK
DNA-dependent protein kinase
DLT
dose limiting toxicity
DPP-4
dipeptidyl peptidase-4
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EOT
End of Treatment
ER+
estrogen receptor positive
FLT3
FMS-like tyrosine kinase 3
FBG
fasting blood glucose
FDA
Food and Drug Administration
FIH
first-in-human
GCP
Good Clinical Practice
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Abbreviation
Term
G-CSF
granulocyte colony stimulating factor
GLP
Good Laboratory Practice
GM-CSF
granulocyte macrophage colony stimulating factor
HbA1c
glycosylated hemoglobin
HBcAb
hepatitis B core antibody
HBsAb
hepatitis B surface antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HCVAb
hepatitis C virus antibody
HDPE
high-density polyethylene
HER2-
human epidermal growth factor receptor-2 negative
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IRB
institutional review board
IV
intravenous(ly)
MedDRA
Medical Dictionary for Regulatory Activities
MEK1
mitogen-activated protein kinase 1
MEK2
mitogen-activated protein kinase 2
MFDS
Ministry of Food and Drug Safety
MRI
magnetic resonance imaging
mTOR
mammalian (or mechanistic) target of rapamycin
mTORC1
mTOR complex 1
mTORC2
mTOR complex 2
MTD
maximum tolerated dose
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
pAKT
phosphorylated protein kinase B
PD
progressive disease
PDGFR
platelet-derived growth factor alpha receptor
PDGFR
platelet-derived growth factor beta receptor
PI3K
phosphoinositide 3-kinase
PI3KC2
phosphoinositide 3-kinase-C2-alpha
PI3KC2
phosphoinositide 3-kinase-C2-beta
PK
pharmacokinetic(s)
PMDA
Pharmaceuticals and Medical Devices Agency
PO
orally
PPI
proton pump inhibitor
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Abbreviation
Term
PR
partial response
PT/INR
prothrombin time/international normalized ratio
QD
once daily
QTc
corrected QT interval
QW
once weekly
RECIST
Response Evaluation Criteria in Solid Tumors
RIPK2
receptor-interacting protein kinase 2
RNA
ribonucleic acid
RP2D
recommended phase 2 dose
SAE
serious adverse event
SAP
statistical analysis plan
SD
stable disease
SUSAR
suspected unexpected serious adverse reaction
t1/2
terminal disposition phase half-life
TEAE
treatment-emergent adverse event
tmax
time of first occurrence of Cmax
TORC1
mammalian (or mechanistic) target of rapamycin complex 1
TORC2
mammalian (or mechanistic) target of rapamycin complex 2
UGT
uridine diphosphate glucuronosyltransferase
ULN
upper limit of normal
Vz/F
apparent volume of distribution during the terminal disposition phase
WHO
World Health Organization
3.4
Corporate Identification
Millennium
Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical 
Company Limited.
TDC Japan
Takeda Development Center Japan
TDC Asia
Takeda Development Center Asia, Pte Ltd.
TDC Europe
Takeda Development Centre Europe Ltd.
TDC Americas
Takeda Development Center Americas, Inc.
TDC
TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as applicable
Takeda
Millennium Pharmaceuticals, Inc., TDC Japan, TDC Asia, TDC Europe and/or TDC 
Americas, as applicable
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4.0
INTRODUCTION
4.1
Background
The mammalian (or mechanistic) target of rapamycin (mTOR) is a central regulator of cell growth, 
metabolism, and angiogenesis that functions in 2 distinct multiprotein complexes: mTOR complex 
1 (TORC1) and mTOR complex 2 (TORC2). mTOR kinase plays a key role in several pathways 
that are frequently dysregulated in human cancer [1]. Inhibiting mTOR may inhibit abnormal cell 
proliferation, tumor angiogenesis, and abnormal cellular metabolism, thus providing the rationale 
for mTOR inhibitors as potential agents in the treatment of a number of indications including solid
tumor and hematological malignancies, either as monotherapy or in combination with other
chemotherapeutic agents. Like rapamycin, several newly approved rapalogs (temsirolimus and 
everolimus) are specific and allosteric inhibitors of TORC1 but only partially inhibit TORC1 
substrates. They do not directly inhibit TORC2, which has shown to be an emerging target in 
cancer research. TAK-228 (sapanisertib) is a novel, selective, orally bioavailable mTOR inhibitor 
that targets both TORC1 and TORC2, thus enabling more profound blockage of angiogenesis, 
growth, and survival signaling within the pathophysiologically relevant signaling pathway which 
may lead to increased antitumor activity.
TAK-228 is being investigated as a treatment for advanced solid tumors and hematologic 
malignancies, either as monotherapy or in combination with chemotherapy, other molecularly 
targeted therapies, or antihormonal agents. TAK-228 is also being developed in combination with 
TAK-117 (an oral phosphoinositide-3-kinase alpha inhibitor) as a treatment for advanced 
nonhematologic malignancies.
4.2
Nonclinical Experience
TAK-228 is an orally available, potent, and highly selective adenosine triphosphate competitive 
inhibitor of mTOR kinase that exhibits dual specificity against both the TORC1 and TORC2 
complexes.
In vitro studies have demonstrated that TAK-228 selectively and potently inhibits mTOR kinase 
(1 nmol/L). Relative to mTOR inhibition, TAK-228 has >100-fold less potency on class I (PI3K 
isoforms , , γ, and ), class II (PI3KC2and PI3KC2), and class III (VPS34) PI3K family 
members. TAK-228 inhibits (>80%) the biochemical activity of 5 kinases (mTOR, DNA-PK, 
PDGFR, FLT3, and CK1 epsilon kinases) out of a panel of 222 protein kinases. Out of a panel of 
402 distinct kinases, TAK-228 inhibits the ligand binding of only 10 receptor and intracellular 
protein kinases (ACVR1, BMPR1B, CSF1R, CSNK1D, CSNK1E, DDR1, MEK1, MEK2, 
PDGFR, and RIPK2). TAK-228 also displays potent cellular inhibition of both the TORC1 and 
TORC2 pathway with cellular pharmacodynamically active concentrations at 50% inhibition 
values of <10 nmol/L.
TAK-228, administered orally in multiple human tumor xenograft mouse models, can inhibit 
angiogenesis and tumor growth by inhibiting mTOR signaling at plasma concentrations associated 
with in vitro inhibition of mTOR in a dose- and time-dependent manner. These effects display a 
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clear pharmacokinetic (PK)-to-pharmacodynamic relationship [2]. TAK-228 inhibits the 
phosphorylation of ribosomal protein S6, eukaryotic translation initiation factor 4E binding 
protein 1, the downstream substrates of TORC1, and selectively inhibits serine/threonine-specific 
protein kinase (AKT) phosphorylation at Serine 473, as evidenced by decreased pAKT, the 
downstream substrate of TORC2 [2][3][4]. Dual TORC1/2 inhibition mitigates the feedback 
activation of AKT, which is known to cause resistance to TORC1-only inhibitors such as 
rapamycin [5]. TAK-228 inhibits mTOR signaling and has demonstrated anticancer activity 
against a number of human solid tumor cell-line xenograft mouse models, including phosphatase 
and tensin homolog mutant endometrial, breast, and renal cell carcinomas.
The toxicity profile of TAK-228 in rats and monkeys, as established in Good Laboratory Practice
(GLP)-compliant repeat-dose studies, is consistent with pharmacologic inhibition of TORC1/2 
activity. TAK-228 is not mutagenic or phototoxic, does not present a genotoxic risk, and has a low
potential for adverse effects on the respiratory, cardiovascular, and central nervous systems.
Detailed information regarding the nonclinical pharmacology and toxicology of TAK-228 may be 
found in the Investigator’s Brochure (IB).
4.3
Clinical Experience
As of the clinical data cutoff of 09 December 2016, TAK-228 is being investigated in 3 ongoing 
phase 2 studies: C31004, a study of TAK-228 as a single agent or in combination with paclitaxel or 
TAK-117 in patients with advanced, recurrent, or persistent endometrial cancer; C31005, a study 
of TAK-228 as a single agent or in combination with TAK-117 as compared with everolimus in 
patients with clear-cell renal cell carcinoma; C31006, a study of TAK-228 in combination with 
fulvestrant in women with estrogen receptor positive (ER+)/human epidermal growth factor 
receptor-2 negative (HER2-) advanced or metastatic breast cancer. In addition, C31001, a 
phase 1b/2 study is ongoing for TAK-228 in combination with exemestane or fulvestrant in 
women with ER+/HER2- advanced or metastatic breast cancer.
TAK-228 was investigated in 3 completed phase 1 studies in patients with advanced solid tumors 
or hematologic malignancies as a single agent (Studies INK128-001, INK128-002) or in 
combination with paclitaxel, with or without trastuzumab (Study INK128-003). Milled TAK-228 
was investigated as either a single agent or in combination with paclitaxel in a completed phase 1 
study in patients with advanced solid tumors (Study MLN0128-1004).
The effect of TAK-228 on the corrected QT interval (QTc) in patients with advanced solid tumors 
has been studied in the ongoing, single-arm, dedicated QTc study (Study C31002).
As of the clinical data cutoff (09 December 2016), a total of 538 patients across the studies had 
received at least 1 dose of study drug. A total of 25 deaths that occurred during treatment or within 
30 days of the last study drug dose had been reported to the clinical database. Of these events, 1 
case of ventricular fibrillation and cardiac arrest that occurred in Study INK128-001 was 
considered related to TAK-228. The most common treatment-emergent adverse events (TEAEs) 
observed with TAK-228 are consistent with the pharmacodynamic mechanism of mTOR 
inhibition that is also seen with rapalogs (TORC1 inhibition) or other dual TORC1/2 inhibitors. 
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The TEAEs observed across the TAK-228 single-agent studies include diarrhea, fatigue, vomiting, 
rash, mucosal inflammation, asthenia, dysgeusia, thrombocytopenia, stomatitis, blood creatinine 
increased, hyperglycemia, nausea, anorexia, and decreased appetite. In general, observed toxicities 
have been mostly Grade 1 or Grade 2 and have been manageable with supportive care and/or 
TAK-228 dose interruption or reduction.
Results from a dedicated QTc study, C31002 support the conclusion that 40 mg TAK-228 does not 
produce clinically relevant (ie, >20 msec) effects on QT interval in patients with cancer. 
Importantly, there was no concentration-dependent increase in the change from time-matched 
baseline individual QT interval correction in the PK/QTc analysis.
Further details on these studies are provided in the TAK-228 IB.
Clinical Pharmacokinetics of TAK-228
The PK parameters measured for TAK-228 in the phase 1 clinical studies have been generally 
consistent across a range of doses and schedules. TAK-228 has shown linear PK and fast oral 
absorption with single-dose median tmax occurring between 1 and 4 hours after dosing. The mean 
t1/2 of TAK-228 is approximately 5 to 8 hours, and no accumulation has been observed in plasma 
after repeat daily dosing. Recently completed in-vitro metabolism experiments in human 
hepatocytes using 14C labeled TAK-228 suggest that TAK-228 is metabolized primarily via 
cytochrome P-450 (CYP)1A2 (approximately 31% to 40%) with a minor contribution from 
CYP3A4 (approximately 11% to 22%). These data suggest that TAK-228 is also metabolized by 
direct glucuronidation (approximately 22%) as well as an unidentified non-uridine diphosphate 
glucuronosyltransferase (UGT) pathway (approximately 18%). The new data differ from the 
previous in-vitro CYP phenotyping data that was conducted using recombinant CYP enzymes, 
which suggested the involvement of CYP2C9 (approximately 35%), CYP2C19 (approximately 
28%), and CYP3A4 (approximately 28%) in TAK-228 metabolism. Physiologically based 
pharmacokinetic modeling and simulation using the new metabolism data suggest that the risk for 
a metabolism based drug-drug interaction with TAK-228 appears to be low.
The PK properties of TAK-228 are further detailed in the IB.
4.4
Potential Risks and Benefits
The most common TEAEs observed with TAK-228 are consistent with the pharmacodynamic 
mechanism of mTOR inhibition and are also seen with other TORC1 or dual TORC1/2 inhibitors. 
The most common TEAEs observed across TAK-228 single-agent studies include diarrhea, 
fatigue, vomiting, rash, mucosal inflammation, asthenia, dysgeusia, thrombocytopenia, stomatitis, 
blood creatinine increased, hyperglycemia, nausea, anorexia, and decreased appetite.
During this study, risk mitigation strategies include, but are not limited to, strict application of the 
study eligibility criteria, frequent monitoring of clinical and laboratory results, guidelines for 
management and prophylaxis of potential toxicities, guidelines for dose modification, and regular 
monitoring of adverse events (AEs) and serious adverse events (SAEs) by the sponsor.
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Nonclinical data supporting the potential benefits of TAK-228 as anticancer therapy are 
summarized in Section 4.2. Preliminary signs of antitumor activity have been seen in patients 
treated with TAK-228, supporting further development of TAK-228 in clear-cell renal cell 
carcinoma, hormone-receptor positive breast cancer, and endometrial cancer. Further details are 
presented in the TAK-228 IB.
4.5
Rationale for the Proposed Study
To facilitate the global expansion of the TAK-228 program, this phase 1 study is to be conducted
to evaluate the safety, tolerability, PK, and preliminary efficacy of single-agent TAK-228 in adult 
East Asian patients with advanced nonhematological malignancies.
To date TAK-228 clinical studies have only been conducted in Western regions. Based on the
results of these studies, TAK-228 exhibits a manageable safety profile along with preliminary 
evidence of clinical activity in selected types of cancer including renal cell carcinoma, breast 
cancer, bladder cancer, and endometrial cancer. AEs reported in clinical studies to date are
consistent with the mechanism of action of TAK-228 and are generally reversible and manageable. 
Results from the studies conducted in predominantly Western patients support the initiation of this 
phase 1 study in East Asian patients with advanced nonhematologic malignancies.
4.5.1
Rationale for Dose and Schedule Selection
In Study INK128-001 (FIH study) conducted in Western population, single-agent TAK-228 was 
administered with 4 dosing schedules (QD, QW, QD×3d QW [once daily for 3 consecutive days 
followed by a 4-day dosing holiday every week] and QD×5d QW [once daily for 5 consecutive 
days followed by a 2-day dosing holiday every week]) in a 28-day cycle in patients with advanced 
nonhematological malignancies. QD and QW schedules were selected for further development in 
combination with either exemestane or fulvestrant in women with ER+/HER2- breast cancer, and 
QW dosing schedule was selected for further development in patients with clear-cell renal cell 
carcinoma and endometrial cancer. To support future clinical development in those indications in 
East Asian patients, single-agent TAK-228 given with QD or QW schedule will be evaluated in 
this study. This study will consist of 2 arms: the QD arm and the QW arm.
The selected doses for QD and QW schedules to be tested in this study are based on the findings 
from 3 studies conducted in Western patients: INK128-001, MLN0128-1004, and C31001.
4.5.1.1
QW Dosing
In Study INK128-001, 116 patients with advanced solid tumors received single-agent TAK-228 
(2 to 40 mg with 4 dosing schedules in 28 day cycles) in the dose escalation phase. Doses of 40 mg 
QW, 30 mg QW, and 5 mg QD were further evaluated in an additional 82 patients in the expansion 
part, where 30 mg QW and 5 mg QD were selected as the recommended phase 2 doses (RP2Ds) 
and schedules for further development of TAK-228.
Scale-up manufacturing of TAK-228 required the introduction of a physical milling step to control 
particle size distribution of TAK-228 drug substance. With the introduction of milled TAK-228, 
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the recommended dose to be used for QW schedule was further confirmed in Study 
MLN0128-1004. A total of 14 patients were enrolled and assigned, sequentially, to 2 QW dosing 
cohorts (20 mg QW and 30 mg QW). PK, safety, and tolerability were evaluated (Table 4.a).
Table 4.a
Dose Limiting Toxicities Observed with Weekly TAK-228 in Study 
MLN0128-1004
Dose of Milled TAK-228
Number of Evaluable Patients
DLTs Observed in Cycle 1
20 mg QW
6
None
30 mg QW
6
None
Abbreviations: DLTs=dose limiting toxicity, QW=once weekly
As none of the patients in either dose cohort experienced dose limiting toxicity (DLT) in Cycle 1, 
a dose of 30 mg TAK-228 QW was selected for further development. No clinically meaningful 
differences in PK of TAK-228 were noted between the unmilled TAK-228 (Study INK128-001) 
and milled TAK-228 (Study MLN0128-1004) when given QW.
The starting dose for QW arm in this study will be 20 mg. This dose is lower than the current RP2D 
(30 mg) for milled TAK-228 determined in Western population when administered on a QW 
schedule in a 28-day cycle and is considered a safe starting dose to evaluate the PK characteristics 
and safety and tolerability of single agent QW schedule in East Asian patients. TAK-228 doses for 
subsequent cohorts may be escalated to 30 mg depending upon tolerability observed in the prior 
cohort.
During Phase 1 and Phase 2 development of TAK-228 QW doses have been administered under 
either fed or fasted conditions. Fed administration is expected to improve the tolerability of 
TAK-228. The effects of food on a 4 mg dose of TAK-228 PK were evaluated in Study 
MLN0128-1004. Administration of a 4 mg dose of TAK-228 following a standard high-fat 
breakfast was associated with a 40% reduction in Cmax and a delay in tmax (median tmax 6 hours [fed] 
vs. 2 hours [fasted]), without any meaningful change in AUC.
The apparent lack of food effect on systemic exposure (AUC) and improved long term tolerability 
following a light meal support oral dosing of TAK-228 in the fed state after Cycle 2. In Study 
C31008, patients in the QW arm will receive TAK-228 in the fasted state during Cycle 1 and after 
a light meal during Cycle 2 and beyond. Serial PK samples to characterize the PK of TAK-228 will 
be collected during Cycle 1 (fasted dosing) and sparse PK samples will be collected during Cycle 2 
(fed dosing), which will enable the comparison of the PK of TAK-228 between Asian patients and 
Western patients in the both dosing conditions.
4.5.1.2
QD Dosing
The RP2D of 4 mg milled TAK-228 QD in combination with either exemestane or fulvestrant was 
determined in the phase 1b dose finding portion of Study C31001. In the phase 1b portion of the 
study, 12 patients were initially dosed in a safety lead-in with 5 mg QD of the unmilled TAK-228 
material in combination with either fulvestrant or exemestane (6 patients each). No DLTs were 
observed during Cycle 1; however, 6 of the 12 patients did require dose reductions in Cycles 2 and 
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3 (2 patients each), and 1 patient each in Cycles 4 and 7. In order to evaluate the safety of milled 
TAK-228 material, escalation cohorts of 3 mg and 4 mg QD of the milled material were studied in 
combination: 6 patients at the 3 mg dose (3 in combination with exemestane and 3 with 
fulvestrant) and 6 patients at the 4 mg dose (all with exemestane). Of the 6 patients treated with 
4 mg TAK-228 in combination with exemestane, 1 experienced a DLT of nausea and diarrhea. 
After review of the data with the investigators, including events occurring outside of the DLT 
evaluation period, it was agreed to stop escalation and move forward with 4 mg QD in the phase 2 
portion of the study (in combination with either exemestane or fulvestrant), as well as in Study 
C31006 (in combination with fulvestrant). As of data cut of February 2016, 79 patients have been 
treated in the phase 2 portion of Study C31001 with 4 mg QD TAK-228 in combination with 
fulvestrant or exemestane.
Study MLN0128-1004 demonstrated that there were no meaningful differences in the PK of 
TAK-228 administered as 4 mg unmilled versus milled active pharmaceutical ingredient capsules 
under fasting conditions. In study C31008, TAK-228 4 mg QD will be administered under fasting 
conditions to avoid possible reductions in Cmax of TAK-228 at the lower dose of 4 mg.
The starting dose for the QD arm in this study will be 2 mg, which is 50% below the current RP2D 
(4 mg) for milled TAK-228 determined in Western population when administered on a QD 
schedule, in a 28-day cycle. This dose is considered a safe starting dose to evaluate the PK 
characteristics and the safety and tolerability of the single-agent QD schedule in East Asian 
patients. During the treatment period, the QD dose of TAK-228 may be escalated to 4 mg, 
depending upon tolerability observed in the prior cohort.
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5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objectives
The primary objectives are:
!
To evaluate safety and tolerability and to determine RP2D of TAK-228 administered daily 
(QD arm) or weekly (QW arm) to East Asian patients with advanced nonhematological 
malignancies.
!
To characterize PK of TAK-228 in East Asian patients with advanced nonhematological 
malignancies.
5.1.2
Secondary Objectives
The secondary objective is:
!
To evaluate preliminary anti-tumor activity of TAK-228.
5.1.3
Exploratory Objectives
5.2
Endpoints
5.2.1
Primary Endpoints
The primary endpoints are:
!
The number and percentage of patients with TEAEs.
!
The number and percentage of patients with Grade 3 or higher TEAEs.
!
The number and percentage of patients with serious TEAEs.
!
Number of patients with DLTs during Cycle 1.
!
The number and percentage of patients discontinuing study drug due to TEAEs.
!
TAK-228 Cmax, Tmax, and AUC on Cycle 1 Days 1 and 15.
5.2.2
Secondary Endpoints
The secondary endpoint is:
!
Clinical benefit rate defined as the proportion of patients with a best overall response of 
complete response (CR), partial response (PR) or stable disease (SD) (SD of any duration).
CCI
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5.2.3
Exploratory Endpoints
CCI
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6.0
STUDY DESIGN
6.1
Overview of Study Design
This study is a multicenter, open-label, phase 1 study of TAK-228 administered orally as a single 
agent in adult East Asian patients with advanced nonhematological malignancies for whom 
effective standard anticancer treatment is not available or is no longer effective.
The study will consist of 2 arms to evaluate the safety and tolerability, characterize the PK, and 
determine the RP2Ds of single-agent TAK-228 to be used for 2 schedules (daily and weekly) in 
East Asian patients.
1. QD (daily dosing schedule) arm: milled TAK-228 will be administered on an empty stomach, 
once daily, in repeated 28-day treatment cycles.
2. QW (weekly dosing schedule) arm: milled TAK-228 will be administered on an empty 
stomach in Cycle 1 and following a light meal in Cycle 2 and the subsequent cycles, weekly 
(ie, on Days 1, 8, 15, and 22), in repeated 28-day treatment cycles.
The 2 arms will enroll in parallel. Patient assignment to a specific schedule will be decided jointly 
by the investigator and sponsor with the aim of maximizing enrollment efficiency in the study.
During dose escalation, 2 planned dose levels of TAK-228 will be tested in each arm (2 mg and 
4 mg in the QD arm; 20 mg and 30 mg in the QW arm) following standard 3+3 dose escalation 
rules. Dosing will increase to 4 mg in QD arm or 30 mg in QW arm, provided that the safety and 
tolerability of the starting dose has been demonstrated (Figure 6.a).
If a dose is deemed safe in any cohort based on 3+3 rules, then the cohort may be expanded to as 
many as 12 patients in total to further confirm safety, investigate PK and determine RP2D. At least 
1 Japanese patient will be enrolled in each group of 3 patients during dose escalation. The total 
number of Japanese patients dosed at the RP2D level will be at least 6. On the basis of the 
geographic distribution of patients enrolled or any emerging safety data or PK, additional patients 
may be added, as needed, to further characterize the safety, tolerability, or PK in patients from a 
particular East Asian geographic region.
As Western population based RP2D have been defined as 4 mg for the QD schedule and the 30 mg 
QW schedule, the dose escalation schemas in the current study are designed to confirm Cycle 1 
based RP2D in East Asian patients or determine an alternative appropriate lower dose. Escalation 
beyond 4 mg QD or 30 mg QW is not expected to be necessary in this study. However, if 
TAK-228 exposures are unexpectedly lower than anticipated in the East Asian populations, and no 
DLTs have occurred in the dose escalation parts, the TAK-228 dose may be escalated further after 
discussion between the investigators and the sponsor based on the available PK and safety data.
If ≥2 of 6 patients experience a DLT at the starting dose level (ie, 2 mg in QD arm or 20 mg in QW 
arm), depending on the overall safety profile, the types of AEs/DLTs observed, and following the 
examination of the preliminary PK results in relation to the PK data in the Western population, a 
decision will be made either to evaluate a lower dose or to terminate the study, following 
discussion between the investigators and the sponsor.
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For either treatment arm, more conservative dose escalation, evaluation of intermediate doses, and 
expansion of an existing or previously tested dose level are all permissible following discussions 
and agreement between the investigators and the sponsor, if such measures are needed for patient 
safety or for a better understanding of the dose-toxicity and dose-exposure relationships of 
TAK-228.
Blood samples will be collected at prespecified time points in Cycle 1 Days 1, 2, 8, 15, 16, and 22 
to characterize the PK of TAK-228 when given daily (QD) or weekly (QW). Blood samples will 
also be collected at prespecified time points during Cycle 2 Days 1 and 15 to characterize the PK of 
TAK-228 when given QW with light meals. Details of the PK measurements are described in 
Section 9.4.20.
Radiological tumor evaluations will be used to evaluate disease response according to Response 
Evaluation Criteria in Solid Tumors (RECIST) guidelines (Version 1.1) [6].
Toxicity will be evaluated according to the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE), Version 4.03, effective date 14 June 2010 [7]. 
Dose-limiting toxicities (DLTs) are defined in Section 8.2.
Figure 6.a
Study Overview Diagram
Abbreviations: C1D1=Cycle 1 Day 1, QD=once daily, QW=once weekly
6.2
Number of Patients
Approximately 36 DLT-evaluable patients (approximately 18 patients in each arm) will be 
enrolled from approximately 4 study sites in East Asia. Enrollment is defined as the time of the 
first dose of TAK-228. Assuming a 20% dropout rate, approximately 23 patients will be needed for 
each arm to have approximately 18 DLT-evaluable patients; the total sample size for this study 
will be approximately 46.
QD arm
TAK-228 QD in 28-day continues cycles
QW arm
TAK-228 QW in 28-day continues cycles
Cohort 1 
2 mg QD
Cohort 2 
4 mg QD
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12 patients
Screening
(≤28 days before 
C1D1)
End of Treatment Visit
(30 to 40 days after last 
dose of TAK-228)
Cohort 1 
20 mg QW
Expand up to 
12 patients
Cohort 2 
30 mg QW
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6.3
Duration of Study
6.3.1
Duration of an Individual Patient’s Study Participation
Patients may receive study drug until they experience disease progression, unacceptable toxicity, 
withdrawal of consent, or for any of the other reasons outlined in Section 9.8 and the maximum 
duration of treatment for patients will be 12 months except as set forth in Section 9.6.
Patients will be followed for 30 days after the last dose of TAK-228 to permit further detection of 
any treatment-related AEs.
6.3.2
End of Study/Study Completion Definition and Planned Reporting
Primary Completion/Study Completion
The final analyses for the safety, PK, and efficacy endpoints and authoring of a clinical study 
report (CSR) will be conducted after all patients enrolled in the study have completed the study 
treatment and a 30-day safety follow-up. The estimated time frame for study completion is 
approximately 23 months. The study is considered completed after the last patient completes study 
treatment and a 30-day safety follow-up.
6.3.3
Timeframes for Primary and Secondary Endpoints to Support Disclosures
Please refer to Table 6.a for disclosures information for all primary and secondary endpoints.
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Table 6.a
Primary and Secondary Endpoints for Disclosures
Endpoint
Definition
Maximum Time Frame (a)
Primary:
• The number and percentage of 
patients with TEAEs (b).
The number and percentage of patients 
with TEAEs.
Approximately 23 months.
• The number and percentage of 
patients with Grade 3 or higher
TEAEs.
The number and percentage of patients 
with Grade 3 or higher TEAEs.
Approximately 23 months.
• The number and percentage of 
patients with serious TEAEs.
The number and percentage of patients 
with serious TEAEs.
Approximately 23 months.
• Number of patients with DLTs 
during Cycle 1.
Number of patients with DLTs during 
Cycle 1.
Up to dosing on Cycle 2 Day 1.
• The number and percentage of 
patients with TEAEs leading study 
drug discontinuation.
The number and percentage of patients 
with TEAEs leading study drug 
discontinuation.
Approximately 22 months.
• TAK-228 Cmax on Cycle 1 Days 1 
and 15 by dose.
Geometric mean and CV for Cmax on 
Cycle 1 Days 1 and 15 by dose in the 
PK-evaluable population.
Up to Cycle 1 Day 15.
• TAK-228 tmax on Cycle 1 Days 1 
and 15 by dose.
Median (range) for tmax on Cycle 1 Days 
1 and 15 by dose in the PK-evaluable 
population.
Up to Cycle 1 Day 15.
• TAK-228 AUC on Cycle 1 Days 1 
and 15 by dose.
Geometric mean and CV for AUC on 
Cycle 1 Days 1 and 15 by dose in the 
PK-evaluable population.
Up to Cycle 1 Day 15.
Secondary
Clinical benefit rate
Proportion of patients with a best 
overall response of CR + PR + SD (SD 
of any duration).
Approximately 23 months.
Abbreviations: AUC=area under the plasma concentration-time curve, Cmax=maximum observed concentration,
CR=complete response, CV=coefficient of variation, DLT=dose-limiting toxicity, PK=pharmacokinetic(s), 
PR=partial response, SD=stable disease, TEAE=treatment-emergent adverse event, tmax=time of first occurrence of 
Cmax
(a) Time to last assessment for that endpoint for an individual patient.
(b) TEAEs are defined as AEs that occur after the first dose of study drug until 30 days after the last dose of study drug 
or the start of subsequent antineoplastic therapy, whichever occurs first.
6.3.4
Total Study Duration
It is anticipated that this study will last for approximately 23 months.
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7.0
STUDY POPULATION
7.1
Inclusion Criteria
Each patient must meet all of the following inclusion criteria to be enrolled in the study:
1. Patients of the primary East Asian ethnicity (ie, Japanese, Korean, or Chinese) aged 18 years or 
older (if local regulation requires a minimum age for informed consent of more than 18 years, 
then patients must be the minimum age or older per the local regulation) when written study 
informed consent is obtained.
2. Patients with advanced nonhematologic malignancies, with the exception of primary brain 
tumor, and have failed or are not eligible for standard of care therapy. History of brain 
metastasis may be allowed if all of the following criteria are met: 

Brain metastases have been treated.

There is no evidence of progression or hemorrhage after treatment.

Steroid has been discontinued for ≥4 weeks before the first dose of study drug.

There is no ongoing requirement for steroids or anti-epileptic drugs.
3. Received not more than 4 prior lines of systemic cytotoxic chemotherapy for advanced or 
metastatic disease.
4. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1.
5. Screening clinical laboratory values as specified below:

Bone marrow reserve consistent with absolute neutrophil count (ANC) ≥2000/mm3, 
platelet count ≥125,000/mm3, and hemoglobin ≥10 g/dL without transfusion in the last 
4 weeks.
Note: Prophylactic transfusions of blood products or any prophylactic use of hematopoietic 
growth factors (such as erythropoietin, thrombopoietin, granulocyte colony stimulating 
factor [G-CSF], and granulocyte macrophage colony stimulating factor [GM-CSF]) is not 
permitted during the screening period.

Hepatic: Total bilirubin ≤1.5 × upper limit of normal (ULN), alanine aminotransferase 
(ALT)/aspartate aminotransferase (AST) ≤2.5 × ULN (≤5 × ULN if their elevation can be 
reasonably ascribed to the presence of hepatocellular carcinoma, biliary tract cancer, or 
metastatic disease in liver).

Adequate renal function, defined as meeting any 1 of the following criteria:
–
Serum creatinine <1.5 × ULN.
–
Creatinine clearance based on the Cockcroft-Gault estimate ≥40 mL/min.
–
Creatinine clearance based on urine collection (12- or 24-hour) ≥40 mL/min.
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
Metabolic: Glycosylated hemoglobin (HbA1c) ≤7%, fasting serum glucose ≤130 mg/dL, 
and fasting triglycerides ≤300 mg/dL.
6. Female patients who:

Are postmenopausal (natural amenorrhea, not caused by other medical reasons) for at least 
1 year before the screening visit, OR

Are surgically sterile, OR

If they are of childbearing potential, agree to practice 1 highly effective method of 
contraception and 1 additional effective (barrier) method (see Appendix G) at the same 
time, from the time of signing the informed consent through 90 days after the last dose of 
study drug, OR

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle 
of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 
methods], condoms only, withdrawal, spermicides only, and lactational amenorrhea are not 
acceptable methods of contraception.)
Male patients, even if surgically sterilized (ie, status postvasectomy), who:

Agree to practice effective barrier contraception during the entire study treatment period 
and through 120 days after the last dose of study drug, or

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle 
of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 
methods for the female partner], condoms only, withdrawal, spermicides only, and 
lactational amenorrhea are not acceptable methods of contraception.)
7. Ability to swallow oral medications.
8. Voluntary written consent obtained 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.
7.2
Exclusion Criteria
Patients meeting any of the following exclusion criteria are not to be enrolled in the study:
1. Diagnosis of primary brain tumor.
2. Untreated brain metastasis or history of leptomeningeal disease or spinal cord compression.
3. Failed to recover from the reversible effects of prior anticancer therapies with the exception of 
alopecia, and after-effects associated with prior tyrosine kinase inhibitor therapy, such as hair 
depigmentation, hypothyroidism, and/or splinter hemorrhage.
4. Received prior cancer therapy or other investigational therapy within 2 weeks before the first 
dose of study drug. For prior therapies with a half-life longer than 3 days, the interval must be 
at least 28 days before the first dose of study drug.
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5. Initiation of hematopoietic growth factors within 1 week before the first dose of study drug.
6. Requirement of systemic corticosteroid treatment within 7 days before receiving the first dose 
of TAK-228. Inhalers and low-dose glucocorticoids for replacement therapy are allowed.
7. Manifestations of malabsorption caused by prior gastrointestinal surgery, gastrointestinal 
disease, or for some other reason that may alter the absorption of TAK-228. In addition, 
patients with enteric stomata are also excluded.
8. Poorly controlled diabetes mellitus defined as HbA1c >7%; patients with a history of transient 
glucose intolerance caused by corticosteroid administration are allowed if all other eligibility 
criteria are met.
9. Other clinically significant comorbidities, such as uncontrolled pulmonary disease (eg, severe 
chronic obstructive pulmonary disease with hypoxemia, interstitial lung disease, radiation 
induced lung injury), active central nervous system disease, active infection, or any other 
condition that could compromise the patient’s safety and participation in the study per 
protocol.
10. Known human immunodeficiency virus infection.
11. Known hepatitis B surface antigen (HBsAg) positive, or known or suspected active hepatitis C 
virus (HCV) infection. 
Note: Patients who have isolated positive hepatitis B core antibody (HBcAb) and/or hepatitis B 
surface antibody (HBsAb) (ie, in the setting of negative HBsAg) may be enrolled but must 
have an undetectable hepatitis B virus (HBV) viral load. Patients who have positive hepatitis C 
virus antibody (HCVAb) may be enrolled but must have an undetectable HCV viral load.
12. Female patients who are lactating and breastfeeding or have a positive serum pregnancy test 
during the Screening period or a positive urine pregnancy test on Cycle 1 Day 1 before the first 
dose of the study drug.
(Note: Female patients who are lactating will be excluded, even if they discontinue 
breastfeeding.)
13. History of any of the following within the last 6 months before the first dose of study drug:

Ischemic myocardial event, including angina requiring therapy and artery 
revascularization procedures.

Ischemic cerebrovascular event, including transient ischemic attack and artery 
revascularization procedures.

Requirement for inotropic support (excluding digoxin) or serious (uncontrolled) cardiac 
arrhythmia (including atrial flutter/fibrillation, ventricular fibrillation, or ventricular 
tachycardia).

Placement of a pacemaker for control of rhythm.

New York Heart Association Class III or IV heart failure.
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
Pulmonary embolism.
14. Significant active cardiovascular or pulmonary disease before the first dose of study drug, 
including:

Uncontrolled hypertension (ie, systolic blood pressure >180 mmHg; diastolic blood 
pressure >95 mmHg).

Pulmonary hypertension.

Uncontrolled asthma or oxygen saturation <90% by pulse oximetry on room air.

Significant valvular disease; severe regurgitation or stenosis by imaging independent of 
symptom control with medical intervention; or history of valve replacement.

Medically significant (symptomatic) bradycardia.

History of arrhythmia requiring an implantable cardiac defibrillator.

Baseline prolongation of the rate QTc (eg, repeated demonstration of QTc interval
>480 ms, or history of congenital long QT syndrome, or torsades de pointes).
15. Diagnosed or treated for another malignancy within 2 years before the first dose or previously 
diagnosed with another malignancy and have any evidence of residual disease. Patients with 
nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have 
undergone complete resection.
16. Requirement of daily or chronic use of proton pump inhibitors (PPIs) and/or the use of a PPI 
within 7 days before receiving the first dose of TAK-228. Use of PPIs is prohibited during the 
study.
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8.0
STUDY DRUG
8.1
Study Drug Administration
All protocol-specific criteria for administration of study drug must be met and documented before 
drug administration. Study drug will be administered only to eligible patients under the 
supervision of the investigator or identified subinvestigator(s). If required by local regulations or 
local clinical guidelines or preferred by the investigator, study drugs and protocol assessments 
may be administered in an in-patient setting during Cycle 1 (eg. patients enrolled in Japan in dose 
escalation cohorts will be hospitalized during Cycle 1 DLT evaluation period).
TAK-228 will be administered according to the assigned dosing schedule (ie, QD or QW schedule). 
For the QD arm, TAK-228 will be dosed daily in 28-day cycles. For the QW arm, TAK-228 will be 
dosed weekly in 28-day cycles (ie, on Days 1, 8, 15 and 22). TAK-228 will be administered at 
approximately the same time on each dosing day. On dosing days when the patient does not have a 
clinic visit, patients will take their assigned TAK-228 dose at home. TAK-228 will be taken on an 
empty stomach in all cycles in the QD arm and Cycle 1 in the QW arm. Patients should be 
instructed to refrain from eating and drinking (except water and prescribed medications) for 
2 hours before and 1 hour after each dose. In Cycle 2 and subsequent cycles in the QW arm, 
TAK-228 will be administered following a light meal. It is recommended that each dose of 
TAK-228 be taken with 240 mL of water.
Table 8.a
Nutritional Information for a Light Meal
Low-Fat Breakfast
Light Snack
Nutritional information
Approximately 330 kilo calories, with 
9 g of fat
Approximately 100 to 300 kilo calories, with 
1.5 g of fat
During the study treatment period, patients will be instructed to record in their dosing diary (see 
the Pharmacy Manual) each TAK-228 dose they take. If severe emesis or mucositis prevents the 
patient from taking a TAK-228 dose, that dose will be skipped. If emesis occurs after TAK-228 
ingestion, the dose should be counted as missed and will not be re-administered, and patients 
should simply adhere to the dosing schedule and resume dosing at the next scheduled time with the 
prescribed dosage. Patients should record the time of the emesis in their dosing diary (see the 
Study Manual). Under no circumstance should a patient repeat a dose or double-up doses. A 
forgotten or missed dose of TAK-228 should be taken if it is possible to do so within 12 hours of 
the scheduled dosing time for the QD arm and within 24 hours of the scheduled dosing time for the 
QW arm; otherwise, that dose should be skipped, and the next dose should be taken as scheduled. 
Any skipped dose should be considered a missed dose.
8.2
Definitions of Dose Limiting Toxicity
Toxicity will be evaluated according to NCI CTCAE (Version 4.03, effective 14 June 2010) [7].
DLT is defined as any of the following events that occur within the first 28 days of the 
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administration of TAK-228 and are considered by the investigator to be at least possibly related to 
therapy with TAK-228.

Grade 3 or higher nonhematologic toxicity, except for the following:
–
Inadequately treated Grade 3 nausea and/or vomiting and Grade 3 diarrhea (all subjects
should receive optimal antiemetic and/or antidiarrheal prophylaxis and/or treatment. 
Optimal antiemetic prophylaxis is defined as an antiemetic regimen that includes
5-hydroxytryptamine 3 serotonin receptor (5-HT3) antagonists and a corticosteroid given 
in standard doses and according to standard schedules).
–
Grade 3 hyperglycemia lasting ≤14 days (all patients should receive optimal antiglycemic 
treatment, including insulin).
–
Grade 3 rash lasting ≤3 days (all patients should receive topical steroid treatment, oral 
antihistamines, and oral steroids, if necessary).

Grade 3 thrombocytopenia with hemorrhage or requiring platelet transfusion.

Grade 3 anemia requiring blood transfusion.

Grade 4 neutropenia lasting >7 days.

Grade 3 or higher neutropenia of any duration accompanied by fever ≥38.5°C and/or systemic 
infection.

Any other ≥Grade 4 hematologic toxicity.

Inability to administer at least 75% of planned doses of TAK-228 within Cycle 1 due to 
treatment-related toxicity.

Any clinically significant occurrence that the investigator and sponsor agree would place 
patients at an undue safety risk.
Note: Prophylactic transfusions of blood products or any prophylactic use of hematopoietic 
growth factors (such as erythropoietin, thrombopoietin, G-CSF, and GM-CSF) is not permitted 
during the DLT evaluation period.
Patients who experience an AE that meets the definition of a DLT during or after completing 
Cycle 1 should have their study drug treatment interrupted. If the event resolves to Grade 1 or 
baseline values within 2 weeks of interrupting planned therapy, and in the opinion of the 
investigator and the sponsor’s project clinician the benefits of continuing treatment outweigh the 
risks posed by the toxicity, patients may continue study treatment with TAK-228 dose reduction 
with approval of the sponsor’s project clinician.
Although DLTs may occur at any point during treatment, only DLTs occurring during Cycle 1 of 
treatment will necessarily influence decisions regarding dose escalation, expansion of a dose level, 
or evaluation of intermediate dose levels. Patients will be monitored through all cycles of therapy 
for treatment-related toxicities.
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8.3
Dose Escalation Rules
This study will use 3+3 dose escalation rules. The starting dose will be 2 mg in the QD arm and 
20 mg in the QW arm. Provided the safety and tolerability of the starting dose has been 
demonstrated, the dose will be escalated to 4 mg in Cohort 2 QD arm and 30 mg in Cohort 2 QW 
arm (Table 8.b).
Table 8.b
Planned Dose Levels
Dose Level
Dose (unit)
QD arm
QW arm
1
2 mg QD
20 mg QW
2
4 mg QD
30 mg QW
More conservative dose escalation, evaluation of intermediate doses, and expansion of an existing or previously tested 
dose level are all permissible following discussions and agreement between the investigators and the sponsor, if such 
measures are needed for patient safety or for a better understanding of the dose-toxicity and dose-exposure 
relationship of TAK-228.
Abbreviations: QD=once daily, QW=once weekly.
Specific rules for the 3+3 algorithm are as follows:
1. If 0 of 3 patients experiences a DLT, dose escalation will proceed to the next higher dose level, 
at which 3 patients will be enrolled.
2. If 1 of 3 patients experiences a DLT, 3 more patients will be enrolled at the same dose level. 
Escalation will continue if 1 of 6 patients experiences a DLT.
3. If 2 or more patients at any dose level experience a DLT, dosing will stop, and 1 of the
following options may be chosen by the sponsor:
a) Three additional patients will be treated at the previous dose level if fewer than 6 patients 
have been studied at that dose level, or the lower dose level may be declared as tolerable if 
6 patients have already been dosed.
b) An intermediate dose may be tested.
4. If 0 of 3 patients experiences DLT at the highest dose level, 3 additional patients will be 
enrolled at that dose level, making a total of 6 patients in the dose escalation phase at the 
highest dose level.
Escalation beyond 4 mg QD or 30 mg QW is not anticipated in this study. However, if TAK-228
exposures are unexpectedly lower than anticipated in the East Asian populations, and no DLTs 
have occurred during dose escalation, the TAK-228 dose may be escalated further after discussion 
between the investigator and the sponsor, based on available PK and safety data.
Dose escalation algorithms are outlined in Figure 8.a for the QD arm and Figure 8.b for the QW 
arm.
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Figure 8.a
QD Arm Dose Escalation Algorithm
Abbreviations: DLT=dose limiting toxicity, QD=once daily.
*
Stop the study or evaluate a lower dose following discussion between investigators and the sponsor.
** Stop enrollment and 1 of the following options will be chosen following discussion between the sponsor and 
investigators:
(a) Three additional patients will be treated at the previous dose level if fewer than 6 patients have been studied at 
that dose level, or declare the lower dose level as tolerable dose if 6 patients have already been dosed.
(b) An intermediate dose between 2 mg and 4 mg may be tested.
2 mg QD 3 pts
2 mg QD 3 pts
1 DLT / 3 pts
4 mg QD 3 pts
0 DLT / 3 pts
≥2 DLTs / 3 pts*
≤1 DLT / 6 pts
4 mg QD 3 pts
≤1 DLT / 3 pts
Expansion: enroll up to 12 patients in total at 4 mg 
QD (including escalation)
≤1 DLT / 6 pts
≥2 DLTs / 6 pts*
≥2 DLTs / 3 pts**
≥2 DLTs / 6 pts**
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Figure 8.b
QW Arm Dose Escalation Algorithm
Abbreviations: DLT=dose limiting toxicity, QW=once weekly.
*
Stop the study or evaluate a lower dose following discussion between investigators and the sponsor.
** Stop enrollment and following discussion between the sponsor and investigators, either 3 additional patients will 
be treated to the previous dose level if fewer than 6 patients have been studied at that dose level, or declare the 
lower dose level as tolerable dose if 6 patients have already been dosed.
While the primary escalation schema is designed to determine a classic Cycle 1-based maximum 
tolerated dose (MTD), dose escalation may be halted at any time after consultation between the 
sponsor and investigators if cumulative toxicity beyond Cycle 1 indicates that a given dose 
exceeds a tolerable RP2D. The MTD and/or RP2D should be evaluated with a total of ≥6 
DLT-evaluable patients. The RP2D will be determined on the basis of the safety, tolerability, and 
preliminary PK and efficacy data (if available) observed in Cycle 1 and beyond. Intrapatient dose 
escalation is not allowed in this protocol.
DLT-evaluable patient is defined as patients who have received at least 75% of planned doses of 
TAK-228 in Cycle 1 (21 doses for the QD arm and 3 doses for QW arm) unless interrupted by 
study drug-related AEs and have sufficient follow-up data to allow the sponsor and investigator to 
determine whether DLT occurred.
Patients who are not considered DLT-evaluable for the given dose cohort will be replaced within 
the same cohort. However, all AEs observed in each dose cohort, including those observed in DLT 
non-evaluable patients, will be considered together with DLTs when making dose escalation 
decisions.
20 mg QW 3 pts
20 mg QW 3 pts
1 DLT / 3 pts
30 mg QW 3 pts
0 DLT / 3 pts
≥2 DLTs / 3 pts*
≤1 DLT / 6 pts
30 mg QW 3 pts
≤1 DLT / 3 pts
Expansion: enroll up to 12 patients in total at 30 mg 
QW (including escalation)
≤1 DLT / 6 pts
≥2 DLTs / 6 pts*
≥2 DLTs / 3 pts**
≥2 DLTs / 6 pts**
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8.4
Dose Modification Guidelines
8.4.1
Intrapatient Dose Escalation
Intrapatient dose escalation is not allowed.
8.4.2
Criteria for Beginning or Delaying a Subsequent Treatment Cycle
TAK-228 will be administered in continuous cycles. For a new cycle of treatment to begin, 
subjects must be free of Grade 3 or greater TAK-228-related AEs or laboratory abnormalities. 
Guidelines for TAK-228 interruption are provided in Section 8.4.3 and for dose reduction in 
Section 8.4.4. If there is a delay of a subsequent cycle longer than 2 weeks because of incomplete 
recovery from treatment-related toxicity, the patient will be withdrawn from treatment unless there 
is clinical benefit as assessed by the investigator, with agreement by the sponsor’s project 
clinician.
8.4.3
Criteria for Dose Interruption During a Cycle
Subjects who experience an AE that meets the definition of a DLT during or after completing 
Cycle 1 should have their study drug treatment interrupted as described in Section 8.2.
TAK-228 administration must be interrupted for treatment-related AEs that are Grade 3 or higher 
despite supportive treatment per standard clinical practice.
The following nonhematologic AEs would not require study drug interruption:

Grade 3 or higher nausea and/or emesis in the absence of optimal antiemetic prophylaxis. 
(Optimal antiemetic prophylaxis is defined as an antiemetic regimen that employs both a 
5-HT3 antagonist and a corticosteroid given in standard doses and according to standard 
schedules.)

Grade 3 or higher diarrhea that occurs in the absence of optimal supportive therapy.

Grade 3 fatigue.
Patients who have study drug interrupted because of treatment-related AEs may resume study drug 
treatment only upon resolution of the AE to ≤Grade 1 (Grade 2 for hyperglycemia or rash) or to
baseline within 2 weeks.
8.4.4
Criteria for Dose Reduction
TAK-228 administration must be interrupted for treatment-related AEs that are Grade 3 or higher 
despite supportive treatment per standard clinical practice. If the event resolves to Grade 1 (or 
Grade 2 for hyperglycemia or rash, as detailed in Section 8.8.1 and 8.8.4, respectively) or to
baseline values within 2 weeks of interrupting treatment, the patient may resume study treatment at
reduced dose by 1 dose level. If a subject does not tolerate the starting dose, then the investigator 
and the sponsor’s project clinician should discuss whether the subject would benefit from a further 
dose reduction.
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All patients who continue to experience any toxicity (hematologic or nonhematologic) of a 
severity that requires more than 2 dose reductions of TAK-228, given administration of 
appropriate supportive care, should discontinue study treatment. However, if the patient has 
evidence of clinical benefit and is considered to possibly benefit from continued study treatment, 
the patient may continue study treatment with further dose reductions, upon review and written 
approval by the sponsor’s project clinician. These circumstances should be discussed on a 
case-by-case basis. As a general rule, if a patient requires dose reduction because of a study 
drug-related toxicity, the drug dose may not be re-escalated.
8.4.5
Criteria for Discontinuation
If TAK-228 dosing is delayed because of TAK-228-related toxicities for longer than 14
consecutive days despite supportive treatment per standard clinical practice or if more than 2 
TAK-228 dose reductions are required, then study drug treatment should be stopped. However, if 
the patient has evidence of clinical benefit and is considered to possibly benefit from continued 
protocol treatment, the patient may continue protocol treatment with further dose reductions, upon 
review and approval by the sponsor’s project clinician.
For all patients, the End of Treatment (EOT) visit should be completed within 30 to 40 days after 
the last dose of study drug, or before the start of subsequent antineoplastic therapy, whichever 
occurs first.
8.5
Excluded Concomitant Medications and Procedures
The following medications, therapies, and foods are prohibited during the study, except as 
indicated below:

Other investigational agents or mTOR inhibitors.

Other anticancer therapies, including chemotherapy, immunotherapy, radioimmunotherapy, 
targeted agents, radiation, or surgery (patients can have palliative radiation or surgery during 
the study for preexisting lesions).

Systemic corticosteroids (either intravenously [IV] or oral steroids), unless necessary for 
treatment of a TAK-228-related AE (eg, rash). Inhalers and low-dose glucocorticoids for 
replacement therapy are allowed.

Anti-epileptic drugs for patients with a history of treated brain metastasis.

Strong CYP1A2 inhibitors and clinically significant enzyme inducers may not be used within 
7 days before the first dose of TAK-228 or at any time during Cycle 1 (see the nonexhaustive 
list provided in Appendix H). After Cycle 1, strong CYP1A2 inhibitors and CYP inducers 
should be administered with caution and at the discretion of the investigator. Alternative 
treatments, if available, should be considered.

Concomitant administration of any PPI is not permitted during the study. All patients are 
required to stop taking PPIs at least 7 days before receiving the first dose of study drug. 
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Examples of PPIs include omeprazole, esomeprazole, pantoprazole, lansoprazole, and 
rabeprazole.

Histamine H2 receptor antagonists may be allowed if needed, provided that the histamine H2
receptor antagonist is not taken within 12 hours before or within 6 hours after study drug 
administration. Patients receiving histamine H2 receptor antagonists must stop using these 
medications for at least 24 hours before their first dose of study drug. Examples of histamine 
H2 receptor antagonists include ranitidine, famotidine, nizatidine, and cimetidine.

Administration of neutralizing antacids and calcium preparations is permitted except from 
4 hours before until 2 hours after study drug administration. Some antigas preparations may 
also have antacid properties and should also not be permitted from 4 hours before until 2 hours 
after study drug administration
8.6
Permitted Concomitant Medications and Procedures
Prophylactic use of anti-emetic (including ondansetron and granisetron), antinausea, and 
antidiarrheal medications is encouraged, and these may be administered before the first dose of 
study drug, as needed throughout the study before each dosing, and as clinically indicated per 
standard practice.
Concomitant treatment with bisphosphonates is permitted for treatment of osteoporosis or 
management of existing bone metastasis if initiated at least 4 weeks before the first dose of study 
drug. Bisphosphonates should be given after Cycle 1 to minimize confounding factors that may 
contribute to potential drug-related toxicities.
Other medications considered necessary for the safety and wellbeing of the patient may be 
administered at the discretion of the investigator. Any concomitant medications added or 
discontinued during the study should be recorded on the electronic case report form (eCRF).
8.7
Precautions and Restrictions
The only dietary restrictions imposed on study patients include avoidance of foods listed in 
Section 8.5 and Appendix H starting 1 week before the first dose of study drug and throughout the 
study, consumption of a light meal prior to weekly TAK-228 administration (QW Arm, from 
Cycle 2 onward) and fasting for glucose sampling and monitoring (as outlined in Appendix A and 
Section 9.4.15). Patients who show evidence of hyperglycemia during the study should be 
encouraged to follow a low carbohydrate diet.
8.7.1
Pregnancy and Contraception
It is not known what effects TAK-228 has on human pregnancy or development of the embryo or 
fetus. Therefore, female patients participating in this study should avoid becoming pregnant, and 
male patients should avoid impregnating a female partner. Nonsterilized female patients of 
reproductive age group and male patients should use effective methods of contraception through 
defined periods during and after study treatment as specified below.
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1. Some examples of effective contraceptive methods include intrauterine devices and hormonal 
contraceptives (Appendix G).
2. Use only contraceptive methods that are locally approved and available in each country.
3. Female patients must meet 1 of the following:

Postmenopausal for at least 1 year before the screening visit, or

Surgically sterile, or

If they are of childbearing potential, agree to practice 1 highly effective method and 1 
additional effective (barrier) method of contraception from the time of signing of the 
informed consent form (ICF) through 90 days after the last dose of study drug, or

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle 
of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 
methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable 
methods of contraception. Female and male condoms should not be used together.)
4. Male patients, even if surgically sterilized (ie, status postvasectomy) must agree to 1 of the 
following:

Agree to practice effective barrier contraception during the entire study treatment period 
and through 120 days after the last dose of study drug, or

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle 
of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 
methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable 
methods of contraception. Female and male condoms should not be used together.)
8.7.2
Patients With Prior Exposure to HBV or HCV
Patients who have detectable HBV or HCV viral loads are excluded from study participation (see 
Section 7.2, Exclusion Criterion #11). Patients with prior exposure to HBV or HCV who have 
subsequently cleared the infection (determined by a negative viral load) are allowed in the study, 
but should be monitored for reactivation every 2 months. Patients who develop detectable HBV or 
HCV in their blood during the study will have TAK-228 treatment interrupted and will be treated 
with antivirals medication per local institutional standard practice; a consultation with a 
hepatologist should be considered. For such patients enrolled in Japan, HBV infection will be 
treated as per the Japan Society of Hepatology Guidelines for the Treatment of 
Immunosuppression- or Chemotherapy-Induced Reactivation of Hepatitis B Virus Infection.
Resuming TAK-228 after HBV or HCV is no longer detected may be considered in the setting of 
continued prophylaxis and after a discussion with the sponsor’s project clinician to review the 
potential benefit versus risk to the patient in the setting of a controlled HBV or HCV infection.
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8.7.3
Overdose
There is no specific antidote for overdose with TAK-228. Patients who experience overdose 
should be closely monitored and general supportive care should be instituted.
8.8
Management of Clinical Events
Detailed TAK-228 dose modification and prevention/prophylaxis guidelines for specific clinical 
events are provided in the following sections. General guidelines for TAK-228 interruption and 
dose reduction are provided in Section 8.4.3 and Section 8.4.4.
8.8.1
Management of Hyperglycemia
On the basis of the clinical experience in TAK-228 trials, most episodes of hyperglycemia 
observed occurred within the first 60 days after initiation of treatment with TAK-228 and have 
been either Grade 1 or Grade 2, and have responded quickly to oral metformin. Hyperglycemia has 
not been dose-limiting since the institution of a standard regimen for early treatment of 
hyperglycemia.
All patients developing hyperglycemia during the study should have their glucose closely 
monitored by study staff. The investigator may choose to continue close monitoring of patients 
who develop Grade 1 hyperglycemia (fasting glucose >ULN ≤160 mg/dL) or, alternatively, 
consider initiating treatment with an oral hypoglycemic agent, such as metformin. All patients 
with ≥Grade 2 hyperglycemia (fasting glucose >160 mg/dL) must be treated aggressively with oral 
hypoglycemic agents and/or insulin as clinically indicated. The investigator should consult an 
endocrinologist, if needed, to aid in optimizing the patient’s hyperglycemia treatment plan.
It is recommended that patients be initially treated with a fast acting insulin sensitizer such as 
metformin at 500 mg orally (PO) QD, and titrate up to a maximum of 1000 mg PO twice daily as 
needed. Concurrent addition to metformin of dipeptidyl peptidase-4 (DPP-4) inhibitors (eg, 
sitagliptin or vildagliptin) and/or insulin should also be considered. Oral sulfonylureas (eg, 
glipizide or glyburide) should be used with caution, due to the higher risk of inducing 
hypoglycemia in patients. The dose of oral hypoglycemic agents should be adjusted in patients 
with renal insufficiency. In addition, patients should be encouraged to follow a low carbohydrate 
diet once hyperglycemia is first observed.
If any fasting serum glucose reading performed at the site indicates hyperglycemia (>ULN or
≥110 mg/dL), the study staff should first confirm that the patient was fasting at the time of blood 
specimen collection (ie, nothing by mouth for at least 8 hours before collection). To aggressively 
manage the hyperglycemia per standard clinical practice, the following guidelines (Table 8.c) are 
provided to aid the investigator in initiating antiglycemic therapies.
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Table 8.c
Management of Hyperglycemia
Grade
Description
Treatment
Dose Modification
1
FBG 
>ULN-160 mg/dL
Continue close monitoring of blood 
glucose. Initiate oral hypoglycemic 
agent.
None
2
FBG 
>160-250 mg/dL
Initiate oral hypoglycemic agent 
and/or insulin if not well controlled 
on oral agent.
None
3
FBG >250 mg/dL
Initiate oral hypoglycemic agent 
and/or insulin.
Interrupt TAK-228 until Grade 2.
Resume TAK-228 based on timing of 
recovery:
1 week: resume at same dose and 
schedule.
>1 but 2 weeks: reduce to the next 
lower dose.
>2 weeks: discontinue TAK-228 
treatment permanently.
Prevention/Prophylaxis

Follow fasting serum glucose levels during clinic visits.

Monitor home glucometer test results.

Check HbA1c levels every 3 months during therapy.

Recommend lifestyle modifications, as appropriate (balanced diet, limited alcohol consumption, increased 
physical activity).

Most episodes of Grade 1 and 2 hyperglycemia respond quickly to oral metformin. Early initiation of therapy is 
recommended to prevent higher grade hyperglycemia.

FBG levels 150 mg/dL by glucometer should be followed by closer monitoring of serum glucose and possible 
intervention.
Abbreviations: FBG=fasting blood glucose; HbA1c=glycosylated hemoglobin; ULN=upper limit of normal.
8.8.2
Management of Hyperlipidemia
Guidance on study drug dose modification for patients with hyperlipidemia is provided in Table 
8.d.
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Table 8.d
Management of Hyperlipidemia
Grade
Description
Treatment
Dose Modification
1
Cholesterol:
>ULN-300 mg/dL
Triglycerides:
>150-300 mg/dL
None
None
2
Cholesterol:
>300-400 mg/dL
Triglycerides:
>300-500 mg/dL
Treat hyperlipidemia according to 
standard guidelines. Triglycerides 
≥500 mg/dL should be treated urgently 
because of the risk of pancreatitis.
Maintain dose if tolerable. If toxicity 
becomes intolerable, interrupt 
TAK-228 dosing until recovery to
≤Grade 1. Resume TAK-228 at 
same dose.
3
Cholesterol:
>400-500 mg/dL
Triglycerides:
>500-1000 mg/dL
Same as for Grade 2
Interrupt TAK-228 until recovery to
≤Grade 1 or baseline, then resume 
TAK-228 with the next lower dose.
4
Cholesterol:
>500 mg/dL
Triglycerides:
>1000 mg/dL
Same as for Grade 2
Discontinue TAK-228 treatment 
permanently.
Prevention/Prophylaxis
Lifestyle modifications, as appropriate (balanced diet, limited consumption of alcoholic beverages, increased 
physical activity).
Abbreviation: ULN=upper limit of normal.
8.8.3
Management of Oral Mucositis
Guidance on study drug dose modification for patients with oral mucositis is provided in Table 8.e.
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Table 8.e
Management of Oral Mucositis
Grade
Description
Treatment
Dose Modification
1
Asymptomatic or mild 
symptoms
Nonalcoholic mouthwash or 0.9% 
saltwater rinse; consider topical 
corticosteroids at earliest signs of 
mucositis.
None
2
Moderate pain not 
interfering with oral 
intake; modified diet 
indicated
Topical analgesic mouth treatments; 
topical corticosteroids; initiate 
antiviral or antifungal therapy, if 
indicated.
Maintain dose if tolerable. If toxicity 
becomes intolerable, interrupt 
TAK-228 dosing until recovery to
≤Grade 1. Resume TAK-228 at same 
dose.
3
Severe pain interfering 
with oral intake
Same as for Grade 2; consider 
intralesional corticosteroids.
Interrupt TAK-228 until recovery to
≤Grade 1, then resume TAK-228 with 
the next lower dose.
4
Life-threatening 
consequences
Same as for Grade 2; consider 
intralesional corticosteroids.
Discontinue TAK-228 treatment 
permanently.
Prevention/Prophylaxis

Consider initiation of a nonalcoholic mouthwash or 0.9% saltwater rinses 4 to 6 times daily with start of therapy 
before signs of mucositis develop.

Avoid using agents containing hydrogen peroxide, iodine, and thyme derivatives in management of stomatitis as 
they may worsen mouth ulcers.
8.8.4
Management of Rash
Patients who develop Grade 4 rash should permanently discontinue study treatment, unless they 
derive clinical benefit, in which case they may be retreated at a reduced dose level after recovery to 
Grade 1 severity. Grade 4 rash is defined as rash acneiform/papulopustular with papules and/or 
pustules covering any percentage of body surface area, which may or may not be associated with 
symptoms of pruritus or tenderness, and are associated with extensive superinfection, with 
intravenous antibiotics indicated; life-threatening consequences (NCI CTCAE version 4.03, 
effective date 14 June 2010 [7]).
Guidance on study drug dose modification for patients with rash is provided in Table 8.f.
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Table 8.f
Management of Rash
Grade
Description
Treatment
Dose Modification
≤2
Macules/papules covering 
≤30% body surface area with or 
without symptoms.
Consider treatment with topical 
steroid cream/ointment and/or 
oral antihistamines.
None
3
Macules/papules covering 
30% body surface area with or 
without symptoms.
Consider treatment with topical 
steroid cream/ointment, oral 
antihistamines, and/or pulsed 
steroids.
Interrupt TAK-228 until ≤Grade 2; 
resume TAK-228 based on timing of 
recovery:
≤2 weeks: resume TAK-228 with 
the next lower dose.
>2 weeks: discontinue TAK-228
treatment.
4
Rash acneiform/ 
papulopustular with papules 
and/or pustules covering any 
percentage of body surface 
area, which may or may not be 
associated with symptoms of 
pruritus or tenderness, and are 
associated with extensive 
superinfection with intravenous 
antibiotics indicated; life 
threatening consequences.
Same as for Grade 3.
Permanently discontinue TAK-228, 
unless patient is deriving clinical 
benefit, in which case resume at a 
reduced dose level after recovery to 
Grade 1 severity.
Prevention/Prophylaxis:
Rash should be managed aggressively. The investigator should consider consulting a dermatologist or other 
specialist, if needed.
A skin biopsy at the site of rash should be considered as soon as possible after the initial episode.
8.8.5
Management of Nausea/Vomiting
Guidance on study drug dose modification for patients with nausea and/or vomiting is provided in 
Table 8.g.
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Table 8.g
Management of Nausea/Vomiting
Grade
Description
Treatment
Dose Modification
≤2
Loss of appetite with or 
without decreased oral intake; 
1 to 5 episodes of vomiting 
within 24 hours
Maximize antiemetic therapy.
Consider IV fluid hydration.
None
≥3
Inadequate oral intake; 
≥6 episodes of vomiting 
within 24 hours
Maximize antiemetic therapy.
Initiate tube feeding, IVF or TPN.
If experienced for ≤72 hours, 
interrupt TAK-228 until ≤Grade 1, 
then resume TAK-228 without dose 
modification.
If experienced for >72 hours despite 
optimal therapy, interrupt TAK-228 
until ≤Grade 1, then resume 
TAK-228 with the next lower dose. 
Prevention/Prophylaxis
Prophylactic use of anti-emetic, antinausea, and antidiarrheal medications is encouraged, and these may be 
administered before each dose of TAK-228 as needed throughout the study.
Abbreviations: IV=intravenous(ly); IVF=intravenous fluids; TPN=total parenteral nutrition.
8.8.6
Management of AST/ALT Elevations
Patients who develop Grade 3 or Grade 4 AST/ALT elevation in combination with Grade 2 total 
bilirubin elevation when alternative causes cannot be identified (ie, Hy’s Law) should permanently 
discontinue study treatment.
Guidance on dose adjustment for patients with AST/ALT elevations is provided in Table 8.h.
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Table 8.h
Management of AST/ALT Elevations
Grade
Description
Treatment
Dose Modification
1
>ULN to 3ULN
None
None
2
Asymptomatic with levels 3 to 
5ULN; >3ULN with the 
appearance of worsening 
fatigue, nausea, vomiting, right 
upper quadrant pain or 
tenderness, fever, rash, or 
eosinophilia.
Closely monitor LFTs at least 
weekly or more frequently as 
indicated.
Assess patient for other causes 
of transaminitis (eg, past 
medical history, concomitant 
medications).
None
3
>5 to 20ULN; >5ULN 
for >2 weeks
Same as for Grade 2.
Interrupt TAK-228 until ≤Grade 1 
or baseline; Resume TAK-228 with
the reduced doses.
Permanently discontinue TAK-228 
if in combination with Grade 2 total 
bilirubin elevation when alternative 
causes cannot be identified.
4
>20ULN
Same as for Grade 2.
Discontinue TAK-228 treatment 
permanently.
Prevention/Prophylaxis:
Ensure proper screening of patients for study participation.
Abbreviation: ALT=alanine aminotransferase, AST=aspartate aminotransferase, LFTs=liver function tests,
ULN=upper limit of normal.
8.8.7
Management of Non-Infectious Pneumonitis
Guidance for the management of pneumonitis is provided in Table 8.i.
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Table 8.i
Management of Non-Infectious Pneumonitis
Grade
Description 
Treatment
Dose Modification
1
Asymptomatic: Radiographic findings 
only.
Rule out infection and 
closely monitor.
None
2
Symptomatic:
Not interfering with activities of daily 
living.
Rule out infection and 
consider treatment with 
corticosteroids until 
symptoms improve to
≤Grade 1.
Interrupt TAK-228
When symptoms ≤Grade 1, 
resume TAK-228 with the 
dose reduced by 1 level.
If no recovery within 2 weeks, 
then discontinue TAK-228.
3
Symptomatic:
Interfering with activities of daily living;
Requires administration of oxygen.
Rule out infection and 
consider treatment with 
corticosteroids until 
symptoms improve to
≤Grade 1.
Interrupt TAK-228 until 
symptoms resolve to ≤Grade 1.
Consider resuming TAK-228
with the reduced dose.
If toxicity recurs at Grade 3, 
discontinue TAK-228 
treatment permanently.
4
Life-threatening:
Ventilatory support indicated.
Rule out infection and 
consider treatment with 
corticosteroids.
Discontinue TAK-228 treatment 
permanently.
8.8.8
Management of Other Nonhematologic Toxicities
Guidance on dose adjustment for patients with other nonhematologic toxicities is provided in 
Table 8.j.
Patients who develop Grade 4 nonhematological toxicities (with the exception of isolated 
asymptomatic laboratory values) should permanently discontinue study treatment, unless they 
derive clinical benefit, in which case they may be retreated at a reduced dose level after recovery to 
Grade 1 severity.
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Table 8.j
Management of Other Nonhematologic Toxicities (Including Asthenia, 
Weakness, and Fatigue)
Grade
Description
Treatment
Dose Modification
1
Mild; asymptomatic or mild 
symptoms; clinical or diagnostic 
observations only; intervention 
not indicated.
Initiate appropriate medical 
therapy and monitor.
If tolerable, then no adjustment is 
required.
2
Moderate; minimal, local or 
noninvasive intervention 
indicated.
Initiate appropriate medical 
therapy and monitor.
If tolerable, no adjustment 
required.
If toxicity becomes intolerable, 
interrupt TAK-228 until 
recovery to ≤Grade 1, then 
resume TAK-228 at same dose.
≥3
Severe or medically significant 
but not immediately 
life-threatening; hospitalization 
or prolongation of 
hospitalization indicated
Interrupt TAK-228 until recovery 
to ≤Grade 1 or baseline. Resume 
TAK-228 with the dose of 
TAK-228 reduced by 1 level.
Patients who develop Grade 4 
nonhematological toxicities (with 
the exception of isolated 
asymptomatic laboratory values) 
should permanently discontinue 
study treatment, unless they derive 
clinical benefit, in which case they 
may be retreated at a reduced dose 
level after recovery to Grade 1 
severity.
8.9
Blinding and Unblinding
This is an open-label study; no blinding methods will be used.
8.10
Description of Investigational Agents
Upon receipt of drug supply, contents must be verified promptly and the proper contacts notified 
of any discrepancies or damages as described in the Study/Pharmacy Manual.
TAK-228 will be supplied as capsules for oral administration. TAK-228 is available in 3 dose 
strengths—1 mg, 3 mg, and 5 mg—each containing 1 mg, 3 mg, and 5 mg of TAK-228, 
respectively, in addition to the following inactive ingredients: microcrystalline cellulose (solid 
filler/diluents), magnesium stearate (lubricant), and hard gelatin capsule.
All 3 dose strengths are formulated into size 2 capsules, and each dose strength is differentiated by 
color, as listed below:

1 mg TAK-228 capsules: white opaque color.
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
3 mg TAK-228 capsules: Swedish orange opaque color.

5 mg TAK-228 capsules: gray opaque color.
8.11
Preparation, Reconstitution, and Dispensation
TAK-228 study drug will be provided in labeled bottles in accordance with all applicable 
regulations. TAK-228 will be dispensed with dosing instructions for home use, including the 
requirement that capsules are stored in their original containers and that capsules be swallowed 
whole and not opened, chewed, or manipulated in any way. Materials provided by the sponsor 
should be dispensed to patients with clear administration instructions from the investigator.
TAK-228 is an anticancer drug and, as with other potentially toxic compounds, caution should be
exercised when handling TAK-228 capsules.
8.12
Packaging and Labeling
TAK-228 will be provided by Millennium and will be handled at the investigative site as 
open-label material. TAK-228 will be provided in 30-ct, 60-cc high-density polyethylene (HDPE) 
bottles with polypropylene, child-resistant caps and induction seal.
TAK-228 will be packaged and labeled in accordance with all applicable regulations.
8.13
Storage, Handling, and Accountability
Upon receipt at the investigative site, TAK-228 study drug should be stored in the original bottles 
until use and stored at room temperature from 15C to 30C. All temperature excursions will be 
reported to the sponsor for assessment and authorization for continued use. All investigational 
supplies must be stored in a secure area with controlled access and will be stored in original 
packaging. All study drugs should be used before the retest expiry date. Storage area temperature 
conditions must be monitored and recorded daily. A daily temperature log will also be kept at the 
study site.
A drug dispensing log, including records of drug received from the sponsor and TAK-228 drug 
dispensed to the patients, will be provided and kept at the study site.
Because TAK-228 is an investigational agent, it should be handled with due care. In case of 
contact with broken capsules, raising dust should be avoided during the clean-up operation. The 
product may be harmful if inhaled, ingested, or absorbed through the skin. Gloves and protective 
clothing should be worn during the clean-up operation. The area should be ventilated and the spill 
site washed after material pick-up is complete. The spilled material should be disposed of as 
hazardous medical waste in compliance with federal, state, and local regulations. In case of contact 
with the powder (eg, from a broken capsule), skin should be washed immediately with soap and 
copious amounts of water for at least 15 minutes. In case of contact with the eyes, copious amounts 
of water should be used to flush the eyes for at least 15 minutes. Medical personnel should be 
notified.
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Patients will be given clear dosing instructions from the investigator for home storage and 
administration of TAK-228 capsules, including the requirement that the capsules must be stored in 
their original containers and that the capsules are to be swallowed whole and not chewed or 
manipulated in any way. Patients will also receive diary cards to record dosing compliance with 
their TAK-228 treatment assignment, with instructions for their completion. Patients will be 
instructed to return any unused TAK-228 study drug in the original packaging along with their 
completed diary cards at the appropriate visits.
Please refer to the Study Manual and the Pharmacy Manual for additional instructions.
8.14
Other Protocol-Specified Materials
Not applicable.
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9.0
STUDY CONDUCT
This trial will be conducted in compliance with the protocol, GCP, applicable regulatory 
requirements, and ICH guidelines.
9.1
Study Personnel and Organizations
The contact information for the sponsor’s project clinician for this study, the central laboratory and 
any additional clinical laboratories, and other third-party vendors may be found in the Study 
Manual. A full list of investigators is available in the sponsor’s investigator database.
9.2
Arrangements for Recruitment of Patients
Recruitment and enrollment strategies for this study may include recruitment from the 
investigator’s local practice or referrals from other physicians. If advertisements become part of 
the recruitment strategy, they will be reviewed by the institutional review board 
(IRB)/independent ethics committee (IEC).
9.3
Treatment Group Assignments
This is a phase 1 study to study 2 dosing schedules (QD schedule and QW schedule). Patients will 
be assigned to a dose cohort using the dose escalation rules as described in Section 8.3. The 2 arms 
will enroll in parallel. Patient assignment to a specific schedule will be decided jointly by the 
investigator and sponsor with the aim of maximizing enrollment efficiency in the study. At least 1 
Japanese patient will be enrolled in each group of 3 patients during dose escalation. The total 
number of Japanese patients dosed at the RP2D level will be at least 6.
9.4
Study Procedures
Refer to the Schedule of Events (Appendix A) for timing of assessments. Additional details are 
provided as necessary in the sections that follow.
9.4.1
Informed Consent
Each patient must provide written informed consent before any study-required procedures are 
conducted, unless those procedures are performed as part of the patient’s standard care.
9.4.2
Patient Demographics
The date of birth, race, ethnicity, smoking history, and sex of the patient are to be recorded during 
Screening.
9.4.3
Medical History
During the Screening period, a complete medical history will be compiled for each patient. The 
history will emphasize the background and progress of the patient’s malignancy and include a 
description of prior therapies for it. In addition, concomitant medications will be recorded as 
specified in Section 9.4.10.
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9.4.4
Physical Examination
A physical examination will be completed per standard of care at the time points specified in the 
Schedule of Events (Appendix A).
9.4.5
Patient Height and Weight
Height will be measured only during Screening. Weight will be measured at the time points
specified in the Schedule of Events (Appendix A).
9.4.6
Vital Signs
Vital sign measurements include blood pressure (diastolic and systolic), pulse, temperature, and
oxygen saturation. Vital signs will be assessed at the time points specified in the Schedule of 
Events (Appendix A) except oxygen saturation, which will be measured by pulse oximetry at 
Screening and on Day 15 of Cycles 1 and 2.
9.4.7
Pregnancy Test
A serum pregnancy test will be performed for women of childbearing potential at Screening and 
again at Cycle 1 Day 1. A urine pregnancy test will be performed predose on Day 1 of all cycles, 
and negative results must be obtained before the first dose of TAK-228 may be administered. If the 
serum pregnancy test is performed within 3 days before the first dose and the result is negative, the 
urine pregnancy test on Cycle 1 Day 1 may be waived.
Women of childbearing potential are defined as any sexually active female patients who meet both 
of the following criteria:

Those who have not undergone hysterectomy or bilateral oophorectomy, AND

Those who have not had natural menopause for 12 consecutive months or longer (eg,
follicle-stimulating hormone >40 IU/L and no menopausal period for at least 12 consecutive 
months; loss of menopausal periods following chemotherapy may not rule out childbearing
potential).
9.4.8
Eastern Cooperative Oncology Group Performance Status
The ECOG performance status (refer to Appendix D) will be assessed at the time points specified 
in the Schedule of Events (Appendix A).
9.4.9
Electrocardiogram
A single, 12-lead electrocardiogram (ECG) will be performed at the time points specified in the 
Schedule of Events (Appendix A). Additional ECGs may be obtained as clinically indicated.
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9.4.10 Concomitant Medications and Procedures
Medications used by the patient and therapeutic procedures completed by the patient will be 
recorded in the eCRF according to the Schedule of events (Appendix A). See Section 8.5 and 
Section 8.6 for medications and therapies that are prohibited or allowed during the study.
9.4.11 Adverse Events
Monitoring of AEs, serious and nonserious, will be conducted throughout the study as specified in 
the Schedule of Events (Appendix A). Refer to Section 10.0 for details regarding definitions, 
documentation, and reporting of AEs and SAEs.
9.4.12 Enrollment
A subject is considered to be enrolled in the study when the first dose of study drug is 
administered. Procedures for completing the enrollment information are described in the Study 
Manual.
9.4.13 Clinical Laboratory Evaluations
Clinical laboratory evaluations will be performed locally. Clinical laboratory evaluations will be 
performed as outlined below.
9.4.13.1 Hematology, Chemistry, Coagulation and Urinalysis
Blood samples for analysis of the hematology, chemistry, and coagulation parameters shown in
Table 9.a, as well as urine samples for analysis of the urinalysis parameters shown in Table 9.b will 
be obtained at the time points specified in the Schedule of Events (Appendix A). Results of 
hematology and chemistry labs must be available and reviewed by the investigator before 
enrollment and initial administration of study drug.
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Table 9.a
Hematology, Chemistry, and Coagulation Tests
Hematology and Coagulation 
Serum Chemistry
Hematocrit
Hemoglobin
Leukocytes with differential
Neutrophils (ANC)
Platelet (count)
Activated partial thromboplastin time
(aPTT)
Prothrombin time/international 
normalized ratio (PT/INR)
Albumin
Alkaline phosphatase
ALT
Amylase
AST
Bilirubin (total and direct)(a)
Blood urea nitrogen or urea
Calcium (total)
Carbon dioxide or bicarbonate (if 
available as part of blood chemistry 
panel of local lab)
Chloride
Creatinine
Gamma glutamyl transferase
Glucose
HbA1c
Lactate dehydrogenase
Magnesium
Phosphate
Potassium
Sodium
Protein (total)
Urate
Abbreviations: ALT=alanine aminotransferase, ANC=absolute neutrophil count, aPTT=activated partial 
thromboplastin time, AST=aspartate aminotransferase, HbA1c=glycosylated hemoglobin, PT/INR=prothrombin 
time/international normalized ratio.
(a) Direct bilirubin will be measured only if total bilirubin is altered.
Table 9.b
Urinalysis Tests
Urinalysis
Bilirubin
Glucose
Ketones
Leukocytes
Nitrite
Occult blood
pH
Protein
Specific gravity
Turbidity
Color
Urobilinogen
9.4.14 Fasting Lipid Profile
Prospective monitoring for hyperlipidemia will be managed through fasting lipid testing at the 
time points specified in the Schedule of Events (Appendix A). Patients are required to fast 
overnight (nothing except water and prescribed medications after midnight or for a minimum of 
8 hours) for each of these measurements. The fasting lipid profile is shown in Table 9.c.
Table 9.c
Fasting Lipid Profile
Fasting Lipid Profile
Cholesterol (total)
Triglycerides
High-density lipoprotein cholesterol
Low-density lipoprotein cholesterol
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9.4.15 Fasting Serum Glucose
Fasting serum glucose will be measured in the study site at the time points specified in the 
Schedule of Events (Appendix A) before administration of TAK-228, and at other times at the 
discretion of the investigator. Patients are required to fast overnight (nothing except water and 
prescribed medications after midnight or for a minimum of 8 hours) for each of these 
measurements. In Cycle 2 and subsequent cycles in the QW arm, the sample should be taken 
predose; after predose blood draws are complete, patients receiving TAK-228 QW should 
consume a light meal before dosing (Section 8.1). In-home glucose monitoring is not required on 
days when fasting glucose is measured in the study site.
9.4.16 Hepatitis Testing
HBV and HCV testing will be performed at Screening. As appropriate and according to local 
guidelines for the management of hepatitis B virus infection, HBV screening may include the 
following: HBsAg, HBsAb, HBcAb, and HBV DNA. HCV screening will include the anti-HCV 
antibody (HCVAb). Patients who test positive for HCVAb will also be tested for HCV RNA at 
Screening.
Note that patients who have negative HBsAg but positive HBcAb and/or HBsAb may be enrolled 
but must have undetectable HBV viral load. Patients who have a positive HCVAb can be enrolled 
but must have undetectable HCV viral load.
Patients who are HBsAg negative but HBsAb and/or HBcAb positive, and/or HCVAb positive 
with negative viral load at Screening, enrolled in this study will be monitored by assessment of 
viral load (eg. HBV-DNA titer; HCV-RNA titer) every 2 month during the study treatment.
9.4.17 In-Home Daily Fasting Glucose Monitoring
In addition to obtaining fasting glucose levels at the site visits as outlined in the Schedule of Events
(Appendix A), all patients enrolled in the study will be given a glucometer to monitor their daily 
fasting blood glucose (FBG) levels at home. The level should be collected daily, predose on dosing 
days, and at approximately the same time each day. Before checking their blood glucose levels, 
patients should fast overnight (nothing except water and/or medications after midnight or for a 
minimum of 8 hours before the assessment). After fasted testing is complete, patients in the QW 
arm (Cycle 2 and subsequent cycles) should consume a light meal before TAK-228 dosing 
(Section 8.1).
On Cycle 1 Day 1, the patient will be provided an in-home glucometer. Patients will be trained on 
proper use of the glucometer and instructed to collect a daily FBG level every morning (predose on 
dosing days), starting on Cycle 1 Day 2. Patients will be instructed to bring the glucometer with 
them to each study visit so that the data collected can be reviewed and recorded in the source 
documents. Investigators will be responsible for reviewing the home glucose monitoring logs for 
hyperglycemia.
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The patient will be instructed to contact the site immediately if the value is abnormal (ie,
≥150 mg/dL) for further instructions on the management of their hyperglycemia. Hyperglycemia 
observed during home glucose monitoring should be confirmed in the study site.
If no irregularities in the FBG level are observed during a minimum of 2 consecutive months, then 
the frequency of in-home FBG testing can be reduced to a minimum frequency of once weekly, 
depending on the investigator’s judgment. Patients will continue to notify the investigator of FBG 
levels that exceed 150 mg/dL and, if blood glucose levels are not well controlled, or if the patient 
requires either oral hypoglycemic agents or insulin to control blood glucose levels, then the 
frequency of in-home testing of FBG levels will be reinstated to daily. See also Section 8.8.1.
9.4.18 DNA Measurements
9.4.19
Disease Assessment
Patients will undergo a computed tomography (CT) scan (with contrast) as appropriate to monitor 
and assess disease progression, using RECIST guidelines (Version 1.1), where measurable disease 
is defined as ≥1 extraosseous lesion that can be accurately measured in at least 1 dimension[6].
Specific disease sites that cannot be adequately imaged by CT may be documented by magnetic 
resonance imaging (MRI). Anatomical measurements will be collected at baseline and at each 
subsequent evaluation for each target lesion using an imaging modality consistent with that used at 
CCI
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Screening. The same method (CT with contrast, MRI, or bone scan) must be consistently used on a 
patient throughout the study. Bone scans may be performed on patients with bone metastases 
rather than CT or MRI.
Objective assessments will be performed at each time point as described in the Schedule of Events
(Appendix A). When possible, the same qualified physician will interpret results to reduce 
variability.
Radiographic images will be maintained at the site, and test results and physicians’ findings will be 
filed in patient source documents. The sponsor may request electronic images for those patients 
who demonstrate a response.
9.4.20
Pharmacokinetic Measurements
Serial blood samples for PK analysis of TAK-228 will be collected at the time points specified in 
the Pharmacokinetic Sample Breakdown table (Table A in Appendix A). The dates and exact times 
of administration of TAK-228 before collection of the blood sample for PK analysis and the dates 
and exact times of the postdose PK sample collection will be recorded on the eCRF.
9.5
Documentation of Subjects Failure
Investigators must account for all subjects who sign informed consent.
If the subject is found to be not eligible before the first dose, the investigator should complete the 
eCRF. Interactive response technology should be used to provide notification of subject failure.
The primary reason for subject failure is recorded in the eCRF using the following categories:

Death.

Adverse Event.

Screen Failure (failed inclusion criteria or did meet exclusion criteria).

Protocol deviation.

Lost to follow-up.

Withdrawal by subject.

Study terminated by sponsor.

Pregnancy.
Subject numbers assigned to subjects who fail screening should not be reused.
9.6
Completion of Study Treatment (for Individual Patients)
Patients will be considered to have completed treatment if they discontinue treatment with study 
drug for any of the reasons outlined in Section 9.8 and the maximum duration of treatment for 
patients will be 12 months.
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If, after discussion between the investigator and the sponsor, it is determined that a patient would 
derive benefit from treatment beyond 12 months, then sponsor will make TAK-228 available for 
such patient, except in the event of any of the following:

Progression of disease.

Unacceptable toxicity.

Pregnancy.

Termination of the sponsor’s development of the TAK-228 or sponsor otherwise decides not to 
seek registration of TAK-228 in the country in which the patient seeks access; or

TAK-228 becomes commercially available.
9.7
Completion of Study (for Individual Patients)
Patients will be considered to have completed the study if they discontinue treatment and complete 
EOT visit.
9.8
Discontinuation of Treatment With Study Drug and Patient Replacement
Treatment with study drug may also be discontinued for any of the following reasons:

Adverse Event.

Protocol deviation.

Progressive disease (PD).

Study terminated by sponsor.

Withdrawal by subject.

Lost to follow-up.

Death.

Pregnancy.

Other.
Once study drug has been discontinued, all study procedures outlined for the EOT visit will be 
completed as specified in the Schedule of Events (Appendix A). The primary reason for study drug 
discontinuation will be recorded on the eCRF.
Patients who receive <75% of planned doses of TAK-228 in Cycle 1 for reasons other than related 
AEs during dose escalation are not considered DLT-evaluable and additional patients will be 
enrolled for DLT evaluation.
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9.9
Study Compliance
Study drug will be administered or dispensed only to eligible patients under the supervision of the 
investigator or identified subinvestigator(s). The appropriate study personnel will maintain records 
of study drug receipt and dispensing.
Patients will receive a sufficient quantity of TAK-228 for each treatment cycle and a diary in 
which to record their dosing. The study site staff will check the patient’s diary versus the patient’s 
supply of remaining TAK-228 at each study visit to ensure proper compliance with dosing. 
Patients who are not compliant with the dosing schedule may be withdrawn from the study.
Tests and procedures should be performed on schedule, but unless otherwise specified, occasional 
changes are allowable within a 2-day window for holidays, vacations, and other administrative 
reasons. If extenuating circumstances prevent a patient from beginning treatment or completing a 
planned procedure or assessment within 2 days of the scheduled time, the patient may continue the 
study at the discretion of the investigator and after consultation with the sponsor’s project clinician 
or designee. However, the timing of PK assessment as specified in the Schedule of Events (Table 
A in Appendix A) is not flexible.
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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 Adverse Event Definition
AE means any untoward medical occurrence in a patient or subject administered a pharmaceutical 
product; the untoward medical occurrence does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product whether or not it is related to the medicinal product. This includes any 
newly occurring event, or a previous condition that has increased in severity or frequency since the 
administration of study drug.
An abnormal laboratory value will not be assessed as an AE unless that value leads to 
discontinuation or delay in treatment, dose modification, therapeutic intervention, or is considered 
by the investigator to be a clinically significant change from baseline.
10.1.3 Serious Adverse Event Definition
SAE means any untoward medical occurrence that at any dose:

Results in death.

Is life-threatening (refers to an AE in which the patient was at risk of death at the time of the 
event. It does not refer to an event which hypothetically might have caused death if it were 
more severe).

Requires inpatient hospitalization or prolongation of an existing hospitalization (see 
clarification in the paragraph in Section 10.2 on planned hospitalizations).

Results in persistent or significant disability or incapacity. (Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions).

Is a congenital anomaly/birth defect.

Is a medically important event. This refers to an AE that may not result in death, be 
immediately life threatening, or require hospitalization, but may be considered serious when, 
based on appropriate medical judgment, may jeopardize the patient, require medical or 
surgical intervention to prevent 1 of the outcomes listed above, or involves suspected 
transmission via a medicinal product of an infectious agent. Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at home, 
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blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse; any organism, virus, or infectious particle 
(eg, prion protein transmitting transmissible spongiform encephalopathy), pathogenic or 
nonpathogenic, is considered an infectious agent.
In this study, intensity for each AE, including any lab abnormality, will be determined using the 
NCI CTCAE, Version 4.03, effective date 14 June 2010 [7]. 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 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 Adverse Events and Serious 
Adverse Events
All AEs spontaneously reported by the patient and/or in response to an open question from study 
personnel or revealed by observation, physical examination, or other diagnostic procedures will be 
recorded on the appropriate page of the eCRF (see Section 10.3 for the period of observation). Any 
clinically relevant deterioration in laboratory assessments or other clinical finding is considered an 
AE. When possible, signs and symptoms indicating a common underlying pathology should be 
noted as 1 comprehensive event.
Regardless of causality, SAEs and serious pretreatment events (as defined in Section 10.1) must be 
reported (see Section 10.3 for the period of observation) by the investigator to the Takeda Global 
Pharmacovigilance department or designee (contact information provided below). This should be 
done by faxing the SAE Form within 24 hours after becoming aware of the event. The SAE Form, 
created specifically by Takeda, will be provided to each clinical study site. A sample of the SAE 
Form may be found in the Study Manual. Follow-up information on the SAE or serious 
pretreatment event may be requested by Takeda. SAE report information must be consistent with 
the data provided on the eCRF.
SAE Reporting Contact Information
PPD
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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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. For serious 
pretreatment events, the investigator must determine both the severity (toxicity grade) of the event 
and the causality of the event in relation to study procedures.
Severity (toxicity grade) for each AE, including any lab abnormality, will be determined using the 
NCI CTCAE, Version 4.03, effective date 14 June 2010 [7]. The criteria are provided in the Study 
Manual.
Relationship of the event to study drug administration (ie, its causality) will be determined by the 
investigator responding yes (related) or no (unrelated) to this question: “Is there a reasonable 
possibility that the AE is associated with the study drug?”
10.3
Monitoring of Adverse Events and Period of Observation
AEs, both nonserious and serious, will be monitored throughout the study as follows:

AEs will be reported from the signing of informed consent through 30 days after 
administration of the last dose of study drug and recorded in the eCRFs.

SAEs
–
Serious pretreatment events will be reported to the Takeda Global Pharmacovigilance 
department or designee from the time of the signing of the ICF up to first dose of study 
drug, and will also be recorded in the eCRF.
–
Related and unrelated treatment-emergent SAEs will be reported to the Takeda Global 
Pharmacovigilance department or designee from the first dose of study drug through 
30 days after administration of the last dose of study drug and recorded in the eCRF. After 
this period, only related SAEs must be reported to the Takeda Global Pharmacovigilance 
department or designee. SAEs should be monitored until they are resolved or are clearly 
determined to be due to a patient’s stable or chronic condition or intercurrent illness (es).
10.4
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events
If a woman becomes pregnant or suspects that she is pregnant while participating in this study, she 
must inform the investigator immediately and permanently discontinue study drug. The sponsor 
must also be contacted immediately by faxing a completed Pregnancy Form to the Takeda Global 
Pharmacovigilance department or designee (see Section 10.2). The pregnancy must be followed 
for the final pregnancy outcome.
If a female partner of a male patient becomes pregnant during the male patient’s participation in 
this study, the sponsor must also be contacted immediately by faxing a completed Pregnancy Form 
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to the Takeda Global Pharmacovigilance department or designee (see Section 10.2). Every effort 
should be made to follow the pregnancy for the final pregnancy outcome.
10.5
Procedures for Reporting Product Complaints or Medication Errors (Including 
Overdose)
A product complaint is a verbal, written, or electronic expression that implies dissatisfaction 
regarding the identity, strength, purity, quality, or stability of a drug product. Individuals who 
identify a potential product complaint situation should immediately report this via the phone 
numbers or e-mail addresses provided below.
A medication error is a preventable event that involves an identifiable patient and that leads to 
inappropriate medication use, which may result in patient harm. Whereas overdoses and 
underdoses constitute medication errors, doses missed inadvertently by a patient do not. 
Individuals who identify a potential medication error (including overdose) situation should 
immediately report this via the phone numbers or e-mail addresses provided below.
Call Center
Phone Number
E-mail
Fax
Product complaints in and of themselves are not AEs. If a product complaint results in an SAE, an 
SAE form should be completed and sent to 
 (refer to Section 10.2)
10.6
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities
The sponsor or its designee will be responsible for reporting all suspected unexpected serious 
adverse reactions (SUSARs) and any other applicable SAEs to regulatory authorities, investigators 
and IRBs or IECs or the head of the study site, as applicable, in accordance with national 
regulations in the countries where the study is conducted. Relative to the first awareness of the 
event by/or further provision to the sponsor or sponsor’s designee, SUSARs will be submitted to 
the regulatory authorities as an expedited report within 7 days for fatal and life-threatening events 
and 15 days for other serious events, unless otherwise required by national regulations. The 
sponsor or its designee 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.
PPD
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11.0
STUDY-SPECIFIC COMMITTEES
No steering committee, data safety monitoring committee, or clinical endpoint committee will be 
used in this study.
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12.0
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the Data Management Plan. 
If selected for coding, AEs, pretreatment events, medical history, and concurrent conditions will 
be coded using the Medical Dictionary for Regulatory Activities (MedDRA). Drugs will be coded 
using the World Health Organization (WHO) Drug Dictionary.
12.1
eCRFs
Completed eCRFs are required for each subject who signs an ICF.
The sponsor or its designee will supply investigative sites with access to eCRFs and will make 
arrangements to train appropriate site staff in the use of the eCRF. These forms are used to transmit 
the information collected in the performance of this study to the sponsor, contract research 
organization (CRO) partners, and regulatory authorities. Investigative sites must complete eCRFs 
in English.
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site.
Any change of, modification of, or addition to the data on the eCRFs should be made by the 
investigator or appropriate site personnel. Corrections to eCRFs are recorded in an audit trail that 
captures the old information, the new information, identification of the person making the 
correction, the date the correction was made, and the reason for change.
The principal investigator must review the eCRFs for completeness and accuracy and must sign 
and date the appropriate eCRFs as indicated. Furthermore, the principal investigator must retain 
full responsibility for the accuracy and authenticity of all data entered on the eCRFs.
eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The sponsor or its designee will be permitted to review the subject’s medical 
and hospital records pertinent to the study to ensure accuracy of the eCRFs. The completed eCRFs 
are the sole property of the sponsor and should not be made available in any form to third parties, 
except for authorized representatives of appropriate governmental health or regulatory authorities, 
without written permission of the sponsor.
12.2
Record Retention
The following procedure is applied for the countries except for Japan.
The investigator agrees to keep the records stipulated in Section 12.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating subjects, medical records, temporary media such as thermal-sensitive paper, source 
worksheets, all original signed and dated ICFs, subject authorization forms regarding the use of 
personal health information (if separate from the ICFs), electronic copy of eCRFs, including the 
audit trail, and detailed records of drug disposition to enable evaluations or audits from regulatory 
authorities, the sponsor or its designees. Any source documentation printed on degradable,
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thermal-sensitive paper should be photocopied by the site and filed with the original in the 
subject’s chart to ensure long-term legibility. Furthermore, ICH E6 Section 4.9.5 requires the 
investigator to retain essential documents specified in ICH E6 (Section 8) until at least 2 years after 
the last approval of a marketing application for a specified drug indication being investigated or, if 
an application is not approved, until at least 2 years after the investigation is discontinued and 
regulatory authorities are notified. In addition, ICH E6 Section 4.9.5 states that the study records 
should be retained until an amount of time specified by applicable regulatory requirements or for a 
time specified in the Clinical Study Site Agreement between the investigator and sponsor.
Refer to the Clinical Study Site Agreement for the sponsor’s requirements on record retention. The 
investigator should contact and receive written approval from the sponsor before disposing of any 
such documents.
The following procedure is applied for Japanese sites only.
The investigator and the head of the institution agree to keep the records stipulated in Section 12.1
and those documents that include (but are not limited to) the study-specific documents, the 
identification log of all participating subjects, medical records, temporary media such as 
thermal-sensitive paper, source worksheets, all original signed and dated ICFs, subject 
authorization forms regarding the use of personal health information (if separate from the ICFs), 
and query responses/ electronic copy of eCRFs, including the audit trail, and detailed records of 
drug disposition to enable evaluations or audits from regulatory authorities, the sponsor or its 
designees. Any source documentation printed on degradable thermal-sensitive paper should be 
photocopied by the site and filed with the original in the subject’s chart to ensure long-term 
legibility. Furthermore, ICH E6 Section 4.9.5 requires the investigator and the head of the 
institution to retain essential documents specified in ICH E6 (Section 8) until at least 2 years after 
the last approval of a marketing application for a specified drug indication being investigated or, if 
an application is not approved, until at least 2 years after the investigation is discontinued and 
regulatory authorities are notified. In addition, ICH E6 Section 4.9.5 states that the study records 
should be retained until an amount of time specified by applicable regulatory requirements or for a 
time specified in the Clinical Study Site Agreement between the investigator and/or the head of the 
institution and the sponsor.
Refer to the Clinical Study Site Agreement for the sponsor’s requirements on record retention. The 
investigator and the head of the institution should contact and receive written approval from the 
sponsor before disposing of any such documents.
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13.0
STATISTICAL METHODS
13.1
Statistical and Analytical Plans
A statistical analysis plan (SAP) 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.
Statistical analyses will be primarily descriptive and graphical in nature. No formal statistical 
hypothesis testing will be performed.
13.1.1 Analysis Sets
Analysis sets will include the following:

Safety analysis set: patients who receive at least 1 dose of study drug. The safety analysis set 
will be used for all safety analyses (except for DLT analysis) and efficacy analyses.

PK analysis set: patients with sufficient dosing and PK data to reliably estimate 1 or more PK 
parameters will be included in the PK analyses.

DLT-evaluable set: patients who have received at least 75% of planned doses of TAK-228 in
Cycle 1 (21 doses for the QD arm and 3 doses for QW arm) unless interrupted by study 
drug-related AEs and have sufficient follow-up data considered by sponsor and investigator to 
determine whether DLT occurred.
13.1.2 Analysis of Demographics and Other Baseline Characteristics
Demographic and baseline characteristics will be summarized, including sex, age, race, weight, 
height, and other parameters as appropriate. No inferential statistics will be carried out.
13.1.3 Efficacy Analysis
All efficacy analyses will be performed using the safety analysis set.
Data listings will present the tumor measurements from CT or MRI (including changes from 
baseline), disease response category (ie, CR, PR, SD, and PD), best overall response, duration of 
response, and duration of SD or other appropriate measures of efficacy.
The clinical benefit rate, defined as the proportion of patients with a best overall response of CR, 
PR, or SD will be summarized.
13.1.4 Pharmacokinetic Analysis
All PK analyses will be performed using the PK analysis set.
Plasma TAK-228 concentrations obtained from Cycle 1 will be summarized by descriptive 
statistics according to nominal (scheduled) time postdose and day for each arm. Mean and 
individual plasma TAK-228 concentration data from Cycle 1 will be plotted over time for each day 
(Days 1 and 15) for each arm. All plasma concentration data will be listed by arm.
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PK parameters will be calculated on Cycle 1 Days 1 and 15 for TAK-228 by noncompartmental 
analysis as permitted by the data. These parameters will include, but will not be limited to, Cmax, 
tmax, and AUC. PK parameters will be summarized using descriptive statistics for each arm and 
day. Individual PK parameters will be listed by arm.
Plasma TAK-228 concentrations obtained from Cycle 2 will be summarized by descriptive 
statistics according to nominal (scheduled) time postdose and day for the QW arm only.
13.1.5 Safety Analysis
All safety analyses will be performed using the safety analysis set. The DLT-evaluable analysis set 
will be used for the analysis of DLTs.
Safety will be evaluated by the incidence of AEs, severity and type of AEs, and by changes from 
baseline in the patient’s vital signs, weight, and clinical laboratory results using the safety analysis 
set. Exposure to study drug and reasons for discontinuation will be tabulated.
TEAEs that occur after administration of the first dose of study drug and through 30 days after the 
last dose of study drug will be tabulated.
Adverse events will be tabulated according to MedDRA and will include the following categories:

DLTs.

TEAEs.

Drug-related TEAEs.

Grade 3 or higher TEAEs.

Grade 3 or higher drug-related TEAEs.

The most commonly reported TEAEs.

Serious TEAEs.
The most commonly reported TEAEs will be tabulated by MedDRA preferred term.
A listing of deaths within 30 days of the last dose of study drug and TEAEs resulting in study drug 
discontinuation will be provided.
Shift tables based on changes in NCI CTCAE grade from baseline to the worst postbaseline value 
for laboratory parameters will be generated.
Concomitant medications will be summarized according to WHO Drug Dictionary preferred term.
Additional safety analyses may be performed to more clearly enumerate rates of toxicities and to 
further define the safety profile of TAK-228 QD and TAK-228 QW.
13.2
Interim Analysis and Criteria for Early Termination
No formal interim analysis is planned for this study.
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13.3
Determination of Sample Size
For each arm, dose escalation will be conducted according to a standard 3+3 dose escalation 
schema. There are 2 planned dose cohorts in each of 2 arms (QD arm and QW arm) in this study. 
For each arm, 9 to 12 DLT-evaluable patients will be needed for the dose escalation portion. In 
addition, for each arm, another 6 patients will be needed for safety expansion. Assuming a 20% 
dropout rate, approximately 23 patients will be needed for each arm to have 18 DLT-evaluable 
patients; the total sample size for this study will be 46.
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14.0
QUALITY CONTROL AND QUALITY ASSURANCE
14.1
Study-Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and institution guarantee access to source documents by the sponsor or its 
designee (CRO) and by the IRB or IEC.
All aspects of the study and its documentation will be subject to review by the sponsor or designee, 
including but not limited to the Investigator’s Binder, study medication, subject medical records, 
informed consent documentation, documentation of subject authorization to use personal health 
information (if separate from the ICFs), and review of eCRFs and associated source documents. It 
is important that the investigator and other study personnel are available during the monitoring 
visits and that sufficient time is devoted to the process.
14.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will require 
deviation from protocol-specified procedures, the investigator should consult with the sponsor or 
designee (and IRB or IEC, as required) to determine the appropriate course of action. There will be 
no exemptions (a prospectively approved deviation) from the inclusion or exclusion criteria.
The site should document all protocol deviations in the subject’s source documents. In the event of 
a significant deviation, the site should notify the sponsor or its designee (and IRB or IEC, as 
required). Significant deviations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the subject, or confound interpretation of primary study 
assessment. A Protocol Deviation Form should be completed by the site and signed by the sponsor 
or designee for any significant deviation from the protocol.
The procedure below applies to Japanese sites only.
The investigator can deviate and change from the protocol for any medically unavoidable reason, 
for example, to eliminate an immediate hazard to study subjects, without a prior written agreement 
with the sponsor or a prior approval from IRB. In the event of a deviation or change, the principal 
investigator should notify the sponsor and the head of the site of the deviation or change as well as 
its reason in a written form, and then retain a copy of the written form. When necessary, the 
principal investigator may consult and agree with the sponsor on a protocol amendment. If the 
protocol amendment is appropriate, the amendment proposal should be submitted to the head of 
the site as soon as possible and an approval from IRB should be obtained.
The investigator should document all protocol deviations.
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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 Food and Drug Administration (FDA), the United Kingdom 
Medicines and Healthcare products Regulatory Agency, the Pharmaceuticals and Medical Devices 
Agency of Japan). If the study site is contacted for an inspection by a regulatory body, the sponsor 
should be notified immediately. The investigator and institution guarantee access for quality 
assurance auditors to all study documents as described in Section 14.1.
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15.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will conduct 
the study according to applicable local or regional regulatory requirements and align his or her 
conduct in accordance with the “Responsibilities of the Investigator” that are listed in Appendix B. 
The principles of Helsinki are addressed through the protocol and through appendices containing 
requirements for informed consent and investigator responsibilities.
15.1
IRB and/or IEC Approval
IRBs and IECs must be constituted according to the applicable requirements of each participating 
region. The sponsor or designee will require documentation noting all names and titles of members 
who make up the respective IRB or IEC. If any member of the IRB or IEC has direct participation 
in this study, written notification regarding his or her abstinence from voting must also be 
obtained.
The sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the Investigator’s Brochure, a copy of 
the ICF, and, if applicable, subject recruitment materials and/or advertisements and other 
documents required by all applicable laws and regulations, must be submitted to a central or local 
IRB or IEC for approval. The IRB’s or IEC’s written approval of the protocol and subject 
informed consent must be obtained and submitted to the sponsor or designee before 
commencement of the study (ie, before shipment of the sponsor-supplied drug or study specific 
screening activity). The IRB or IEC approval must refer to the study by exact protocol title, 
number, and version date; identify versions of other documents (eg, ICF) reviewed; and state the 
approval date. The sponsor will notify site once the sponsor has confirmed the adequacy of site 
regulatory documentation and, when applicable, the sponsor has received permission from 
competent authority to begin the trial. Until the site receives notification, no protocol activities, 
including screening may occur.
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the ICF, recruitment 
materials intended for viewing by subjects, local safety reporting requirements, reports and 
updates regarding the ongoing review of the study at intervals specified by the respective IRB or 
IEC, and submission of the investigator’s final status report to IRB or IEC. All IRB and IEC 
approvals and relevant documentation for these items must be provided to the sponsor or its 
designee.
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and sponsor.
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15.2
Subject Information, Informed Consent, and Subject Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The ICF, subject authorization form (if applicable), and subject 
information sheet (if applicable) describe the planned and permitted uses, transfers, and 
disclosures of the subject’s personal and personal health information for purposes of conducting 
the study. The ICF and the subject information sheet (if applicable) further explain the nature of 
the study, its objectives, and potential risks and benefits, as well as the date informed consent is 
given. The ICF will detail the requirements of the participant and the fact that he or she is free to 
withdraw at any time without giving a reason and without prejudice to his or her further medical 
care.
The investigator is responsible for the preparation, content, and IRB or IEC approval of the ICF 
and if applicable, the subject authorization form. The ICF, subject authorization form (if 
applicable), and subject information sheet (if applicable) must be approved by both the IRB or IEC 
and the sponsor before use.
The ICF, subject authorization form (if applicable), and subject information sheet (if applicable) 
must be written in a language fully comprehensible to the prospective subject. It is the 
responsibility of the investigator to explain the detailed elements of the ICF, subject authorization 
form (if applicable), and subject information sheet (if applicable) to the subject. Information 
should be given in both oral and written form whenever possible and in the manner deemed 
appropriate by the IRB or IEC. In the event the subject is not capable of rendering adequate written 
informed consent, then the subject’s legally acceptable representative may provide such consent 
for the subject in accordance with applicable laws and regulations.
The subject, or the subject’s legally acceptable representative, must be given ample opportunity to: 
(1) inquire about details of the study and (2) decide whether or not to participate in the study. If the 
subject, or the subject’s legally acceptable representative, determines he or she will participate in 
the study, then the ICF and subject authorization form (if applicable) must be signed and dated by 
the subject, or the subject’s legally acceptable representative, at the time of consent and before the 
subject entering into the study. The subject or the subject’s legally acceptable representative 
should be instructed to sign using their legal names, not nicknames, using blue or black ballpoint 
ink. The investigator must also sign and date the ICF and subject authorization (if applicable) at 
the time of consent and before subject entering into the study; however, the sponsor may allow a 
designee of the investigator to sign to the extent permitted by applicable law.
Once signed, the original ICF, subject authorization form (if applicable), and subject information 
sheet (if applicable) will be stored in the investigator’s site file. The investigator must document 
the date the subject signs the 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 
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revised consent was obtained should be recorded in the subject’s medical record, and the subject 
should receive a copy of the revised ICF.
15.3
Subject Confidentiality
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or date 
of birth may be used to verify the subject and accuracy of the subject’s unique identification 
number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the sponsor 
requires the investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (eg, FDA, Medicines and Healthcare products Regulatory Agency, 
Pharmaceuticals and Medical Devices Agency), the sponsor’s designated auditors, and the 
appropriate IRBs and IECs to review the subject’s original medical records (source data or 
documents), including, but not limited to, laboratory test result reports, ECG reports, admission 
and discharge summaries for hospital admissions occurring during a subject’s study participation, 
and autopsy reports. Access to a subject’s original medical records requires the specific 
authorization of the subject as part of the informed consent process (see Section 15.2).
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s eCRF).
15.4
Publication, Disclosure, and Clinical Trial Registration Policy
15.4.1 Publication
The investigator is obliged to provide the sponsor with complete test results and all data derived by 
the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the sponsor.
The sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 
this section and the Clinical Study Site Agreement. In the event of any discrepancy between the 
protocol and the Clinical Study Site Agreement, the Clinical Study Site Agreement will prevail.
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15.4.2 Clinical Trial Registration
To ensure that information on clinical trials reaches the public in a timely manner and to comply 
with applicable laws, regulations and guidance, Takeda will, at a minimum register interventional 
clinical trials it sponsors anywhere in the world on ClinicalTrials.gov or other publicly accessible 
websites on or before start of study, as defined in Takeda Policy/Standard. Takeda contact 
information, along with investigator’s city, 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 to find 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 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 or other publicly accessible 
websites (including the Takeda corporate site) and registries, as required by Takeda 
Policy/Standard, applicable laws, and/or regulations.
15.5
Insurance and Compensation for Injury
Each subject in the study must be insured in accordance with the regulations applicable to the site 
where the subject is participating. If a local underwriter is required, then the sponsor or sponsor’s 
designee will obtain clinical study insurance against the risk of injury to clinical study subjects. 
Refer to the Clinical Study Site Agreement regarding the sponsor’s policy on subject 
compensation and treatment for injury. If the investigator has questions regarding this policy, he or 
she should contact the sponsor or sponsor’s designee.
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16.0
REFERENCES
1. Chiang GG, Abraham RT. Targeting the mTOR signaling network in cancer. Trends in 
Molecular Medicine 2007;13(10):433-42.
2. Jessen K, et al. INK128 is a potent and selective TORC1/2 inhibitor with broad oral antitumor 
activity. Mol. Cancer Therapy 2009;8(12):Abstract B148.
3. Kessler L, Wang S, Xin G, Kucharski J, Staunton J, Lan L, et al. INK128, an orally active 
TORC1/2 kinase inhibitor, shows broad antitumor activity and enhances efficacy of cytotoxic 
as well as targeted agents. Cancer Research 2010;70(8; Supplement 1 Abstract 4496).
4. Hassan B, Akcakanat A, Takafumi S, Evans K, Adkins F, Meric-Bernstam F. MTOR Inhibitor 
MLN0128 has Antitumor Efficacy in Cell Lines With Intrinsic and Acquired 
Rapamycin-Resistance. Academic Surgical Congress 2013(Abstract ASC20130420).
5. De P, Sun Y, Wu H, Rommel C, Yi L, Dey N, et al. Pre-clinical potency of INK128, a highly 
potent TORC1/2 kinase inhibitor in the HER2 amplified breast cancer model. Cancer Research 
2012;72(Abstract 2240).
6. 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.
7. U.S. Department of Health and Human Services, National Institutes of Health National Cancer 
Institute. Common Terminology Criteria for Adverse Events (CTCAE). Version 4.03. 14 June 
2010.
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Appendix A
Schedule of Events
Screening (a)
(within 28 
Days before 
C1D1)
Cycles 1 and 2
Cycles 3, 4, 5, and 6
Cycle ≥7
EOT
Visit (b)
Day 1
Day 8
(±2 Days)
Day 15
(±2 Days)
Day 1
Day 8
(±2 Days)
Day 15
(±2 Days)
Day 1
Study Procedures
Informed consent (c)
X
Eligibility criteria
X
Demographics
X
Medical history
X
Physical examination
X
X
X
X
X
X
X
Height
X
Weight
X
X
X
X
X
X
X
Vital signs (d)
X
X
X
X
X
X
X
X
X
ECOG performance status
X
X
X
X
X
X
X
Single, 12-lead ECG (e)
X1
X2 (e)
X1 (e)
X1 (e)
X1 (e)
X1
Concomitant medications and 
procedures reporting
X
Recorded from first dose of study drug through 30 days after the last dose of study drug.
SAE reporting (f)
SAEs (f) recorded from signing of the ICF through 30 days after the last dose of study drug.
Adverse event reporting (f)
Recorded from signing of the ICF through 30 days after the last dose of study drug.
TAK-228 Dosing
Single agent QD arm (g)
QD continuously
Single agent QW arm (g)
Days 1, 8, 15, and 22 of each 28-day cycle
Samples and Laboratory Assessments
Hematology
X1
X1 (h)
X1
X1
X1 (h)
X1
X1
X1 (h)
X1
Chemistry
X1
X1 (h)
X1
X1
X1 (h)
X1
X1
X1 (h)
X1
Urinalysis
X1 (i)
X1 (h)
X1 (h)
X1 (h)
X1
Coagulation (PT/INR, aPTT)
X1
X1
X1
X1
X1
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Screening (a)
(within 28 
Days before 
C1D1)
Cycles 1 and 2
Cycles 3, 4, 5, and 6
Cycle ≥7
EOT
Visit (b)
Day 1
Day 8
(±2 Days)
Day 15
(±2 Days)
Day 1
Day 8
(±2 Days)
Day 15
(±2 Days)
Day 1
HbA1c
X1
X (j)
X(j)
Q3C(j)
Fasting lipid profile
X1 (k)
X1
X1
X1
X1
Fasting serum glucose (l)
X1
X1
X1
X1
X1
X1
X1
In-home fasting glucose monitoring (m)
Measured daily (predose)
Pregnancy test (n)
X1
X1(n)
X1
X1
HBV and HCV screening (o)
X
Disease assessment (q)
X
Q2C (q)
Q2C(q)
X(q)
Plasma sample for TAK-228 PK
Plasma sample for TAK-228 PK analysis will be collected on the days and time points specified in the separate table.
CCI
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le
6
ab
Days)
ys)
D
ica
ppl
e a
the
o
to
aily (predo
y (pre
t t
X1
X1
jec
ubj
ysis will be
sis will b
a
nly
nd su


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aPTT=activated partial thromboplastin time; C=cycle; CT=computed tomography; DNA=deoxyribonucleic acid; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology 
Group; EOT=End of Treatment; ET=early termination; HbA1c=glycosylated hemoglobin; HBV=hepatitis B virus; HCV=hepatitis C virus; ICF=informed consent form; 
INR=international normalized ratio; MRI=magnetic resonance imaging; PK=pharmacokinetic; PT=prothrombin time; Q=every; QD=once daily; QW=once weekly; SAE=serious 
adverse event; X#=number of samples required (eg, 2 samples=X2).
Tests and procedures should be performed on schedule, but occasional changes are allowable (±2 days) with permission from the sponsor’s project clinician for holidays, vacations, 
and other administrative reasons.
(a) Screening assessments are performed within 28 days before Cycle 1 Day 1, unless otherwise specified. Screening assessments performed not more than 3 days before the Cycle 1 
Day 1 need not be repeated, unless otherwise specified.
(b) End of treatment will occur 30 days (+10 days) after the last dose of study drug, or at the start of subsequent antineoplastic therapy, whichever occurs first.
(c) The ICF may be signed more than 28 days before Cycle 1 Day 1 dosing.
(d) Vital sign measurements include blood pressure (diastolic and systolic), pulse, temperature, and oxygen saturation. Oxygen saturation will be measured by pulse oximetry at 
Screening and on Day 15 of Cycles 1 and 2.
(e) When the timing of an ECG coincides with blood samples for PK, the ECG should be completed first. On Cycle 1 Day 1 and Cycle 2 Day 1, an ECG should be completed predose 
in addition to 2 hours (±30 min) postdose. For Days 8 and 15 in Cycles 1 and 2 as well as Day 1 in Cycle 3 through 6, an ECG should be completed predose.
(f) Including serious and non-serious events before the first dose (ie. pretreatment events).
(g) For QD arm, TAK-228 will be administered on an empty stomach throughout the study. For QW arm, TAK-228 will be administered on an empty stomach in Cycle 1 and 
following a light meal in Cycle 2 and the subsequent cycles.
(h) May be assessed up to 24 hours before the study visit.
(i) For screening, creatinine clearance must be ≥40 mL/min based either on Cockcroft-Gault estimate or based on a 12- or 24-hour urine collection.
(j) During the Study Treatment period, HbA1c will be tested on Day 1 of Cycles 2 through 5, and on Day 1 of every third cycle thereafter (ie, Cycle 8, 11, 14, etc.).
(k) To be completed within 14 days before Cycle 1 Day 1.
(l) Fasting serum glucose will be measured in the study sites. Patients are required to fast overnight (nothing except water and prescribed medications after midnight or for ≥8 hours 
before the assessment) for each measurement.
(m) Patients will be given a glucometer on Cycle 1 Day 1 to monitor daily fasting glucose levels at home throughout the study starting on Cycle 1 Day 2, and will be instructed to 
notify the investigators when the fasting glucose is abnormal (ie, ≥150 mg/dL). In-home glucose monitoring is not required on days when fasting glucose is measured in the study 
sites.
(n) A serum pregnancy test will be performed for women of childbearing potential at Screening and again at Cycle 1 Day 1. A urine pregnancy test must be performed predose on Day 
1 of all cycles, with negative results available before the first dose of TAK-228 may be administered in that cycle. If a serum pregnancy test is performed within 3 days before the first 
dosing and the result is negative, the urine pregnant test may be waived on Cycle 1 Day 1.
(o) Patients with prior exposure to HBV or HCV who have subsequently cleared the infection (determined by a negative viral load) are allowed in the study, but should be monitored 
for reactivation every 2 months. Patients who develop detectable HBV or HCV in their blood during the study will have TAK-228 treatment interrupted and will be treated with 
antivirals medication per local institutional standard practice; a consultation with a hepatologist should be considered.
(p) To be collected predose on Cycle 1 Day 1.
(q) Baseline CT (with contrast) or MRI scan of the chest, abdomen, and pelvis must be obtained within 4 weeks before the first dose of TAK-228 and at Cycle 3 Day 1, after which CT 
(with contrast) or MRI may be performed every 2 cycles (ie, Cycle 5 Day 1, Cycle 7 Day 1, Cycle 9 Day 1 etc.), as clinically indicated, according to standard of care. The same 
imaging modality (CT [with contrast], MRI, or bone scan) should be used on a patient throughout the study. Bone scans may be performed on patients with bone metastases rather 
than CT or MRI. Scans are permitted up to 7 days in advance of the scheduled visit. At EOT, tumor assessments will be done only on patients who have not previously demonstrated 
disease progression in the study unless completed within the previous 4 weeks.
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Table A Pharmacokinetic Sampling Time Points
PK Sampling Time Point 
for QD and QW Arms
Cycle 1 Day 1
(Study drug taken 
on an empty 
stomach [a])
Cycle 1 Day 2
Cycle 1 Day 8
(Study drug taken 
on an empty 
stomach [a])
Cycle 1 Day 15
(Study drug taken 
on an empty 
stomach [a])
Cycle 1 Day 16
Cycle 1 Day 22
(Study drug taken 
on an empty 
stomach [a])
Predose (within 0.5 hours)
X1
X1
X1
X1
0.5 hours postdose (10 min)
X1
X1
1 hour postdose (10 min)
X1
X1
2 hours postdose (30 min)
X1
X1
3 hours postdose (30 min)
X1
X1
4 hours postdose (30 min)
X1
X1
6 hours postdose (30 min)
X1
X1
8 hours postdose (45 min)
X1
X1
24 hours postdose (1 hour)
X1
(Predose on Day 2
for QD arm)
X1
(Predose on Day 
16 for QD arm)
PK Sampling Time Point 
for QW Arm only
Cycle 2 Day 1 (c)
(Study drug taken 
after light meal)
Cycle 2 Day 15 (c)
(Study drug taken 
after light meal)
At time of clinic visit (anytime 
postdose)
X1
Approximately 1 hour after 
previous PK sample collection
X1
1-2 hours postdose (±15 min)
X1
3-6 hours postdose (±30 min)
X1(b)
min=minutes; PK=pharmacokinetic; QD=daily; QW=weekly; X#=number of samples required (eg, 1 sample=X1).
(a) Patients will be instructed to fast overnight (nothing except water and prescribed medications after midnight or for a minimum of 8 hours) for Cycle 1 Days 1, 8, 
and 15 visits only. For Cycle 1 Day 22, patients need not be fasted overnight but are to be instructed to refrain from eating and drinking (except water and prescribed 
medications) for 2 hours before and 1 hour after the dose. Patients will receive study drug with a full glass of water (240 mL).
(b) Two samples will be taken no less than 1 hour apart within the specified window.
(c) Patients may bring a light meal with them to this visit. After completion of fasting serum glucose sampling, patients will begin consuming the meal within 
30 min before dosing, after which they will take their regularly scheduled doses of TAK-228. The exact date/time of meal consumption, TAK-228 dosing, and PK 
sampling must be recorded in the eCRF. Over the course of the study, a distribution of sampling times within this time range is encouraged.
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Appendix B
Responsibilities of the Investigator
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations.
The investigator agrees to assume the following responsibilities:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff who will assist in the protocol.
3. Ensure that study related procedures, including study specific (nonroutine/nonstandard panel) 
screening assessments are NOT performed on potential subjects, before the receipt of written 
approval from relevant governing bodies/authorities.
4. Ensure that all colleagues and employees assisting in the conduct of the study are informed of 
these obligations.
5. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform to 
ICH, and local regulatory requirements.
6. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and approval 
of the protocol. Promptly report to the IRB/IEC all changes in research activity and all 
anticipated risks to subjects. Make at least yearly reports on the progress of the study to the 
IRB/IEC, and issue a final report within 3 months of study completion.
7. Ensure that requirements for informed consent, as outlined in ICH and local regulations, are 
met.
8. Obtain valid informed consent from each subject who participates in the study, and document 
the date of consent in the subject’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each ICF should contain a subject authorization section that 
describes the uses and disclosures of a subject’s personal information (including personal 
health information) that will take place in connection with the study. If an ICF does not include 
such a subject authorization, then the investigator must obtain a separate subject authorization 
form from each subject or the subject’s legally acceptable representative.
9. Prepare and maintain adequate case histories of all persons entered into the study, including 
eCRFs, hospital records, laboratory results, etc., and maintain these data for a minimum of 
2 years following notification by the sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
contact and receive written approval from the sponsor before disposing of any such 
documents.
10. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
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11. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor. This responsibility lies on 
the appropriate individual, designated by the site in Japan.
12. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours.
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Appendix C
Investigator Consent to Use of Personal Information
Takeda will collect and retain personal information of investigator, including his or her name, 
address, and other personally identifiable information. In addition, investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, United States, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
Investigator’s personal information may be retained, processed, and transferred by Takeda and 
these other parties for research purposes including the following:

Assessment of the suitability of investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may contain 
the same chemical compound present in the study medication.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of study records.

Posting investigator site contact information, study details and results on publicly accessible 
clinical trial registries, databases, and websites.
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in investigator’s own 
country.
Investigator acknowledges and consents to the use of his or her personal information by Takeda 
and other parties for the purposes described above.
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Appendix D
ECOG Scale for Performance Status
Grade
Description
0
Normal activity. Fully active, able to carry on all predisease performance without restriction.
1
Symptoms but ambulatory. Restricted in physically strenuous activity, but ambulatory and able to 
carry out work of a light or sedentary nature (eg, light housework, office work).
2
In bed <50% of the time. Ambulatory and capable of all self-care, but unable to carry out any work 
activities. Up and about more than 50% of waking hours.
3
In bed >50% of the time. Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair.
5
Dead
Source: Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and response criteria 
of the Eastern Cooperative Oncology Group. American Journal of Clinical Oncology 1982;5(6):649-55.
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Appendix E
Cockcroft-Gault Equation
For men:
Creatinine Clearance = (140 - age [years]) weight [kg]
72 (serum creatinine [mg/dL])
OR
(140 - age [years]) weight [kg]
0.81 (serum creatinine [µmol/L])
For women:
Creatinine Clearance = 0.85 (140 - age [years]) weight [kg]
72 (serum creatinine [mg/dL])
OR
0.85 (140 - age [years]) weight [kg]
0.81 (serum creatinine [µmol/L])
Source: Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
1976;16(1):31-41.
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Appendix F
New York Heart Association Classification of Cardiac Disease
Class
Functional Capacity
Objective Assessment
I
Patients with cardiac disease but without resulting limitations of physical 
activity. Ordinary physical activity does not cause undue fatigue, palpitation, 
dyspnea, or anginal pain.
No objective evidence of 
cardiovascular disease.
II
Patients with cardiac disease resulting in slight limitation of physical activity. 
They are comfortable at rest. Ordinary physical activity results in fatigue, 
palpitation, dyspnea, or anginal pain.
Objective evidence of 
minimal cardiovascular 
disease.
III
Patients with cardiac disease resulting in marked limitation of physical 
activity. They are comfortable at rest. Less than ordinary activity causes 
fatigue, palpitation, dyspnea, or anginal pain.
Objective evidence of 
moderately severe 
cardiovascular disease.
IV
Patients with cardiac disease resulting in inability to carry on any physical 
activity without discomfort. Symptoms of heart failure or the anginal 
syndrome may be present even at rest. If any physical activity is undertaken, 
discomfort is increased.
Objective evidence of 
severe cardiovascular 
disease.
Source: The Criteria Committee of New York Heart Association. Nomenclature and Criteria for Diagnosis of Diseases 
of the Heart and Great Vessels. Ninth Ed. Boston, MA: Little, Brown & Co; 1994:253-256.
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Appendix G
Methods of Contraception Considered to be Effective
Acceptable Methods Considered Highly Effective
Birth control methods that can achieve a failure rate of less than 1% per year when used 
consistently and correctly are considered as highly effective. Such methods include:

Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation (a):
–
Oral.
–
Intravaginal.
–
Transdermal.

Progestogen-only hormonal contraception associated with inhibition of ovulation (a):
–
Oral.
–
Injectable.
–
Implantable (b).

Intrauterine device (b).

Intrauterine hormone-releasing system (b).

Bilateral tubal occlusion (b).

Vasectomized partner (b) (c).

Sexual abstinence (d).
Methods that are Considered Less Highly Effective
Acceptable birth control methods that result in a failure rate of more than 1% per year include:

Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mode of action.

Male or female condom with or without spermicide (e).

Cap, diaphragm, or sponge with spermicide (e).
                                               
Source: European Heads of Medicines Agencies (HMA) Clinical Trial Facilitation Group (CTFG); see 
hma.eu/fileadmin/dateien/Human_Medicines/01-About_HMA/Working_Groups/CTFG/2014_09_HMA_ CTFG_Contraception.pdf
(a) Hormonal contraception may be susceptible to interaction with the investigational medicinal product, which may reduce the efficacy of the 
contraception method.
(b) Contraception methods that in the context of this guidance are considered to have low user dependency.
(c) Vasectomized partner is a highly effective birth control method provided that partner is the sole sexual partner of the woman of childbearing 
potential participant of the study and that the vasectomized partner has received medical assessment of the surgical success.
(d) In the context of this guidance sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation 
to the duration of the clinical trial and the preferred and usual lifestyle of the subject.
(e) A combination of male condom with either cap, diaphragm or sponge with spermicide (double-barrier methods) are also considered acceptable, 
but not highly effective, birth control methods.
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Appendix H
List of Relevant Cytochrome P450 Inhibitors and Inducers
Moderate CYP1A2 Inhibitors
cimetidine
methoxsalen
Strong CYP1A2 Inhibitors
fluvoxamine
ciprofloxacin
Clinically Significant Enzyme Inducers
carbamazepine
rifabutin
St. Johns Wort
phenobarbital
rifampin
phenytoin
rifapentine
Source: fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ 
ucm093664.htm.
Note that these lists are not exhaustive.
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Appendix I
Detailed Description of Amendments to Text
This document describes changes in reference to Protocol Incorporating Amendment No. 02.
Original text that was deleted or revised in Amendment No. 02 is indicated using italics and 
underline font. New or revised text adopted in Amendment No. 02 is shown in bold font.
Page 18, Section 3.3, List of Abbreviations
Added Text
MFDS: Ministry of Food and Drug Safety
Rationale for Amendment
To update the list of abbreviations with additional terms.
Page 37, Section 8.2, Definitions of Dose Limiting Toxicity
Existing Text
Toxicity will be evaluated according to NCI CTCAE (Version 4.03, effective 14 June 2010) [7]. 
DLT is defined as any of the following events that occur within the first 28 days of the 
administration of TAK-228 and are considered by the investigator to be at least possibly related to 
therapy with TAK-228 (note that AEs for which the relationship to study drug cannot be ruled out 
should be considered possibly related to study drug).
Revised Text
Toxicity will be evaluated according to NCI CTCAE (Version 4.03, effective 14 June 2010) [7]. 
DLT is defined as any of the following events that occur within the first 28 days of the 
administration of TAK-228 and are considered by the investigator to be at least possibly related to 
therapy with TAK-228.
Rationale for Amendment
Removed the note for the relationship to be consistent with Section 10.2.
Page 56, Section 9.4.2, Patient Demographics
Existing Text
The date of birth, race, ethnicity, and sex of the patient are to be recorded during Screening.
Revised Text
The date of birth, race, ethnicity, smoking history, and sex of the patient are to be recorded during 
Screening.
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TAK-228
Study No. C31008
Page 95 of 97
Protocol Incorporating Amendment No. 02
8 February 2018
Rationale for Amendment
Added smoking history to be recorded during Screening.
Page 63, Section 9.8, Discontinuation of Treatment With Study Drug and Patient 
Replacement
Added Text
Pregnancy.
Rationale for Amendment
Added pregnancy to the discontinuation criteria for clarification. (To incorporate feedback from 
the MFDS.)
Page 63, Section 9.8, Discontinuation of Treatment With Study Drug and Patient 
Replacement
Existing Text
Patients who receive <75% of planned doses of TAK-228 in Cycle 1 for reasons other than related 
AEs during dose escalation are not considered DLT-evaluable and will be replaced.
Revised Text
Patients who receive <75% of planned doses of TAK-228 in Cycle 1 for reasons other than related 
AEs during dose escalation are not considered DLT-evaluable and additional patients will be 
enrolled for DLT evaluation.
Rationale for Amendment
Revised the text for clarification. (To incorporate feedback from the MFDS.)
Page 73, Section 13.1.4, Pharmacokinetic Analysis
Added Text
Plasma TAK-228 concentrations obtained from Cycle 2 will be summarized by descriptive 
statistics according to nominal (scheduled) time postdose and day for the QW arm only.
Rationale for Amendment
Added PK analysis plan for the samples obtained in Cycle 2 for QW arm. (To incorporate feedback 
from the MFDS.)
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TAK-228
Study No. C31008
Page 96 of 97
Protocol Incorporating Amendment No. 02
8 February 2018
Page 82, Appendix A, Schedule of Events
Existing Text
Screening
(a)
(within 
28 Days 
before 
C1D1)
Cycles 1 and 2
Cycles 3, 4, 5, and 6
Cycle ≥7
EOT
Visit (b)
Day 1
Day 8
(±2 Days)
Day 15
(±2 Days)
Day 1
Day 8
(±2 Days)
Day 15
(±2 Days)
Day 1
Study Procedures
Single, 12-lead ECG (e)
X1
X2 (e)
X1
TAK-228 Dosing
Single agent QD arm (g)
QD continuously
Single agent QW arm (g)
Days 1, 8, 15, and 22 of each 28-day cycle
(e) When the timing of an ECG coincides with blood samples for PK, the ECG should be completed first. On Cycle 1 Day 1 and 
Cycle 2 Day 1, an ECG should be completed predose in addition to 2 hours (±30 min) postdose.
Revised Text
Screening
(a)
(within 
28 Days 
before 
C1D1)
Cycles 1 and 2
Cycles 3, 4, 5, and 6
Cycle ≥7
EOT
Visit (b)
Day 1
Day 8
(±2 Days)
Day 15
(±2 Days)
Day 1
Day 8
(±2 Days)
Day 15
(±2 Days)
Day 1
Study Procedures
Single, 12-lead ECG (e)
X1
X2 (e)
X1 (e)
X1 (e)
X1 (e)
X1
TAK-228 Dosing
Single agent QD arm (g)
QD continuously
Single agent QW arm (g)
Days 1, 8, 15, and 22 of each 28-day cycle
(e) When the timing of an ECG coincides with blood samples for PK, the ECG should be completed first. On Cycle 1 Day 1 and 
Cycle 2 Day 1, an ECG should be completed predose in addition to 2 hours (±30 min) postdose. For Days 8 and 15 in Cycles 1 and 
2 as well as Day 1 in Cycle 3 through 6, an ECG should be completed predose.
Rationale for Amendment
Added additional ECG collection timepoints to collect additional data to verify and confirm that 
treatment with TAK-228 is not associated with an increased risk of cardiac events. (To incorporate 
feedback from the MFDS.)
Page 85, Appendix A, Footnote a in Table A
Existing Text
(a) Patients will be instructed to fast overnight (nothing except water and prescribed medications 
after midnight or for a minimum of 8 hours). Patients then will receive study drug with a full glass 
of water (240 mL).
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TAK-228
Study No. C31008
Page 97 of 97
Protocol Incorporating Amendment No. 02
8 February 2018
Revised Text
(a) Patients will be instructed to fast overnight (nothing except water and prescribed medications 
after midnight or for a minimum of 8 hours) for Cycle 1 Days 1, 8, and 15 visits only. For Cycle 
1 Day 22, patients need not be fasted overnight but are to be instructed to refrain from 
eating and drinking (except water and prescribed medications) for 2 hours before and 1 
hour after the dose. Patients will receive study drug with a full glass of water (240 mL).
Rationale for Amendment
Revised Footnote a in Table A to clarify overnight fasting is not required for PK sampling on 
Cycle 1 Day 22.
Overall
Correct typographical errors, punctuation, grammar, and formatting.
These changes are not listed individually.
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SAP_001.pdf: 


Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: A Phase 1, Open-label Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of 
TAK-228 (a Catalytic TORC1/2 Inhibitor) as Single Agent in Adult East Asian Patients with 
Advanced Nonhematological Malignancies
NCT Number: NCT03370302
SAP Approve Date: 28 August 2019
Certain information within this Statistical Analysis Plan has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable (PPD) information 
or company confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.


1.0
TITLE PAGE
STATISTICAL ANALYSIS PLAN
STUDY NUMBER: C31008
A Phase 1 Study of TAK-228 in East Asian Patients with Advanced Nonhematological 
Malignancies
PHASE 1
Version: Final
Date: 28 August 2019
Prepared by:
Based on:
Protocol Version: Protocol Amendment No. 02
Protocol Date: 8 February 2018
Prope
 of Takeda: For n
rcial use only and subject to the applicable Terms of Use
nced No
ced N
n: : Final
Fin
28 Augu
8 Aug
n:
Proto
Pro
P
PPD


TAK-228 C31008
Page 2 of 22
Statistical Analysis Plan Final
28 August 2019
2.0
TABLE OF CONTENTS
1.0
TITLE PAGE ..................................................................................................................1
2.0
TABLE OF CONTENTS.................................................................................................2
3.0
LIST OF ABBREVIATIONS..........................................................................................4
4.0
OBJECTIVES .................................................................................................................6
4.1
Primary Objectives ....................................................................................................6
4.2
Secondary Objectives.................................................................................................6
4.3
Exploratory Objectives ..............................................................................................6
4.4
Study Design .............................................................................................................6
5.0
ANALYSIS ENDPOINTS...............................................................................................9
5.1
Primary Endpoints .....................................................................................................9
5.2
Secondary Endpoints .................................................................................................9
5.3
Exploratory Endpoints ...............................................................................................9
6.0
DETERMINATION OF SAMPLE SIZE.......................................................................10
7.0
METHODS OF ANALYSIS AND PRESENTATION...................................................11
7.1
General Principles....................................................................................................11
7.1.1
Data Presentation ...............................................................................................11
7.1.2
Definition of Study Days....................................................................................11
7.1.3
Conventions for Partial Adverse Event/Concomitant Medication Dates..............12
7.1.4
Conventions for Other Partial Dates...................................................................12
7.2
Analysis Sets ...........................................................................................................12
7.2.1
Safety Analysis Set ............................................................................................12
7.2.2
Pharmacokinetics Analysis Set...........................................................................12
7.2.3
DLT-evaluable Set.............................................................................................12
7.3
Disposition of Subjects ............................................................................................13
7.4
Demographic and Other Baseline Characteristics.....................................................13
7.5
Medical History and Concurrent Medical Conditions...............................................13
7.6
Medication History and Concomitant Medications...................................................13
7.7
Study Drug Exposure and Compliance.....................................................................13
7.7.1
Study Treatments ...............................................................................................13
7.7.2
Extent of Exposure.............................................................................................14
7.7.3
Action on Drug ..................................................................................................14
7.8
Efficacy Analysis.....................................................................................................14
7.8.1
Primary Efficacy Endpoint(s).............................................................................14
7.8.2
Secondary Efficacy Endpoint(s).........................................................................15
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TAK-228 C31008
Page 3 of 22
Statistical Analysis Plan Final
28 August 2019
7.8.3
Additional Efficacy Endpoint(s).........................................................................15
7.9
Pharmacokinetic/Pharmacodynamic Analysis ..........................................................15
7.9.1
Pharmacokinetic Analysis ..................................................................................15
7.9.2
Pharmacodynamic Analysis ...............................................................................18
7.10
Other Outcomes.......................................................................................................18
7.11
Safety Analysis........................................................................................................18
7.11.1 Adverse Events ..................................................................................................19
7.11.2 Clinical Laboratory Evaluations .........................................................................19
7.11.3 Vital Signs .........................................................................................................20
7.11.4 12-Lead ECGs ...................................................................................................20
7.12
Interim Analysis ......................................................................................................20
7.13
Changes in the Statistical Analysis Plan...................................................................20
8.0
REFERENCES..............................................................................................................21
9.0
DATA LISTINGS .........................................................................................................22
LIST OF IN-TEXT FIGURES
Figure 4.a
Study Overview Diagram.....................................................................................8
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


TAK-228 C31008
Page 4 of 22
Statistical Analysis Plan Final
28 August 2019
3.0
LIST OF ABBREVIATIONS
AE
adverse event
ALT
alanine aminotransferase
ANC
absolute neutrophil count
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AUC
area under the plasma concentration-time curve
AUC0-last
area under the plasma concentration-time curve from time 0 to time of last
measurable concentration
AUC0-inf
area under the plasma concentration-time curve from time 0 to infinity
AUC24
area under the plasma concentration versus time curve from zero to 24 hours
BQL
below quantifiable limit
CL/F
apparent clearance after extravascular administration
Cmax
maximum observed concentration
CR
complete response
Ctrough
observed concentration at the end of a dosing interval
CT
computed tomography
DLT
dose limiting toxicity
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
GGT
Gamma glutamyl transferase
HDL-C
high-density lipoprotein cholesterol
HLT
heart lung transplantation
lambdaz
terminal disposition phase rate constant
LDL-C
low-density lipoprotein cholesterol
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
PD
progressive disease
PK
pharmacokinetic(s)
PR
partial response
QD
once daily
QTcF
QT interval (msec) with Fridericia correction
QW
once weekly
RECIST
Response Evaluation Criteria in Solid Tumors
RP2D
recommended phase 2 dose
SAE
serious adverse event
SAP
statistical analysis plan
SD
stable disease
SLD
sum of the longest diameter
t1/2
terminal disposition phase half-life
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


TAK-228 C31008
Page 5 of 22
Statistical Analysis Plan Final
28 August 2019
TEAE
treatment-emergent adverse event
tmax
time of first occurrence of Cmax
Vz/F
apparent volume of distribution during the terminal disposition phase
WHO
World Health Organization
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TAK-228 C31008
Page 6 of 22
Statistical Analysis Plan Final
28 August 2019
4.0
OBJECTIVES
4.1
Primary Objectives
The primary objectives are:
!
To evaluate safety and tolerability and to determine RP2D of TAK-228 administered daily 
(QD arm) or weekly (QW arm) to East Asian patients with advanced nonhematological 
malignancies.
!
To characterize PK of TAK-228 in East Asian patients with advanced nonhematological 
malignancies
4.2
Secondary Objectives
The secondary objective is:
!
To evaluate preliminary anti-tumor activity of TAK-228.
4.3
Exploratory Objectives
4.4
Study Design
This study is a multicenter, open-label, phase 1 study of TAK-228 administered orally as a single
agent in adult East Asian patients with advanced nonhematological malignancies for whom
effective standard anticancer treatment is not available or is no longer effective.
The study will consist of 2 arms to evaluate the safety and tolerability, characterize the PK, and
determine the RP2Ds of single-agent TAK-228 to be used for 2 schedules (daily and weekly) in
East Asian patients.
1. QD (daily dosing schedule) arm: milled TAK-228 will be administered on an empty stomach,
once daily, in repeated 28-day treatment cycles.
2. QW (weekly dosing schedule) arm: milled TAK-228 will be administered on an empty
stomach in Cycle 1 and following a light meal in Cycle 2 and the subsequent cycles, weekly (ie, 
on Days 1, 8, 15, and 22), in repeated 28-day treatment cycles.
The 2 arms will enroll in parallel. Patient assignment to a specific schedule will be decided 
jointly by the investigator and sponsor with the aim of maximizing enrollment efficiency in the 
study.
During dose escalation, 2 planned dose levels of TAK-228 will be tested in each arm (2 mg and
4 mg in the QD arm; 20 mg and 30 mg in the QW arm) following standard 3+3 dose escalation
rules. Dosing will increase to 4 mg in QD arm or 30 mg in QW arm, provided that the safety and
tolerability of the starting dose has been demonstrated (Figure 4.a).
Property of Takeda: For non-commercial 
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TAK-228 C31008
Page 7 of 22
Statistical Analysis Plan Final
28 August 2019
If a dose is deemed safe in any cohort based on 3+3 rules, then the cohort may be expanded to as
many as 12 patients in total to further confirm safety, investigate PK and determine RP2D. At 
least 1 Japanese patient will be enrolled in each group of 3 patients during dose escalation. The 
total number of Japanese patients dosed at the RP2D level will be at least 6. On the basis of the
geographic distribution of patients enrolled or any emerging safety data or PK, additional 
patients may be added, as needed, to further characterize the safety, tolerability, or PK in patients 
from a particular East Asian geographic region.
As Western population based RP2D have been defined as 4 mg for the QD schedule and the 30 
mg QW schedule, the dose escalation schemas in the current study are designed to confirm Cycle 
1 based RP2D in East Asian patients or determine an alternative appropriate lower dose. 
Escalation beyond 4 mg QD or 30 mg QW is not expected to be necessary in this study. 
However, if TAK-228 exposures are unexpectedly lower than anticipated in the East Asian 
populations, and no DLTs have occurred in the dose escalation parts, the TAK-228 dose may be 
escalated further after discussion between the investigators and the sponsor based on the 
available PK and safety data.
If ≥2 of 6 patients experience a DLT at the starting dose level (ie, 2 mg in QD arm or 20 mg in 
QW arm), depending on the overall safety profile, the types of AEs/DLTs observed, and 
following the examination of the preliminary PK results in relation to the PK data in the Western 
population, a decision will be made either to evaluate a lower dose or to terminate the study, 
following discussion between the investigators and the sponsor.
For either treatment arm, more conservative dose escalation, evaluation of intermediate doses, 
and expansion of an existing or previously tested dose level are all permissible following 
discussions and agreement between the investigators and the sponsor, if such measures are 
needed for patient safety or for a better understanding of the dose-toxicity and dose-exposure 
relationships of TAK-228.
Blood samples will be collected at prespecified time points in Cycle 1 Days 1, 2, 8, 15, 16, and 
22 to characterize the PK of TAK-228 when given daily (QD) or weekly (QW). Blood samples 
will also be collected at prespecified time points during Cycle 2 Days 1 and 15 to characterize 
the PK of TAK-228 when given QW with light meals. 
Radiological tumor evaluations will be used to evaluate disease response according to Response
Evaluation Criteria in Solid Tumors (RECIST) guidelines (Version 1.1) [1].
Toxicity will be evaluated according to the National Cancer Institute Common Terminology
Criteria for Adverse Events (NCI CTCAE), Version 4.03, effective date 14 June 2010 [2].
Approximately 36 DLT-evaluable patients (approximately 18 patients in each arm) will be
enrolled from approximately 4 study sites in East Asia. Enrollment is defined as the time of the
first dose of TAK-228. Assuming a 20% dropout rate, approximately 23 patients will be needed 
for each arm to have approximately 18 DLT-evaluable patients; the total sample size for this 
study will be approximately 46.
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TAK-228 C31008
Page 8 of 22
Statistical Analysis Plan Final
28 August 2019
Figure 4.a
Study Overview Diagram
Abbreviations: C1D1=Cycle 1 Day 1, QD=once daily, QW=once weekly.
QD arm
TAK-228 QD in 28-day continues cycles
QW arm
TAK-228 QW in 28-day continues cycles
Cohort 1 
2 mg QD
Cohort 2 
4 mg QD
Expand up to 
12 patients
Screening
(≤28 days 
before C1D1)
End of Treatment Visit
(30 to 40 days after 
last dose of TAK-228)
Cohort 1 
20 mg QW
Expand up to 
12 patients
Cohort 2 
30 mg QW
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TAK-228 C31008
Page 9 of 22
Statistical Analysis Plan Final
28 August 2019
5.0
ANALYSIS ENDPOINTS
5.1
Primary Endpoints
The primary endpoints are:
!
The number and percentage of patients with TEAEs.
!
The number and percentage of patients with Grade 3 or higher TEAEs.
!
The number and percentage of patients with serious TEAEs.
!
Number of patients with DLTs during Cycle 1.
!
The number and percentage of patients discontinuing study drug due to TEAEs.
!
TAK-228 Cmax, Tmax, and AUC on Cycle 1 Days 1 and 15.
5.2
Secondary Endpoints
The secondary endpoint is:
!
Clinical benefit rate defined as the proportion of patients with a best overall response of 
complete response (CR), partial response (PR) or stable disease (SD) (SD of any duration).
5.3
Exploratory Endpoints
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TAK-228 C31008
Page 10 of 22
Statistical Analysis Plan Final
28 August 2019
6.0
DETERMINATION OF SAMPLE SIZE
For each arm, dose escalation will be conducted according to a standard 3+3 dose escalation 
schema. There are 2 planned dose cohorts in each of 2 arms (QD arm and QW arm) in this study. 
For each arm, 9 to 12 DLT-evaluable patients will be needed for the dose escalation portion. In 
addition, for each arm, another 6 patients will be needed for safety expansion. Assuming a 20% 
dropout rate, approximately 23 patients will be needed for each arm to have 18 DLT-evaluable 
patients; the total sample size for this study will be 46.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


TAK-228 C31008
Page 11 of 22
Statistical Analysis Plan Final
28 August 2019
7.0
METHODS OF ANALYSIS AND PRESENTATION
7.1
General Principles 
All statistical analyses will be conducted using SAS® Version 9.4.
Unless otherwise specified, the baseline value is defined as the value collected at the time closest 
to, but prior to, the start of study drug administration. Cycle 1 day 1 values are considered pre-
dose. Screening values are used for baseline values if a Cycle 1 Day 1 value is unavailable.
Means and medians will be presented to 1 more decimal place than the recorded data. The 
standard deviations (SDs) will be presented to 2 more decimal places than the recorded data. 
Confidence intervals about a parameter estimate will be presented using the same number of 
decimal places as the parameter estimate.
For the categorical variables, the count and proportions of each possible value will be tabulated. 
The denominator for the proportion will be based on the number of subjects who provided non-
missing responses to the categorical variable. For continuous variables, the number of subjects 
with non-missing values, mean, median, SD, minimum, and maximum values will be tabulated.
Additional statistics will be tabulated for pharmacokinetic data (see Section 7.9.1).
A month is operationally defined to be 30.4375 days. 
7.1.1
Data Presentation
In general, data will be presented as follows:
QD Arm:
Dose Escalation
Dose Expansion
Dose Escalation 
+ Expansion
TAK-228
2 mg QD
N=3
TAK-228
3 mg QD
N=3
TAK-228
4 mg QD
N=3
TAK-228
3 mg QD
N=xx
TAK-228
3 mg QD
N=xx
Total
N=xx
QW Arm:
TAK-228
20 mg QW
N=3
TAK-228
30 mg QW
N=3
Total
N=xx
7.1.2
Definition of Study Days
Study Day 1 is defined as the date on which a subject is administered their first dose of the 
medication. Other study days are defined relative to the Study Day 1 with Day -1 being the day 
prior to Study Day 1.
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TAK-228 C31008
Page 12 of 22
Statistical Analysis Plan Final
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7.1.3
Conventions for Partial Adverse Event/Concomitant Medication Dates
Missing or incomplete start dates will be imputed based on the algorithm described below:

If the start date has month and year but day is missing, the adverse event will be considered 
treatment-emergent or the therapy concomitant if both the month and year of the start date 
are on or after the month and year of the date of the first dose of TAK-228 and on or before 
the month and year of the date of the last dose of TAK-228 plus 30 days.

If the start date has year, but day and month are missing, the adverse event will be considered 
treatment -emergent or the therapy concomitant if the year of the start date is on or after the 
year of the date of the first dose of TAK-228 and on or before the year of the date of the last 
dose of TAK-228 plus 30 days.
7.1.4
Conventions for Other Partial Dates 
Missing or incomplete dates recorded during the screening visits (e.g date of initial diagnosis)
will be imputed based on the algorithm described below:

If only the day-component is missing, the first day of the month will be used if the year and 
the month are the same as those for the first dose of study drug. Otherwise, the fifteenth will 
be used. 

If only the year is present, and it is the same as the year of the first dose of study drug, the 
fifteenth of January will be used unless it is later than the first dose, in which case the date of 
the 1st of January will be used. 

If only the year is present, and it is not the same as the year of the first dose of study drug, the 
fifteenth of June will be used, unless other data indicates that the date is earlier.
7.2
Analysis Sets
7.2.1
Safety Analysis Set
The safety set includes all patients who receive at least 1 dose of study drug, and will be used for 
all safety analyses (except for DLT analysis) and efficacy analyses.
7.2.2
Pharmacokinetics Analysis Set
Pharmacokinetic set includes patients with sufficient dosing and PK data to reliably estimate 1 or 
more PK parameters. PK analyses will be performed using the PK population.
7.2.3
DLT-evaluable Set
DLT-evaluable set: patients who have received at least 75% of planned doses of TAK-228 in 
Cycle 1 (21 doses for the QD arm and 3 doses for QW arm) unless interrupted by study drug-
related AEs and have sufficient follow-up data considered by sponsor and investigator to 
determine whether DLT occurred.
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7.3
Disposition of Subjects
The date first subject signed ICF, date of last subject’s last visit/contact, date of last subject’s last 
procedure for collection of data for primary endpoint, MedDRA Version, WHO Drug Dictionary
Version, and SAS Version will be generated in a summary table.
The number of patients who were screening failures and reasons for screen failures will be 
summarized.
The number of patients in the safety population, in the pharmacokinetics population, in the DLT 
evaluable population, and the reason study drug was discontinued will be summarized. 
All percentages will be based on the number of patients in the safety set.
7.4
Demographic and Other Baseline Characteristics
Summaries of demographic and baseline characteristics will be presented for subjects in the 
safety set.
The demographic characteristics consist of: age, sex, ethnicity, Asian sub-category, baseline 
weight and height, smoking history, country. Age will be calculated from date of birth to date of 
informed consent. No inferential statistics will be carried out.
Baseline characteristics assessments consist of: baseline ECOG performance status, primary 
diagnosis, stage of disease at study entry, months since initial diagnosis.
A separate table will summarize the count and proportions of patients with prior surgery, prior 
radiation, prior systemic anticancer therapies, number of prior regimens and best response to 
most recent systemic treatment.
7.5
Medical History and Concurrent Medical Conditions
No summary for medical history and concurrent medical conditions.
7.6
Medication History and Concomitant Medications
Concomitant medications will be coded using the WHO Drug Dictionary. The number and 
percentage of patients taking concomitant medications will be tabulated by WHO generic name
for the safety population. 
7.7
Study Drug Exposure and Compliance
7.7.1
Study Treatments
Cycles consist of 28 days for all treatment arms. In QD arm, TAK-228 will be administered QD 
(every day of a 28-day treatment cycle). In QW arm, TAK-228 will be administered once weekly 
(on Days 1, 8, 15, and 22 of a 28-day treatment cycle). 
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7.7.2
Extent of Exposure
Summaries and descriptive statistics of duration of treatment in weeks ((last dose date – start 
dose date + 1)/7), total number of cycles administered, actual cumulative dose, planned 
cumulative dose and relative dose intensity will be summarized by dose level in each treatment 
arm for patients in the safety population. 
Number of cycles administered = A treated cycle is defined as a cycle in which the patient 
received any amount of TAK-228. This is defined as Actual Dose greater than zero for at least 
one of the dosing day in the cycle for TAK-228.
Actual cumulative dose (mg) = Sum of all doses (mg) administered to a subject during the 
treatment period.
Relative dose intensity = cumulative dose / planned cumulative dose.
TAK-228 QD (every day of a 28-day treatment cycle)
Average daily dose (mg/day) is defined as:
Sum of all doses (mg) actually received (cumulative dose) / duration of treatment in days
Planned cumulative dose is defined as:
(duration of treatment in days * initial dose at start of treatment)
Relative dose intensity for TAK-228 (%) is defined as:
(Cumulative dose / planned cumulative dose) * 100
TAK-228 QW (Days 1, 8, 15 and 22 of a 28-day cycle)
Relative dose intensity for TAK-228 (%) is defined as:
Cumulative dose (mg) / [Number of planned dose from start dose date to last dose date*30mg] * 
100
Planned dose =[(Date of first dose in last cycle + 28 days – date of first dose) / 7] * 30 mg/week
7.7.3
Action on Drug
Action on study drug (e.g. dose reduced due to AE) will be summarized by each cycle (Cycles 1-
6) and total, for each dose level in each arm in the safety population.
7.8
Efficacy Analysis
Analysis of efficacy measures will be descriptive. All efficacy analyses will be based on safety 
set.
7.8.1
Primary Efficacy Endpoint(s)
Not applicable
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7.8.2
Secondary Efficacy Endpoint(s) 
Secondary efficacy endpoint is clinical benefit rate defined as the proportion of patients with a 
best overall response of complete response (CR), partial response (PR) or stable disease (SD) 
(SD of any duration). Best overall response is defined as the best response reported by the 
investigator; ordered from best to worst: Complete Response, Partial Response, Stable Disease, 
Progressive Disease. The best response can also be Not Evaluable (NE) or No assessment 
performed if this is the only investigator assessment of objective response available for the 
patient. Best overall response is defined as the best response recorded after the first dose of study 
drug until subsequent therapy.
The number and percentage of patients in each best response category (CR, PR, SD, Progressive 
Disease, Unable to Assess, Unknown, or no post baseline response assessment) will be 
summarized by dose level in each arm. In addition, overall response (CR+PR) will be 
summarized.
Data listings will present the tumor measurements from CT or MRI (including changes from 
baseline), change/percent change from baseline in sum of the longest diameter (SLD), 
change/percent change from nadir in SLD, non-target disease assessment, new lesion assessment 
and disease response assessment at each response assessment and the best overall response. 
Duration of response and duration of SD will also be presented in data listings. 
Duration of Response (DOR)
The duration of objective response will be calculated for those patients with a best response of
CR or PR, and is defined as the number of days from the start date of CR, or PR (whichever
response is achieved first) until progressive disease or until the last response assessment if there
is no progressive disease. 
Duration of Stable Disease
The duration of stable disease will be calculated for those patients with a best response of SD.
The duration of SD is the number of days from cycle 1 day 1 until progressive disease or until
the last response assessment if there is no progressive disease.
7.8.3
Additional Efficacy Endpoint(s)
Not Applicable
7.9
Pharmacokinetic/Pharmacodynamic Analysis
7.9.1
Pharmacokinetic Analysis
All PK analyses will be performed using the PK analysis set. 
Data Handling
All BLQ values occurring prior to Cmax are replaced by “0” and all BLQ concentrations 
occurring after Cmax will be treated as missing. Embedded BLQ values (between two measurable 
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data points) occurring before/after Cmax will be handled on a case by case basis. Values that are 
embedded between BQLs, or quantifiable values occurring after two or more BQLs, will be set 
to missing at the discretion of the pharmacokineticist. No sample and no result values will 
always be treated as missing data. For the estimation of mean concentration in plots and tabular 
summaries, BLQ values will always be replaced by zero.
All TAK-228 plasma concentrations obtained in the present study, including sparse sampling 
data from Cycle 2, may be combined with data from other studies in which the PK of TAK-228
has been characterized for the purposes of population PK analyses. If conducted, the results of 
population PK analyses will be presented in a separate report.
TAK-228 Plasma Concentration Tables
Descriptive statistics (i.e. number of patients, arithmetic mean, arithmetic standard deviation, 
arithmetic coefficient of variation, geometric mean, geometric coefficient of variation, median, 
minimum, and maximum) will be used to summarize the plasma TAK-228 concentrations by 
nominal (scheduled) time post-dose in Cycle 1 (Days 1 and 15) for each arm.
Concentration values will be excluded from the summary statistics and flagged with code in the
concentration tables when blood draw time deviations are greater than 20% of nominal time 
calculated relative to the time of dosing.
TAK-228 Plasma Concentration Figures
Linear and semi-logarithmic plots of the mean (±SD) TAK-228 plasma concentration versus
scheduled sampling time will be provided separately for each PK visit (Cycle 1 Day 1 and Cycle 
1 Day 15) and each treatment arm (QD arm and QW arm). Plots will be grouped by dose level. 
Linear and semi-logarithmic plots of the mean (±SD) TAK-228 plasma concentration versus 
actual sampling time will be provided separately for each treatment group (QD arm by dose level 
and QW arm by dose level) and grouped by study visit (Cycle 1 Day 1 and Cycle 1 Day 15 
overlay plots).
Linear and semi-logarithmic plots of individual plasma concentration versus actual sampling 
time will be generated by treatment group (QD arm by dose level and QW arm by dose level)
and Day (1 and 15).
Linear mean (±SD) TAK-228 pre-dose or trough concentration versus time plots will generated 
for the QD arm and the QW arm. 
TAK-228 Plasma Concentration Listings
All individual patient plasma concentration data will be listed by treatment arm.
Pharmacokinetic Parameter Calculation
TAK-228 PK parameters will be calculated on Cycle 1 Days 1 and 15 during the dose escalation 
and expansion portions of the study by noncompartmental analysis with WinNonlin®
Professional Version 7.0 or higher (Certara USA, Inc., Princeton, NJ) using the linear log 
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trapezoidal method, unless otherwise stated. Actual sampling times (calculated relative to the last 
study drug administration) will be used for PK parameter calculations. Nominal times will be 
used only when actual times are not available. For concentration-time profiles in which the 
terminal elimination phase cannot be reliably estimated, derived PK parameters will be flagged 
and excluded from summary statistics. Reasons for unreliable estimation include R2adj < 0.8 for 
the log-linear regression and AUC percent extrapolated (%AUCextrap) ≥ 20 %. 
Pharmacokinetic Parameters
Data permitting, the following single-dose PK parameters will be calculated for TAK-228 by 
noncompartmental analysis:
Cycle 1 Day 1 and Cycle 1 Day 15:
Cmax, tmax, AUClast, AUC24, t1/2, CL/F, Vz/F
Cycle 1 Day 1, only:
AUCinf
Cycle 1 Day 15, only:
Accumulation ratio calculated based on Cmax (RA Cmax)
Accumulation ratio calculated based on AUC24 (Rac AUC24 for QD and Rac AUC168 for QW) 
Ctrough
For the QW Arm, the additional parameter AUC168 will be calculated on Cycle 1 Day 1 and 
Cycle 1 Day 15.
Additional supplementary parameters will be presented in a separate table:
Adjusted-R2, number of points used in the λz calculation, λz upper, λz lower, λz, tlast, 
%AUCextrap
Pharmacokinetic Parameter Tables
PK parameters will be summarized using descriptive statistics (i.e. number of patients, arithmetic 
mean, arithmetic standard deviation, arithmetic coefficient of variation, median, minimum value, 
and maximum value) for each arm and day. 
Pharmacokinetic Parameter Figures
Box plots of dose-adjusted exposure parameters (e.g. AUCinf, AUC24 or AUC168 and Cmax) 
vs. the planned doses administered by Arm (QD or QW) in East Asians from this study (total of
2 box plots per PK parameter) will be presented. Individual subject values, mean and median 
value and the upper and lower whiskers (1.5×Interquartile Range [IQR]) will be displayed on 
the plot with outliers (if any) shown as individual round markers.
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Pharmacokinetic Parameter Listings
Individual PK parameters will be listed by arm.
Cross-Study Comparison Tables and Figures
A comparison of PK in Asian patients from this study (C31008) will be made to results from PK 
in a Western population (Study MLN0128-1004). A summary PK table will be generated. For 
the comparison with single-agent 2 mg QD dose in this study (C31008), the PK parameters for 
the 4 mg QD dose in Western patients (MLN0128-1004) will be dose-normalized.
Mean (±SD) (linear; log-linear) concentration-time curves: for the QD or QW schedule, mean
concentration-time profiles in Western patients (MLN0128-1004) following a single dose of 
TAK-228 will be overlayed with Day 1 TAK-228 concentration-time profiles in East Asians
(C31008) by dose level and arm (QD or QW).
Mean (±SD) (linear; log-linear) pre-dose or trough concentration-time curves for Asian subjects
from Study C31008 and for Western subjects from Study MLN0128-1004 overlayed by dose 
level and arm (QD or QW).
Box plots of exposure parameters (e.g. AUCinf, AUC24 or AUC168 and Cmax) vs. Population 
(i.e. QD and QW in East Asians from this study C31008 and in Western patients from Study 
MLN0128-1004) by the planned dose administered and Arm (QD or QW) with a total of 4 box 
plots per PK parameter. Individual subject values, mean and median value and the upper and 
lower whiskers (1.5×Interquartile Range [IQR]) will be displayed on the plot with outliers (if 
any) shown as individual round markers. For the comparison with the 2 mg QD dose in East 
Asians in this study C31008, the mean concentration-time profile data and trough data for the 4 
mg QD dose in Western patients (milled API, fasted state) will be dose-normalized.
7.9.2
Pharmacodynamic Analysis
Genetic polymorphism data collected in this study will be pooled with similar data collected in 
other studies of TAK-228 for population assessment of the impact of genetic polymorphisms on 
the PK of TAK-228. The results of these analyses will not be presented in the clinical study 
report for this study and will be reported separately at a later time. 
7.10
Other Outcomes
Not applicable
7.11
Safety Analysis
Safety will be evaluated by the frequency of AEs, severity and types of AEs, and by changes 
from Baseline in patients’ vital signs, weight, and clinical laboratory results using the safety 
population. Exposure to study drug and reasons for discontinuation will be tabulated.
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7.11.1 Adverse Events
Toxicity will be evaluated according to National Cancer Institute Common Terminology Criteria 
for Adverse Events (NCI CTCAE), Version 4.03, effective date 14 June 2010.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
Version 20.0 or later (based on version at time of database lock). Treatment-emergent AEs are 
defined as: AEs that occur after the first dose of TAK-228 and within 30 days after the last dose 
of TAK-228. 
Treatment-emergent AEs will be tabulated by MedDRA system organ class and preferred term 
and will include the following categories 

Treatment-emergent adverse events

Most commonly reported TEAEs (at least 10% in any arm, sorted by preferred term)

Grade 3 or higher TEAEs

Drug-related TEAEs

Grade 3 or higher drug-related TEAEs

Serious TEAEs

Drug-related treatment emergent serious AEs

TEAEs resulting in study drug discontinuation

TEAEs resulting in dose reduction 

TEAEs resulting in dose interruption 

Most frequent non-serious TEAEs (> 5% of patients in any arm sorted by preferred term)
Patients reporting the same event more than once will have that event counted only once within 
each system organ class, and once within each preferred term.
A by-subject listing of DLTs in Cycle 1 will be generated.
7.11.2 Clinical Laboratory Evaluations
Whenever available, laboratory values will be assigned toxicity grades using the NCI CTCAE 
version 4.03. The number and proportion of patients with grade 3 or higher will be summarized 
for the following laboratory tests:

Hematology: Hemoglobin increased, Lymphocyte count decreased, Neutrophil count 
decreased, Platelet count decreased, White blood cell count decreased.

Chemistry: Alanine aminotransferase (ALT) increased, Alkaline phosphatase increased, 
Aspartate aminotransferase (AST) increased, Bilirubin (total) increased, Cholesterol high, 
Creatinine increased, Gamma glutamyl transferase (GGT) increased, Calcium - decreased, 
Calcium – increased, Glucose – decreased, Glucose – increased, Potassium – decreased, 
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Potassium – increased, Magnesium – decreased, Magnesium – increased, Sodium –
decreased, Sodium – increased, Triglycerides – increased, Albumin – decreased, Phosphate –
decreased, Amylase – increased.
7.11.3 Vital Signs
Vital sign results (diastolic and systolic blood pressure, pulse, temperature, and oxygen 
saturation and body weight) will be summarized by dose level in each arm as follows:

Baseline value

Minimum post-baseline value

Maximum post-baseline value
Changes to the minimum and maximum post-baseline values will be calculated relative to the 
baseline value. 
7.11.4 12-Lead ECGs
ECG results (QT, QTcF, PR interval, QRS interval, Ventricular Rate) will be summarized by 
dose level in each arm as follows:

Baseline value

Minimum post-baseline value

Maximum post-baseline value
Changes to the minimum and maximum post-baseline values will be calculated relative to the 
baseline value. 
In addition, the number and percent of patients with increases >30 ms and >60 ms from pre-dose 
in QTcF will also be summarized.
All QT values will be converted to QTcF using Fridericia’s correction:
(sec)
[Note: RR (sec) = 60 / ventricular rate in beats/minute].
7.12
Interim Analysis
Not applicable
7.13
Changes in the Statistical Analysis Plan
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8.0
REFERENCES
1. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New 
response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J 
Cancer 2009;45(2):228-47.
2. U.S. Department of Health and Human Services, National Institutes of Health National 
Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE). Version 4.03. 
14 June 2010.
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9.0
DATA LISTINGS
The below subject-level listings will be generated:

Disposition (date of first dose, date of last dose, number of cycles, reason for discontinuation 
of study treatment).

Populations (can be included with disposition listing).

Demographics.

Baseline characteristics.

Prior therapy.

Study drug exposure.

TEAEs leading to study drug discontinuation.

TEAEs resulting in dose modifications.

Serious AEs.

On-study deaths (defined as death that occurs between the first dose of study drug and 30 
days after the last dose of study drug (adverse events with an outcome of death)).

DLTs during Cycle 1.

Pharmacokinetic concentrations.

Pharmacokinetic parameters.

Efficacy (target lesions, non-target lesions, investigator assessment of response, best 
response).

Significant protocol deviations.
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