Clinical trial NCT02551055
Conditions: Advanced and Metastatic Gastric or Gastroesophageal Adenocarcinoma
Keywords: Drug Therapy
Sponsor: Millennium Pharmaceuticals, Inc.
Start date: 2015-10-15; Completion date: 2017-02-17
Enrollment: 32 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the maximum tolerated dose (MTD) or recommended Part 2 dose, safety and efficacy of MLN1117 (TAK-117) in combination with docetaxel, paclitaxel, investigational TAK-659 or investigational alisertib in adult participants with advanced and metastatic gastric or gastroesophageal adenocarcinoma. The study consists of a dose escalation phase (Part 1) and a dose expansion phase (Part 2).

Detailed description:
The drug being tested in this study is called MLN1117. MLN1117 is being tested to treat people who have locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma. This study will look at the dose-limiting toxicity and response to treatment in participants who take MLN1117 in combination with TAK-659, alisertib, paclitaxel, or docetaxel.

The study will enroll 32 participants in the dose escalation phase (Part 1) and 118 participants in the dose expansion phase (Part 2). Participants will be assigned to 1 of the 7 treatment groups:

* MLN1117 300 mg+Alisertib
* MLN1117 600 mg+Alisertib
* MLN1117 300 mg+Paclitaxel
* MLN1117 600 mg+Paclitaxel
* MLN1117 300 mg+TAK-659
* MLN1117 200 mg+Docetaxel
* MLN1117 300 mg+Docetaxel

In Part 1, the dose of MLN1117 will be increased step by step. All participants will be asked to take tablets of MLN1117 for 3 days on and 4 days off per week in 28-day treatment cycles or 21-day treatment cycles when given in combination with the other companion drugs.

This multi-center trial will be conducted in Spain and United States. The overall time to participate in this study is 10 months for Part 1 and 24 months for Part 2. Participants will make multiple visits to the clinic, and be contacted by telephone, e-mail or mail every 12 weeks for up to 6 months or 1 year after the last dose of study drug for a follow-up assessment.

Arms: arm 1: MLN1117 300 mg, tablets, orally, once daily for 3 days on (Days 1, 2, 3; 8, 9, 10; 15, 16, 17; 22, 23, and 24) and 4 days off per week and alisertib 40 mg, tablets, orally, twice daily for 3 days on (Days 1, 2, 3; 8, 9, 10; 15,16, and 17) and 4 days off per week on Weeks 1-3, and 1 week off in 28-day treatment cycles until PD or unacceptable toxicity. arm 2: MLN1117 600 mg, tablets, orally, once daily for 3 days on (Days 1, 2, 3; 8, 9, 10; 15, 16, 17; 22, 23, and 24) and 4 days off per week and alisertib 40 mg, tablets, orally, twice daily for 3 days on (Days 1, 2, 3; 8, 9, 10; 15,16, and 17) and 4 days off per week on Weeks 1-3, and 1 week off in 28-day treatment cycles until PD or unacceptable toxicity. arm 3: MLN1117 300 mg, tablets, orally, once daily for 3 days on (Days 2, 3, 4; 9, 10, 11; 16, 17, 18; 23, 24, and 25) and 4 days off per week and paclitaxel 80 mg/m\^2, infusion, intravenously, once weekly on (Days 1, 8, and 15) and 1 week off, in 28-day treatment cycles until PD or unacceptable toxicity. arm 4: MLN1117 600 mg, tablets, orally, once daily for 3 days on (Days 2, 3, 4; 9, 10, 11; 16, 17, 18; 23, 24, and 25) and 4 days off per week and paclitaxel 80 mg/m\^2, infusion, intravenously, once weekly on (Days 1, 8, and 15) and 1 week off, in 28-day treatment cycles until PD or unacceptable toxicity. arm 5: MLN1117 300 mg, tablets, orally, once daily for 3 days on (Days 1, 2, 3; 8, 9, 10; 15, 16, 17; and 22, 23, and 24) and 4 days off per week and TAK-659 100 mg (as determined in study C34001 \[NCT02000934\]), tablets, orally, once daily, in 28-day treatment cycles until progressive disease (PD) or unacceptable toxicity. arm 6: MLN1117 200 mg, orally, once daily for 3 days on (Days 2, 3, 4; 9, 10, 11; 16, 17, and 18) and 4 days off per week and docetaxel 75 mg/m\^2, infusion, intravenously, on Day 1 once every 3 weeks in 21-day treatment cycles until PD or unacceptable toxicity. arm 7: MLN1117 300 mg, orally, once daily for 3 days on (Days 2, 3, 4; 9, 10, 11; 16, 17, and 18) and 4 days off per week and docetaxel 75 mg/m\^2, infusion, intravenously, on Day 1 once every 3 weeks in 21-day treatment cycles until PD or unacceptable toxicity.
Interventions: intervention 1: MLN1117 intervention 2: TAK-659 intervention 3: Alisertib intervention 4: Paclitaxel intervention 5: Docetaxel
Intervention descriptions: intervention 1: MLN1117 Tablets intervention 2: TAK-659 Tablets intervention 3: Alisertib Tablets intervention 4: Paclitaxel intravenous infusion intervention 5: Docetaxel intravenous infusion

Protocol documents:
Prot_SAP_000.pdf: 
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly 
from view with a black bar) to protect either personally identifiable information or company 
confidential information. 
This may include, but is not limited to, redaction of the following: 

Named persons or organizations associated with the study.

Proprietary information, such as scales or coding systems, which are considered confidential
information under prior agreements with license holder.

Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.


1.0 TITLE PAGE
PROTOCOL
An Umbrella Study to Evaluate MLN1117 in Combination with Taxanes (Docetaxel or 
Paclitaxel) and Other Investigational Anticancer Agents for the Treatment of Patients with 
Previously Treated Advanced and Metastatic Gastric and Gastroesophageal 
Adenocarcinoma
MLN1117 in Combination with Docetaxel, Paclitaxel, and Other Investigational Anticancer 
Agents to Treat Patients with Gastric and Gastroesophageal Adenocarcinoma 
Sponsor:
Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of 
Takeda Pharmaceutical Company Limited
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:
C032-6001 (also known as MLN1117-1003)
IND Number:
112,048
EudraCT Number:
2015-001032-38
Compound:
MLN1117 (also known as TAK-117)
Original Protocol Date:
24 June 2015
Amendment 1 Date:
11 December 2015
Amendment 2 Date:
25 January 2016


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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 11.0, as is 
information on reporting product complaints. 
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site. Information on service providers is given in Section 3.1 and relevant guidelines 
provided to the site.
Contact Type/Role
North America
Europe
Serious adverse event and pregnancy reporting
See Section 11.0
See Section 11.0


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1.2
Approval 
REPRESENTATIVES OF TAKEDA 
This study will be conducted with the highest respect for the individual participants in accordance 
with the requirements of this clinical study protocol and also in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Conference on Harmonisation E6 Good Clinical Practice: Consolidated 
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws, clinical 
trial disclosure laws, and regulations.
SIGNATURES
The signature of the responsible Takeda medical officer and other signatories can be found on the 
signature page.
Electronic Signatures may be found on the last page of this document.
MD, PhD, Oncology Clinical Research,
 
Date
PhD, Oncology Statistics, 
 
Date
MD, PhD, Oncology Clinical Research,
 
Date
PhD, Clinical Pharmacology, 
 
Date
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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Study No. C032-6001 (also known as MLN1117-1003)
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INVESTIGATOR AGREEMENT 
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, package 
insert, 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 11.1.3 of this 
protocol.

Terms outlined in the Clinical Study Site Agreement.

Appendix B – Responsibilities of the Investigator.
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 2 Summary of Changes 
This document describes the changes in reference to Protocol Incorporating Amendment No. 2.
The primary purpose of this amendment is to revise the definition of dose-limiting toxicity (DLT) 
in regards to the attribution of study drug causality, and to remove inaccurate exceptions for Grade 
4 nonhematologic treatment-emergent adverse events (TEAEs). 
In addition, a minor change was made to the window for obtaining pretreatment tumor biopsies in 
Part 2 of the study. Grammatical and editorial changes have also been made for purposes of 
clarification and correction of inconsistencies. Full details on changes to the text are given in 
Appendix H. The following is a summary of the changes.
1. The DLT definition has been clarified to state that the listed events will qualify as DLTs when 
they are considered at least possibly related to 1 or both of the study drugs (MLN1117, 
TAK-659, alisertib, paclitaxel, or docetaxel) administered in a given combination regimen.
Justification: To ensure that the DLT assessments reflect the toxicity of the administered 
combination regimens and not exclusively a single agent within the combination.
2. The DLT-qualifying event list has been updated to reflect that a Grade 4 TEAE of diarrhea 
and/or vomiting will be considered a DLT regardless of the event duration and/or response to 
supportive care treatment.
Justification: Grade 4 events are life-threatening per the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.03 and, therefore, are 
always DLTs.
3. For Part 2 of the study, the required timeframe during which fresh pretreatment tumor biopsies 
may be obtained has been expanded. If a fresh biopsy is needed, it may be obtained at any time 
within the 28-day screening window.
Justification: To allow for flexibility in obtaining fresh pretreatment biopsies.
4. Minor edits have been made regarding archival tumor specimens and tumor biopsy samples.
Justification: To provide clarification.
5. Typographical errors, punctuation, grammar, and formatting have been corrected.


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TABLE OF CONTENTS
1.0
ADMINISTRATIVE.......................................................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
1.3
Protocol Amendment 2 Summary of Changes............................................................5
2.0
STUDY SUMMARY ....................................................................................................13
3.0
STUDY REFERENCE INFORMATION ......................................................................18
3.1
Study-Related Responsibilities.................................................................................18
3.2
Principal Investigator/Coordinating Investigator ......................................................18
3.3
List of Abbreviations ...............................................................................................19
3.4
Corporate Identification...........................................................................................21
4.0
INTRODUCTION.........................................................................................................22
4.1
Background .............................................................................................................22
4.1.1
Gastric Cancer ...................................................................................................22
4.1.2
Study Drugs.......................................................................................................23
4.2
Rationale for the Proposed Study.............................................................................28
4.2.1
Rationale for Combining MLN1117 with Docetaxel, Paclitaxel, or Alisertib......28
4.2.2
Rationale for Combining MLN1117 with TAK-659...........................................29
5.0
STUDY OBJECTIVES .................................................................................................30
5.1
Primary Objectives ..................................................................................................30
5.2
Secondary Objectives...............................................................................................30
5.3
Tertiary/Exploratory Objectives...............................................................................30
6.0
STUDY ENDPOINTS...................................................................................................31
6.1
Primary Endpoints ...................................................................................................31
6.2
Secondary Endpoints ...............................................................................................31
6.3
Exploratory Endpoints .............................................................................................32
7.0
STUDY DESIGN..........................................................................................................33
7.1
Overview of Study Design.......................................................................................33
7.2
Number of Patients ..................................................................................................36
7.3
Duration of Study ....................................................................................................36
8.0
STUDY POPULATION................................................................................................38
8.1
Inclusion Criteria .....................................................................................................38
8.1.1
Part 1 and Part 2.................................................................................................38
8.1.2
Part 1 Only.........................................................................................................39


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8.1.3
Part 2 Only.........................................................................................................39
8.2
Exclusion Criteria ....................................................................................................40
8.2.1
Part 1 and Part 2.................................................................................................40
8.2.2
Part 2 Only.........................................................................................................41
9.0
STUDY DRUG .............................................................................................................42
9.1
Study Drug Administration......................................................................................42
9.1.1
MLN1117+TAK-659 (Cohort A).......................................................................42
9.1.2
MLN1117+Alisertib (Cohort B).........................................................................42
9.1.3
MLN1117+Paclitaxel (Cohort C).......................................................................42
9.1.4
MLN1117+Docetaxel (Cohort D) ......................................................................42
9.2
Definitions of Dose-Limiting Toxicity.....................................................................45
9.3
Dose Escalation Rules (Part 1).................................................................................46
9.4
Dose Modification Guidelines..................................................................................48
9.4.1
Intrapatient Dose Escalation (Part 1) ..................................................................50
9.4.2
Intrapatient Dose Reduction(Part 1, Cycle 1)......................................................50
9.4.3
Dose Modification Guideline for Cohort A (MLN1117+TAK-659)....................50
9.4.4
Dose Modification Guidelines for Cohorts B, C, and D 
(MLN1117+Alisertib/Paclitaxel/Docetaxel) ................................................55
9.4.4.1
Criteria for Beginning or Delaying a Treatment Cycle for Cohort B .......55
9.4.4.2
Retreatment Criteria for Paclitaxel or Docetaxel (Cohort C or D) ...........56
9.4.4.3
Dose Modification for Hematologic and Nonhematologic Toxicity: 
MLN1117 and Other Combination Agents 
(Alisertib/Paclitaxel/Docetaxel)..............................................................57
9.5
Excluded Concomitant Medications and Procedures ................................................64
9.5.1
Excluded Concomitant Medications Applicable to All Cohorts (Cohorts A-D)...64
9.5.2
Excluded Concomitant Medications Applicable to a Specific Cohort .................65
9.6
Permitted Concomitant Medications and Procedures................................................65
9.6.1
Paclitaxel or Docetaxel Premedication for Cohorts C or D .................................65
9.6.2
Histamine-2 Receptor Antagonists and Neutralizing Antacids............................66
9.6.3
Additional Concomitant Medications and Procedures.........................................66
9.7
Precautions and Restrictions ....................................................................................67
9.8
Management of Clinical Events ...............................................................................68
9.8.1
Hematologic Events ...........................................................................................68
9.8.2
Hyperglycemia...................................................................................................68
9.8.3
Nausea and Vomiting.........................................................................................71


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9.8.4
Diarrhea.............................................................................................................71
9.8.5
Stomatitis/Oral Mucositis...................................................................................71
9.8.6
Rash...................................................................................................................71
9.8.7
Asthenia, Weakness, and Fatigue .......................................................................72
9.8.8
Elevated Serum Lipase (Cohort A).....................................................................72
9.8.9
Central Nervous System Effects (Cohort B) .......................................................72
9.8.10
Paclitaxel-Related Clinical Events (Cohort C)...............................................72
9.8.11
Docetaxel-Related Clinical Events (Cohort D)..............................................72
9.9
Blinding and Unblinding..........................................................................................72
9.10
Description of Investigational Agents ......................................................................73
9.10.1
MLN1117.....................................................................................................73
9.10.2
TAK-659 ......................................................................................................73
9.10.3
Alisertib........................................................................................................73
9.10.4
Paclitaxel and Docetaxel...............................................................................73
9.11
Preparation, Reconstitution, and Dispensation..........................................................73
9.11.1
MLN1117.....................................................................................................74
9.11.2
TAK-659 ......................................................................................................74
9.11.3
Alisertib........................................................................................................74
9.11.4
Paclitaxel and Docetaxel...............................................................................74
9.12
Packaging and Labeling...........................................................................................74
9.12.1
MLN1117.....................................................................................................74
9.12.2
TAK-659 ......................................................................................................74
9.12.3
Alisertib........................................................................................................74
9.12.4
Paclitaxel and Docetaxel...............................................................................75
9.13
Storage, Handling, and Accountability.....................................................................75
9.13.1
MLN1117.....................................................................................................75
9.13.2
TAK-659 ......................................................................................................75
9.13.3
Alisertib........................................................................................................76
9.13.4
Paclitaxel and Docetaxel...............................................................................76
9.14
Other Protocol-Specified Materials ..........................................................................76
10.0
STUDY CONDUCT......................................................................................................77
10.1
Study Personnel and Organizations..........................................................................77
10.2
Arrangements for Recruitment of Patients................................................................77
10.3
Treatment Group Assignments.................................................................................77
10.4
Study Procedures.....................................................................................................77


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10.4.1
Informed Consent .........................................................................................77
10.4.2
Enrollment....................................................................................................77
10.4.3
Patient Demographics ...................................................................................77
10.4.4
Medical History............................................................................................78
10.4.5
Physical Examination....................................................................................78
10.4.6
Patient Height ...............................................................................................78
10.4.7
Vital Signs....................................................................................................78
10.4.8
Eastern Cooperative Oncology Group Performance Status............................78
10.4.9
Electrocardiogram.........................................................................................78
10.4.10
Concomitant Medications and Procedures.....................................................78
10.4.11
Adverse Events.............................................................................................78
10.4.12
Pregnancy Test .............................................................................................78
10.4.13
Clinical Laboratory Evaluations....................................................................79
10.4.13.1 Clinical Chemistry, Hematology, and Urinalysis.....................................79
10.4.13.2 Fasting Lipid Profile...............................................................................80
10.4.13.3 Fasting Serum Glucose...........................................................................80
10.4.14
In-Home Daily Fasting Glucose Monitoring..................................................81
10.4.15
Pharmacokinetic Measurements....................................................................81
10.4.16
DNA Measurements......................................................................................81
10.4.17
Banked Tumor Specimen Measurements.......................................................82
10.4.18
Tumor Biopsies.............................................................................................82
10.4.19
Disease Assessment ......................................................................................82
10.4.20
Pharmacodynamic Measurements .................................................................82
10.5
Completion of Treatment .........................................................................................82
10.6
Completion of Study................................................................................................83
10.7
Discontinuation of Treatment With Study Drug and Patient Replacement................83
10.8
Withdrawal of Patients From Study .........................................................................83
10.9
Study Compliance....................................................................................................84
10.10 Posttreatment Follow-up Assessments (Progression-Free Survival and Overall 
Survival)..................................................................................................................84
11.0
ADVERSE EVENTS ....................................................................................................85
11.1
Definitions...............................................................................................................85
11.1.1
Pretreatment Event Definition.......................................................................85
11.1.2
Adverse Event Definition..............................................................................85
11.1.3
Serious Adverse Event Definition .................................................................85


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11.2
Procedures for Recording and Reporting Adverse Events and Serious 
Adverse Events........................................................................................................86
11.3
Monitoring of Adverse Events and Period of Observation........................................87
11.4
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events.........88
11.5
Procedures for Reporting Product Complaints..........................................................88
12.0
STUDY-SPECIFIC COMMITTEES .............................................................................89
13.0
DATA HANDLING AND RECORDKEEPING............................................................90
13.1
eCRFs......................................................................................................................90
13.2
Record Retention .....................................................................................................90
14.0
STATISTICAL METHODS..........................................................................................92
14.1
Statistical and Analytical Plans ................................................................................92
14.1.1
Analysis Sets ................................................................................................92
14.1.2
Randomization and Stratification ..................................................................93
14.1.3
Analysis of Demographics and Other Baseline Characteristics......................93
14.1.4
Efficacy Analysis..........................................................................................93
14.1.4.1
Analysis of Primary Efficacy Endpoints .................................................93
14.1.4.2
Analysis of Secondary Efficacy Endpoints .............................................94
14.1.5
Pharmacokinetic Analysis.............................................................................95
14.1.6
Exploratory Analysis ....................................................................................95
14.1.6.1
Exploratory Endpoints............................................................................95
14.1.6.2
Exploratory
.....................................................96
14.1.7
Biomarker Analysis ......................................................................................96
14.1.8
Safety Analysis.............................................................................................96
14.1.9
Procedures for Handling Missing, Unused, and Spurious Data......................97
14.2
Interim Analysis and Criteria for Early Termination ................................................97
14.3
Determination of Sample Size..................................................................................97
14.3.1
Dose Escalation Phase (Part 1)......................................................................97
14.3.2
Dose Expansion Phase (Part 2)......................................................................98
15.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................99
15.1
Study-Site Monitoring Visits ...................................................................................99
15.2
Protocol Deviations..................................................................................................99
15.3
Quality Assurance Audits and Regulatory Agency Inspections ................................99
16.0
ETHICAL ASPECTS OF THE STUDY......................................................................100
16.1
IRB and/or IEC Approval ......................................................................................100
16.2
Subject Information, Informed Consent, and Subject Authorization .......................101


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16.3
Subject Confidentiality ..........................................................................................102
16.4
Publication, Disclosure, and Clinical Trial Registration Policy...............................102
16.4.1
Publication and Disclosure..........................................................................102
16.4.2
Clinical Trial Registration...........................................................................103
16.4.3
Clinical Trial Results Disclosure.................................................................103
16.5
Insurance and Compensation for Injury..................................................................103
17.0
REFERENCES............................................................................................................104
LIST OF IN-TEXT TABLES
Table 4.a
INK1117-001 Dosing Regimens ........................................................................23
Table 4.b
TAK-659 Drug-Related Treatment-Emergent Adverse Events (≥10% of 
Patients) (N=30).................................................................................................27
Table 9.a
Cohort A: MLN1117+TAK-659 Dosing Schedule .............................................44
Table 9.b
Cohort B: MLN1117+Alisertib Dosing Schedule ...............................................44
Table 9.c
Cohort C: MLN1117+Paclitaxel Dosing Schedule .............................................44
Table 9.d
Cohort D: MLN1117+Docetaxel Dosing Schedule.............................................44
Table 9.e
Dose Reduction Levels for MLN1117 and Combination Partners.......................49
Table 9.f
Dose Modification Guidelines for Hematologic Toxicities for Cohort A 
(MLN1117+TAK-659) ......................................................................................51
Table 9.g
Dose Modification Guidelines for Nonhematologic Toxicity for Cohort A 
(MLN1117+TAK-659) ......................................................................................53
Table 9.h
Dose Modification Guidelines for Hematologic Toxicities for Cohort B 
(MLN1117+Alisertib), Cohort C (MLN1117+Paclitaxel), and 
Cohort D (MLN1117+Docetaxel) ......................................................................57
Table 9.i
Dose Modification Guidelines for Nonhematologic Toxicity for Cohort B 
(MLN1117+Alisertib), Cohort C (MLN1117+Paclitaxel), and Cohort D 
(MLN1117+Docetaxel)......................................................................................60
Table 9.j
Dose Modification Guidelines for Abnormal Liver Function Tests or 
Hepatotoxicity for Cohort D (MLN1117+Docetaxel) .........................................64
Table 9.k
Management of Hyperglycemia .........................................................................70
Table 10.a
Hematology and Clinical Chemistry Tests..........................................................79
Table 10.b
Clinical Coagulation Tests .................................................................................80
Table 10.c
Clinical Urinalysis Tests ....................................................................................80


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LIST OF IN-TEXT FIGURES
Figure 7.a
Study Design for Part 2 of the Study ..................................................................35
Figure 9.a
Dose Escalation Algorithm.................................................................................48
LIST OF APPENDICES
Appendix A
Schedules of Events .........................................................................................107
Appendix B
Responsibilities of the Investigator...................................................................124
Appendix C
Eastern Cooperative Oncology Group (ECOG) Scale for Performance Status...126
Appendix D
Cockcroft-Gault Equation ................................................................................127
Appendix E
Methods of Contraception Considered to be Effective......................................128
Appendix F
Examples of Strong CYP3A Inhibitors and Inducers Prohibited During the 
Study ...............................................................................................................130
Appendix G
Examples of P-Glycoprotein Inhibitors and Inducers Prohibited During the 
Study ...............................................................................................................131
Appendix H
Detailed Description of Amendments to Text...................................................132


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2.0
STUDY SUMMARY
Name of Sponsor(s):
Millennium Pharmaceuticals, Inc.
Compounds:
MLN1117 (TAK-117), TAK-659, MLN8237 
(alisertib)
Title of Protocol: An Umbrella Study to Evaluate 
MLN1117 in Combination with Taxanes (Docetaxel or 
Paclitaxel) and Other Investigational Anticancer Agents for 
the Treatment of Patients with Previously Treated 
Advanced and Metastatic Gastric and Gastroesophageal 
Adenocarcinoma 
IND No.: 112,048
EudraCT No.: 
2015-001032-38
Study Number: C032-6001 (also known as 
MLN1117-1003)
Phase: 1b
Study Design:
This is an open-label, multicenter, phase 1b study of MLN1117 (also known as TAK-117) in combination with 
TAK-659, alisertib (MLN8237), paclitaxel, or docetaxel in adult patients with locally advanced and metastatic gastric 
or gastroesophageal adenocarcinoma. The study consists of a dose escalation phase in patients with solid tumors 
(Part 1) and a dose expansion phase in patients with gastric or gastroesophageal junction cancers (Part 2). The 
statistical design for the dose expansion consists of equal randomization and adaptive randomization phases.
Part 1 (Dose Escalation)
During Part 1, the dose of MLN1117 will be escalated (planned doses of 300 mg, 600 mg, and 900 mg) according to a 
3+3 dose escalation scheme (Section 9.3), while TAK-659, alisertib, paclitaxel, and docetaxel will be administered at 
a fixed dose and regimen until the maximum tolerated dose (MTD) or recommended dose for Part 2 is determined. 
Serial pharmacokinetic (PK) samples will be collected at prespecified time points in Cycle 1 to characterize the PK of 
MLN1117 when given in each of the combination regimens, and the PK of alisertib and TAK-659 when given in 
combination with MLN1117. Toxicity will be evaluated according to National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE), Version 4.03 [1].
Part 2 (Dose Expansion)
All patients who enter Part 2 of the study will be screened to determine whether or not their tumor tissue is positive for 
Epstein-Barr virus (EBV) (approximately 9% of patients with gastric cancer) [2]. An estimated 28 patients who are 
EBV positive will be assigned to treatment with TAK-659 in combination with MLN1117 (Cohort A). Patients who 
are EBV negative, initially will be randomized equally to 1 of the other treatment cohorts, 5 patients per group: 
MLN1117+alisertib (Cohort B), MLN1117+paclitaxel (Cohort C), or MLN1117+docetaxel (Cohort D). These 
patients will be assessed using a proportional weighted clinical utility function (allocating specific weights for 
complete response [CR], partial response [PR], stable disease [SD], and progressive disease [PD]). Disease response 
will be evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1 [3]. Patients then 
will be randomized to treatment according to an adaptive randomization algorithm, which incorporates weighted 
clinical utility function. The resulting probability will be updated continually per accumulating data on the 
associations between the overall response rate (ORR) and Bayesian stopping rules. Adaptive randomization will be 
applied to newly enrolling patients every 2 months based on cumulative data. The adaptive randomization will 
increase the opportunity for each patient to receive the most effective experimental treatment possible based on 
posterior probabilities.
ORR will be used as the efficacy benchmark: target 25% (0.25); undesirable 10% (0.1). Early stopping rules will be 
prespecified if there is a clear signal of efficacy or lack of efficacy. The stopping rules are as follows: (1) achieve 
maximum sample size of each arm (30 patients); (2) stop an arm if probability (Pr) (response rate [RR]>0.25/Data) 
>80% and Pr (RR>0.10)/Data) >90%; (3) suspend accrual to an arm if Pr (RR≤0.10/Data) >80%. The treatment arm(s) 
is/are chosen in relation to the efficacy bar prespecified (target and undesirable); therefore, it is possible to select 
multiple treatment arms per this study design.


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Adverse events (AEs) will be assessed, and laboratory values, vital signs measurements, and electrocardiograms 
(ECGs) will be obtained to evaluate the safety and tolerability of MLN1117 when administered in combination with 
TAK-659, alisertib, paclitaxel, or docetaxel.
Sparse PK blood samples will be collected at prespecified time points for all patients in all treatment cohorts to 
contribute to future population PK analysis of MLN1117, TAK-659, and alisertib.
Primary Objectives:
The primary objective in Part 1 (dose escalation) is:

To determine the initial safety of MLN1117 when administered with each of the combination partners measured 
as the MTD or recommended Part 2 dose.
The primary objective in Part 2 (dose expansion) is:

To evaluate the ORR as the primary efficacy measure of MLN1117 in combination with each of the combination 
partners in patients with gastric or gastroesophageal junction adenocarcinoma.
Secondary Objectives:
The secondary objective in Part 1 (dose escalation) is:

To evaluate initial activity for each combination.
The secondary objective in Part 2 (dose expansion) is:

To evaluate additional efficacy measures, such as progression-free survival (PFS), disease control rate, duration 
of response (DOR), time to progression (TTP), and overall survival (OS) of MLN1117 in combination with each 
of the combination partners in patients with gastric or gastroesophageal junction adenocarcinoma.
The secondary objectives in Parts 1 and 2 are:

To determine the recommended phase 2 dose (RP2D).

To evaluate the overall safety and tolerability of MLN1117 in combination with each of the combination partners.

To evaluate the PK of MLN1117 when dosed in combination with alisertib, TAK-659, docetaxel, or paclitaxel, 
and to evaluate the PK of alisertib and TAK-659 when these agents are dosed in combination with MLN1117.
Subject Population: Male and female patients aged 18 years or older with advanced solid tumor with no other 
standard therapeutic option (Part 1 only). In Part 2, patients with stage IIIB or IV gastric or gastroesophageal junction 
adenocarcinoma progressing to a previous first line of systemic therapy for advanced or metastatic disease.
Number of Subjects:
Part 1 (dose escalation): Estimated 60 patients; 15 patients 
in each combination treatment group, with potentially 3 to 
6 patients in each dose cohort. 
Part 2 (dose expansion): Estimated maximum of 
118 patients
Cohort A (MLN1117+TAK-659): estimated 28 patients
Cohort B (MLN1117+alisertib): estimated 30 patients
Cohort C (MLN1117+paclitaxel): estimated 30 patients
Cohort D (MLN1117+docetaxel): estimated 30 patients 
Estimated total: 149 to 178 patients (based on adaptive 
randomization and rules specified to achieve efficacy bar; 
treatment arm[s] may be selected early without achieving 
target sample size of 30).
Number of Sites: 
Approximately 30 sites in North America and Europe.


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Dose Level(s):
Cohort A: Starting dose for MLN1117, 300 mg orally (PO) 
once daily (QD) for 3 days on (Days 1-3, 8-10, 15-17, and 
22-24) and 4 days off per week in each 28-day cycle. 
TAK-659 100 mg PO, continuous QD dosing in each 
28-day cycle.
Cohort B: Starting dose for MLN1117, 300 mg PO QD for 
3 days on (Days 1-3, 8-10, 15-17, and 22-24) and 4 days off 
per week in each 28-day cycle. Alisertib 40 mg PO twice 
daily (BID) for 3 days on (Days 1-3, 8 10, and 15-17) and 
4 days off per week in Weeks 1-3, and 1 week off in each 
28-day cycle.
Cohort C: Starting dose for MLN1117, 300 mg PO QD for 
3 days on (first weekly dose on the day after paclitaxel each 
week; Days 2-4, 9-11, 16-18, and 23-25) and 4 days off per 
week in each 28-day cycle. Paclitaxel, 80 mg/m2
intravenously (IV) once weekly on Days 1, 8, and 15, and 
1 week off, in each 28-day cycle.
Cohort D: Starting dose for MLN1117, 300 mg PO QD for 
3 days on (first dose on the day after docetaxel; Days 2-4, 
9-11, and 16-18) and 4 days off per week in each 21-day 
cycle. Docetaxel, 75 mg/m2 IV on Day 1 once every 
3 weeks in a 21-day cycle.
Route of Administration:
MLN1117, oral
TAK-659, oral
Alisertib, oral
Paclitaxel, intravenous
Docetaxel, intravenous
Duration of Treatment:
Patients may receive study drugs until they experience PD 
or unacceptable toxicity. The maximum duration of 
treatment for patients will be 1 year for MLN1117, alisertib, 
and TAK-659, and 6 cycles for paclitaxel and docetaxel. If 
it is necessary to discontinue paclitaxel or docetaxel due to
cumulative toxicity, it is possible to continue treatment with 
MLN1117 as single agent. Patients with clinical benefit can 
receive MLN1117, alisertib, or TAK-659 beyond 1 year. If 
it is necessary to discontinue MLN1117 for safety reasons, 
the patient should be withdrawn from the trial. For special 
circumstances, in which it is recommended that the patient 
continue only on the companion drug, agreement between 
the investigator and sponsor is required. Paclitaxel and 
docetaxel may be administered after Cycle 6 if the 
investigator and sponsor determine that the patient would 
derive benefit from continued treatment.
Period of Evaluation:
Patients will be followed for 30 days after the last dose 
of any study drug, or the start of subsequent alternative 
anticancer therapy to permit the detection of any 
delayed treatment-related AEs. Patients who 
discontinue study drug treatment for reasons other than 
PD will undergo computed tomography/magnetic 
resonance imaging (CT/MRI) scans every 12 weeks 
from End of Treatment (EOT) until the occurrence of 
PD, the start of subsequent antineoplastic therapy, or 
until 6 months after the discontinuation of study 
treatment, whichever occurs first. Patients will be 
followed for OS every 12 weeks until death or until 
1 year after the last dose of study drug, whichever 
occurs first.
Main Criteria for Inclusion:
Male and female patients aged 18 years or older at the time of consent. In Part 1 (dose escalation), patients must have 
a histologically confirmed diagnosis of advanced solid tumor, including but not limited to gastric or gastroesophageal 
adenocarcinoma, and are refractory to or relapsed after prior line(s) of therapy with no effective therapeutic options 
available. In Part 2 (dose expansion), patients must have a histologically confirmed diagnosis of metastatic or locally 
advanced adenocarcinoma of the stomach or gastroesophageal junction (Stage IIIb or IV according to International 
Union Against Cancer [UICC] tumor, node, metastases [TNM] classification, 7th edition), with at least 1 measurable 
lesion per RECIST, Version 1.1 by radiographic techniques (CT or MRI), and have received 1 prior systemic 
chemotherapy regimen for advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction with 


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documented PD.
Main Criteria for Exclusion:
Patients who have received prior systemic anticancer therapies, or other investigational agents or radiotherapy within 
2 weeks before first dose of study drug; are receiving treatment with P-glycoprotein (P-gp) inhibitors/inducers 
(MLN1117+TAK-659 arm only); have received strong cytochrome P-450 (CYP) 3A4 inducers/inhibitors or proton 
pump inhibitors (PPIs) within 7 days before the first administration of study drug or have conditions that require the 
concomitant use of CYP3A4 inducers/inhibitors or PPIs during the course of the study; have poorly controlled 
diabetes mellitus; have signs of peripheral neuropathy ≥NCI CTCAE Grade 2; have symptomatic brain metastases or 
brain metastases with a stable neurologic status for <2 weeks after completion of the definitive therapy and steroids. In 
Part 2 (dose expansion), prior treatment with any of the following: Aurora A-targeted agent (excluding the 
MLN1117+TAK-659 arm); taxane-containing regimen (excluding the MLN1117+TAK-659 arm); spleen tyrosine
kinase (SYK) inhibitor (MLN1117+TAK-659 arm only); or I phosphoinositide 3-kinase (PI3K) or serine/threonine 
kinase, also known as protein kinase B or PKB (AKT) inhibitor.
Main Criteria for Evaluation and Analyses:
The primary endpoints in Part 1 (dose escalation) are: the number (percentage) of patients who experience Cycle 1 
dose-limiting toxicity (DLT) in Part 1; number (percentage) of patients with at least 1 treatment-emergent adverse 
event (TEAE) in Part 1; number (percentage) of patients with at least 1 ≥Grade 3 TEAE in Part 1; number (percentage) 
of patients with at least 1 treatment-emergent serious adverse event (SAE) in Part 1; and number (percentage) of 
patients with at least 1 dose modification due to AE in Part 1.
The primary endpoint in Part 2 (dose expansion) is the ORR (CR+PR) in patients with gastric or gastroesophageal 
junction adenocarcinoma when treated with MLN1117 in combination with TAK-659, alisertib, paclitaxel, or 
docetaxel.
Secondary endpoints for this study are the number (percentage) of patients with AEs, including SAEs from the first 
dose of study drug through 30 days after the last dose of study drug; overall drug exposure for each drug in each 
combination measured as the number (percentage) of patients with dose modifications due to AEs from the first dose 
of study drug through 30 days after the last dose of study drug in both Parts 1 and 2; measures of disease response 
(PFS, disease control rate, DOR, TTP, and OS) based on RECIST, Version 1.1; and summary statistics of the PK 
parameters maximum observed plasma concentration (Cmax), time to reach Cmax (tmax), and area under the plasma 
concentration-time curve (AUC).
Statistical Considerations:
Part 1 (Dose Escalation)
There is no primary efficacy endpoint in Part 1 of the study. The secondary efficacy endpoint in Part 1 of the study is 
the ORR, defined as CR+PR, which will be presented in a listing.
The PK of MLN1117, TAK-659, and alisertib will be evaluated at prespecified time points during Part 1 (dose 
escalation).
Part 2 (Dose Expansion)
The primary efficacy endpoint for Part 2 is ORR (defined as CR+PR). The estimate of the RR will be presented with 
2-sided 95% exact binomial CIs for each treatment arm. The number and percentage of patients in each response 
category will be tabulated for each treatment arm based on RECIST, Version 1.1.
The secondary endpoints in Part 2 of the study include PFS, disease control rate (CR+PR+SD), DOR, TTP, and OS. 
PFS is defined as the time from the date of randomization to the date of first documentation of PD or death due to any 
cause, whichever occurs first. An unstratified log-rank test will be used to compare the treatment arms with respect to 
PFS.
Disease control rate is defined as CR+PR+SD. The estimate of the disease control rate will be presented with 2-sided 
95% exact binomial CIs for each treatment arm. The number and percentage of patients in each response category will 
be tabulated for each treatment arm based on RECIST, Version 1.1 [3]. 
DOR is defined as the time from the date of first documentation of a response to the date of first documentation of PD. 


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Patients without documentation of PD at the time of analysis will be censored at the date of their last response 
assessment that is SD or better.
TTP is defined as the time from the date of randomization to the date of first documentation of PD. Patients without 
documentation of PD at the time of analysis will be censored at the date of their last response assessment that is SD or 
better.
OS is defined as the time from the date of randomization to the date of death from any cause.
DOR, TTP, and OS will be analyzed using the Kaplan-Meier method. Unstratified long-rank tests will be performed 
for the comparisons between the 2 treatment arms.
Sparse PK of MLN1117, TAK-659, and alisertib will be evaluated at prespecified time points during Part 2 (dose 
expansion).
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 population.
Sample Size Justification:
Part 1 (Dose Escalation)
The number of patients enrolled in this study will be driven initially by the dose escalation part and then by the dose 
expansion part. In Part 1 (dose escalation), approximately 15 patients may be enrolled in each combination treatment 
group, with potentially 3 to 6 patients in each dose cohort. Therefore, approximately 60 patients may be enrolled in the 
dose escalation phase.
Part 2 (Dose Expansion)
All patients who enter Part 2 of the study will be screened to determine whether or not their tumor tissue is positive for 
EBV (approximately 9% of patients with gastric cancer). An estimated 28 patients who are EBV positive will be 
assigned to treatment with TAK-659 in combination with MLN1117 (Cohort A). The sample size is estimated based 
on the following parameters: a 1-sided test at the significance level of alpha=0.05, power of 75%, a null hypothesis of 
RR=10%, and an alternative hypothesis of RR=25%. Based on a single proportion test, 28 evaluable patients need to 
be enrolled in Cohort A. For patients who are EBV negative, there will be 2 parts to the randomization phase. Patients 
initially will be randomized equally to 1 of the other treatment cohorts, 5 patients per group: MLN1117+alisertib 
(Cohort B), MLN1117+paclitaxel (Cohort C), or MLN1117+docetaxel (Cohort D). These patients will be assessed 
using a proportional weighted clinical utility function (allocating specific weights for CR, PR, stable SD, and PD. 
Initially the clinical utility function will assign weights for CR=5, PR=2, SD=1 and PD=0; after 6 months of having 
CR, PR, or SD, weights will increase to CR=6, PR=4, SD=2, and PD weighting will remain the same. Patients then 
will be randomized to treatment according to an adaptive randomization algorithm, which incorporates weighted 
clinical utility function. The resulting probability will continually be updated per accumulating data on the 
associations between the ORR and Bayesian stopping rules (defined below). Adaptive randomization will be applied
to newly enrolling patients every 2 months based on cumulative data. The adaptive randomization will increase the 
opportunity for each patient to receive the most effective experimental treatment possible based on posterior 
probabilities. Up to an additional 25 patients may be enrolled in each treatment regimen during the part of the study 
with adaptive randomization. Based on simulation results, the sample size for Part 2 (the umbrella portion) may be 
between 61 and 90 patients. Therefore, a maximum number of 118 patients may be enrolled in the dose expansion 
phase.
ORR will be used as the efficacy benchmark: target 25% (0.25); undesirable 10% (0.1). Early stopping rules will be 
prespecified if there is a clear signal of efficacy or lack of efficacy. The stopping rules are as follows:
1.
Achieve maximum sample size of each arm (30 patients).
2.
Select an arm if Pr (RR>0.25/Data) >80% and Pr (RR>0.10)/Data) >90%.
3.
Suspend accrual to an arm if Pr (RR≤0.10/Data) >80%.
The treatment arm(s) is/are chosen in relation to the efficacy bar prespecified (target and undesirable); therefore, it is 
possible to select multiple treatment arms per this study design.


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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. The identified vendors in the template for specific study-related 
activities will perform these activities in full or in partnership with the sponsor.
3.2
Principal Investigator/Coordinating Investigator
Takeda will select a Signatory Coordinating Investigator from the investigators who participate in 
the study. Selection criteria for this investigator will include significant knowledge of the study 
protocol, the study medication, their expertise in the therapeutic area and the conduct of clinical 
research as well as study participation. The Signatory Coordinating Investigator will be required to 
review and sign the clinical study report and by doing so agrees that it accurately describes the 
results of the study.


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3.3
List of Abbreviations
5-FU
5-fluorouracil
5-HT3
serotonin receptor subtype 3
ADME
absorption, distribution, metabolism, and excretion
AE
adverse event
AKT
serine/threonine kinase, also known as protein kinase B or PKB
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ASCO
American Society of Oncology
AST
aspartate aminotransferase
AUC
area under the plasma concentration-time curve
AUCt
area under the plasma concentration-time curve from time 0 to time of the last quantifiable 
concentration
AUC∞
area under the plasma concentration-time curve from time 0 to infinity, calculated as 
AUC∞=AUCt+Clast/λzAUC∞
BID
bis in die (twice daily)
BSC
best supportive care
BUN
blood urea nitrogen
CL/F
apparent clearance after extravascular administration, calculated as dose/AUC∞after a 
single dose and as dose/AUCτ after multiple dosing (at steady state)
Clast
last observed quantifiable plasma concentration
Cmax
maximum observed plasma concentration
CR
complete response
CRO
contract research organization
CT
computed tomography
CYP
cytochrome P-450
DLBCL
diffuse large B-cell lymphoma
DLT
dose-limiting toxicity
DNA
deoxyribonucleic acid
DOR
duration of response
EBV
Epstein-Barr virus
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form 
ECT
enteric-coated tablet
EOT
End of Treatment
FBG
fasting blood glucose
FDA
Food and Drug Administration
FIH
first-in-human


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FLT-3
fms-related tyrosine kinase 3
GCP
Good Clinical Practice
GGT
-glutamyl transferase
GI
gastrointestinal
HbA1c
glycosylated hemoglobin
HDPE
high-density polypropylene
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IND
investigational new drug
IRB
institutional review board
ITAM
immunoreceptor tyrosine-based activation motif
ITT
intent-to-treat
IV
intravenous
IWRS
interactive web response system
λz
terminal elimination rate constant, calculated as the negative of the slope of the log-linear 
regression of the natural logarithm concentration-time curve during the terminal phase
LDH
lactate dehydrogenase
LFT
liver function test
LMP2A
latent membrane protein 2A
MAD
maximum administered dose
MedDRA
Medical Dictionary for Regulatory Activities
MLN1117
TAK-117
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NSCLC
non-small cell lung cancer
ORR
overall response rate
OS
overall survival
PD
progressive disease
PFS
progression-free survival
P-gp
P-glycoprotein
PIK3CA / PI3Kα
phosphoinositide 3-kinase alpha isoform
PK
pharmacokinetic(s)
PO
per orum (oral, orally)
PPI
proton pump inhibitor
Pr
probability
PR
partial response
PTE
pretreatment event


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QD
quaque die (once daily)
RBC
red blood cell
RECIST
Response Evaluation Criteria in Solid Tumors
RP2D
recommended phase 2 dose
RR
response rate
SAE
serious adverse event
SAP
statistical analysis plan
SD
stable disease
SLD
sum of longest diameters
SmPC
Summary of Product Characteristics
SOE
Schedule of Events
SYK
spleen tyrosine kinase
t1/2
terminal elimination half-life
TAK-117
MLN1117
TEAE
treatment-emergent adverse event
tmax
time to reach Cmax
TTP
time to progression
ULN
upper limit of the normal range
US
United States
USPI
US prescribing information
WHO
World Health Organization
3.4
Corporate Identification 
Millennium
Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda 
Pharmaceutical Company Limited.
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
4.1.1
Gastric Cancer
Gastric cancer is the world’s third leading cause of cancer mortality, responsible for 
723,000 deaths in 2012 [http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx. Accessed 
28 May 2015]. The vast majority of gastric cancers are adenocarcinomas, which can be further 
subdivided into papillary, tubular, mucinous (colloid), and poorly cohesive adenocarcinomas 
based on World Health Organization (WHO) classification. Recently, based on a comprehensive 
molecular evaluation of 295 primary gastric adenocarcinomas by The Cancer Genome Atlas 
project, molecular classification of gastric cancer to 4 subtypes has been proposed, which includes 
tumors positive for Epstein-Barr virus (EBV), microsatellite unstable tumors, genomically stable 
tumors, and tumors with chromosomal instability. The PIK3CA (phosphoinositide 3-kinase alpha 
isoform) gene is found to be frequently mutated in gastric cancer, especially in tumors positive for 
EBV and microsatellite unstable tumors (with a mutation rate of 80% and 42%, respectively, in 
these 2 subtypes) [2].
Patients with advanced gastric cancer are treated with standard first-line options, including DCF 
(docetaxel, cisplatin, and 5-fluorouracil [5-FU]), which showed a cumulative 37% to 45.6%
overall response rate (ORR), and 40% to 41.9% 1-year overall survival (OS) rate [4-8]; ECF 
(epirubicin, cisplatin and 5-FU), which showed an ORR of 40.2% to 46%, and 37% to 40.2% 
1-year OS rate [4,7,9]; EOX (epirubicin, oxaliplatin, and capecitabine), which showed an ORR of 
34.6 to 46% and OS of 6.9 to 8.8 months [10,11]; or FOLFOX (5-FU and oxaliplatin). As 
second-line agents, docetaxel, paclitaxel, and irinotecan are used to treat patients who have 
progressed on first-line treatment [12-14]. Recent Food and Drug Administration (FDA)-approved 
drug ramucirumab, a recombinant monoclonal antibody targeting the vascular endothelial growth 
factor receptor 2 (VEGFR-2), when combined with best supportive care (BSC), showed a 
1.4-month median OS improvement (hazard ratio [HR]=0.78 [95% confidence interval (CI) 
0.60 to 0.998, p=0.47]) as compared to placebo in combination with BSC (5.2 months vs 
3.8 months). Median progression-free survival (PFS) was 2.1 months for ramucirumab+BSC 
compared with 1.3 months for placebo+BSC; the HR for PFS was 0.48 (95% CI 0.38 to 0.62,
p<0.001) [15]. Ramucirumab in combination with paclitaxel also demonstrated improved median 
OS as compared to paclitaxel in combination with placebo (9.6 months vs 7.4 months), with an 
HR=0.81 (95% CI 0.68 to 0.96, p=0.017). In this trial, ORR was 28% (95% CI 23% to 33%) for 
the combination versus 16% (95% CI 13% to 20%) for paclitaxel+placebo [16]. Therefore, current 
management for advanced and metastatic gastric and gastroesophageal adenocarcinoma still 
remains suboptimal and there is a need for new and effective treatments for these patients.


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4.1.2
Study Drugs
MLN1117 (TAK-117)
MLN1117 (also known as TAK-117) is an orally available, potent, and selective small molecule
inhibitor of the class I phosphoinositide 3-kinase (PI3K) alpha isoform (PI3Kα). In human tumor 
mouse xenograft models harboring activating mutations for PI3Kα, MLN1117 inhibited 
pharmacodynamic markers of the PI3K pathway that correlate with strong tumor growth inhibition 
in a specific and dose-dependent manner. MLN1117 displayed consistent and predictable oral 
(PO) pharmacokinetic (PK) parameters across mice, rats, and monkeys. Toxicology studies were 
performed in rats and in monkeys. Detailed information regarding the nonclinical pharmacology 
and toxicology of MLN1117 may be found in the current version of the MLN1117 Investigator’s 
Brochure (IB).
MLN1117 is being developed for the treatment of patients with malignancies in which the PI3K 
pathway is believed to contribute significantly to the pathologic process and response to standard 
therapies. MLN1117 is also being developed in combination with MLN0128 (a novel, highly 
selective, orally bioavailable adenosine 5’ triphosphate-competitive inhibitor of the 
serine/threonine kinase referred to as the metabolic target of rapamycin) as a treatment for 
advanced nonhematologic malignancies. In addition, MLN1117 in combination with docetaxel as 
the second line of treatment in non-small cell lung cancer (NSCLC) is being evaluated in a
phase1b/2 study. 
In the phase 1, first-in-human (FIH) study (Study INK1117-001), MLN1117 is administered PO in
21-day treatment cycles of daily and intermittent dosing schedules. The study consists of a dose 
escalation phase and a dose-level expansion phase. The escalation phase will enroll approximately 
120 patients with solid tumors. The expansion phase will enroll approximately 70 patients who 
have breast cancer or NSCLC. As of 22 June 2015, a total of 121 patients have received at least 
1 dose of MLN1117. Most (68%) patients were women, and the median age was 61 years (range, 
31-80 years). Of the 121 patients, 116 discontinued study drug treatment, including 83 (69%) who 
discontinued due to disease progression, 13 (11%) who discontinued due to ≥1 treatment-emergent 
adverse events (TEAEs), 10 (8%) who discontinued due to patient decision, and 10 (8%) who 
discontinued due to taking a medication prohibited per protocol, were lost-to-follow-up, or for 
other reasons. A total of 5 patients remained ongoing as of the clinical data cutoff. A tabular 
summary of the weekly dosing regimens administered as of 23 June 2014 is presented in Table 4.a
Table 4.a
INK1117-001 Dosing Regimens
Weekly Dosing Regimen
Dose (mg)
QD
100, 150, 200, 300
QD on MWF
200, 300, 400, 600, 900, 1200
QD on MTW
200, 400, 600, 900
BID on MWF
300
BID=twice daily, MTW=Monday, Tuesday, and Wednesday, MWF=Monday, Wednesday, and Friday, QD=once 
daily, QW=each week.


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In the PK analysis portion of this study, MLN1117 capsules were administered PO using 
3 different dosing schedules: once daily (QD); 3 days each week (QW) of consecutive-day dosing 
(eg, Monday, Tuesday, and Wednesday [MTW] QW); and 3 days each week of every-other-day 
dosing (eg, Monday, Wednesday, and Friday [MWF] QW). The plasma PK of MLN1117 was 
evaluated in Study INK1117-001 for 24 hours after dosing of MLN1117 on Day 1 of Cycles 1 and 
2, and during Week 2 of Cycle 1. Preliminary PK data suggest fast PO absorption following 
MLN1117 dosing, with a mean plasma terminal disposition half-life (t½) of approximately 
11 hours across cohorts. The extent of accumulation following QD dosing was low (accumulation 
ratio of approximately 1.2). Systemic exposures of MLN1117 increased with increasing dose over 
the 100 to 1200 mg dose range. There was a 9-fold increase in plasma exposure (area under the 
plasma concentration-versus-time curve [AUC] from zero to infinity [AUC]) of MLN1117, with 
a 12-fold increase in dose from 100 to 1200 mg. 
MLN1117 Clinical Safety
A total of 118 of the 121 patients (98%) overall experienced at least 1 TEAE as of the data cutoff 
date. Nine patients (7%) experienced ≥1 dose-limiting toxicity (DLT) in Cycle 1. A total of 
106 patients (88%) had ≥1 TEAE that was considered by the investigator to be related to study 
drug, 64 (53%) had an adverse event (AE) that was severity ≥Grade 3, and 36 (30%) had at least 
1 TEAE ≥Grade 3 that was considered by the investigator to be study drug-related. A total of 
10 (8% of patients) on-study deaths were reported as of the data cutoff date, none of which was 
considered to be related to study drug.
AEs experienced by at least 10% of the 121 patients included nausea (60% of patients); 
vomiting (50%); fatigue (48%); diarrhea (45%); hyperglycemia (37%); decreased appetite (36%); 
constipation (31%); aspartate aminotransferase (AST) increased (28%); alanine aminotransferase 
(ALT) increased (23%); anemia (20%); cough, dehydration, dyspepsia, hypokalemia (17%, each); 
dyspnea (16%); abdominal pain, insomnia, weight decreased (15%, each); headache (13%); 
asthenia, back pain, dizziness, pyrexia (12%, each); stomatitis, urinary tract infection (11%); and 
peripheral edema (10%). 
Protocol-defined DLTs in Cycle 1 of Study INK1117-001 have informed the selection of 900 mg 
MLN1117 as the proposed maximum tolerated dose (MTD) and recommended phase 2 dose 
(RP2D) for the intermittent schedules (MWF QW and MTW QW). The MTD for the QD schedule 
is 150 mg. As of data cutoff, 13 DLT event terms were reported among 8 patients. The DLTs and 
dose assignments for these 8 patients were as follows: drug-induced liver injury (200 mg QD); 
increased ALT/AST (1 patient at 300 mg QD and 1 at 900 mg MWF QW); hyperosmolar state 
(900 mg MWF QW); nausea (900 mg MTW QW); decreased appetite (1200 mg MWF QW); 
hyperglycemia (1200 mg MWF QW); and concomitant events of diarrhea, nausea, vomiting, and 
hyperglycemia (1200 mg MWF QW). All events were considered to be at least possibly related to 
study drug. None of the DLTs resulted in permanent discontinuation of study drug.
Hyperglycemia was reported in 45 patients (37%) and increased blood glucose was reported in 
1 additional patient. TEAEs of hyperglycemia were considered related to study drug in 44 patients 
(36%) overall. The 3 intermittent dosing schedules (MWF QW, MTW QW, and twice daily (BID) 


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MWF QW) were associated with the highest percentages (38%, 40%, and 41%, respectively) of 
patients with hyperglycemia TEAEs compared with the QD schedule (29%), regardless of 
causality. Serious adverse events (SAEs) of hyperglycemia were reported in 4 patients (2 each in 
the MWF QW and the BID MWF QW cohorts); all 4 events were considered possibly related to 
study drug and all but 1 resolved without sequelae after dose interruption (the final event was 
ongoing as of data cutoff). Concomitant SAEs of hyperosmolar state and diabetic ketoacidosis 
were reported in 1 patient (MWF QW schedule); both events were considered Grade 3 and 
possibly related to study drug but resolved without sequelae after dose interruption.
As of the clinical data cutoff and regardless of causality, 34 patients (28%) had elevations in AST, 
28 patients (23%) had elevations in ALT, 6 patients (5%) had elevations in blood alkaline 
phosphatase, 6 patients (5%) had increased blood bilirubin, 5 patients (4%) had elevations in 
gamma-glutamyltransferase, 4 patients (3%) had transaminases increased, and 1 patient 
experienced drug-induced liver injury. A total of 10 patients (8%) had study drug-related ≥Grade 3 
increased ALT; 6 patients (5%) had study drug-related ≥Grade 3 increased AST; 3 patients (2%) 
had study drug-related ≥Grade 3 increased transaminases; and 1 patient (1%), each, experienced 
study drug-related ≥Grade 3 hyperbilirubinemia and drug-induced liver injury with 200 mg QD. 
Three patients discontinued study drug due to TEAEs consistent with increased liver function 
tests: 1 patient who received MLN1117 in the 300 mg QD regimen, 1 in the 900 mg MTW QW 
regimen, and 1 in the 1200 mg MWF QW regimen. To date, the incidence of increased AST and 
ALT overall and regardless of causality, has been generally higher in patients receiving MLN1117 
QD (42% and 38%, respectively) than the intermittent MWF (AST 28%, ALT 20%); MTW (AST 
29%, ALT 20%); and BID MWF (AST 14%, ALT 18%) schedules. Further details regarding the 
clinical experience with MLN1117 may be found in the current version of the MLN1117 IB.
Based on the available safety information, 900 mg MTW QW was declared the MTD and RPD2. 
The MTW QW schedule is the one that will be tested in this study. The 900 mg dose is the highest 
dose to be tested in this study because it is the single-agent MTD.
In this study, stress-inducing agents, such as docetaxel, paclitaxel, and the investigational agents 
TAK-659 and alisertib (MLN8237), will be evaluated for combinability and efficacy with 
MLN1117 in 1 of 4 combination regimens in patients with advanced gastric or gastroesophageal 
junction adenocarcinoma.
Docetaxel and Paclitaxel
Paclitaxel is the first member of the taxane family (a drug class that acts by disrupting the 
microtubular network essential for cell division) to receive marketing approval for cancer 
treatment. Paclitaxel has demonstrated clinical activity both as single-agent therapy and in 
combination with other chemotherapeutic agents in a variety of cancer types, including breast 
cancer, NSCLC, ovarian cancer, and pancreatic cancer. In Japan, paclitaxel is commonly used in 
practice as second-line chemotherapy in patients with gastric cancer and adenocarcinoma of the 
gastroesophageal junction, and weekly paclitaxel therapy has yielded an ORR ranging from 21%
to 24%, OS of 5 to 9.5 months, and has shown a good toxicity profile [12-14].


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Docetaxel is the second member of the taxane family to receive marketing approval for cancer 
treatment and has shown significant clinical activity both as single-agent therapy and in 
combination with other chemotherapeutic agents in a wide range of solid tumors. Docetaxel, in 
combination with cisplatin and fluorouracil, is approved in the United States (US), Europe, and 
Japan for the treatment of patients with untreated, advanced gastric adenocarcinoma, including 
adenocarcinoma of the gastroesophageal junction. In addition, docetaxel alone is commonly used 
as second-line therapy in patients with locally advanced and metastatic gastric cancer.
Alisertib
Alisertib (MLN8237) is a selective, small molecule inhibitor of Aurora A kinase, a critical 
regulator of mitotic progression and is amplified/over-expressed in colon, breast and other 
cancers. Alisertib inhibited proliferation and induced phenotypes consistent with Aurora A 
inhibition in cultured cancer cells. Alisertib demonstrated antitumor activity in several 
experimental solid and hematologic human tumor models. The results of drug metabolism and PK 
studies have shown that alisertib has an acceptable absorption, distribution, metabolism, and 
excretion (ADME) profile. The toxicity of alisertib in both rats and dogs was consistent with the 
inhibition of Aurora A kinase. Detailed information regarding the nonclinical pharmacology and 
toxicology of alisertib may be found in the current version of the alisertib IB.
As of 29 March 2015, company-sponsored alisertib studies include 10 single-agent phase 1 
studies; 2 single-agent, phase 1, drug-drug interaction (DDI) studies; 3 single-agent, phase 2 
studies; 1 single-agent, phase 1/2 study; 1 single–agent, phase 3 study; and 5 combination studies 
(3 studies with paclitaxel, 1 study with docetaxel, and 1 study with either rituximab or 
rituximab+vincristine). A total of 1197 patients have been dosed with alisertib in 
company-sponsored clinical trials (including 36 patients from 2 company-sponsored, non-US 
investigational new drug [IND] studies in Japan). AEs observed to date (as of 29 March 2015) are 
generally reversible, dose-dependent, and are consistent with the pharmacologic profile of alisertib 
as an anti-mitotic agent with predominant effects in proliferative tissues. The more commonly 
observed (≥30% incidence) TEAEs from pooled data across the alisertib single-agent studies 
include: neutropenia (48%), anemia (47%), fatigue (46%), diarrhea (44%), alopecia (36%), 
stomatitis (32%), and nausea (31%). Central nervous system (CNS) effects, including transient 
dose-dependent somnolence and/or confusion, have also been observed. Alisertib has shown 
anti-tumor activity in the form of objective tumor responses and/or prolonged disease stabilization 
in a number of different tumor types, including solid tumors (small cell lung cancer [SCLC], 
ovarian, head/neck, NSCLC, liposarcoma, colorectal, and breast) and hematological tumors 
(peripheral T-cell lymphoma [PTCL], multiple myeloma, follicular lymphoma, diffuse large 
B-cell lymphoma [DLBCL], Burkitt’s lymphoma, mantle cell lymphoma [MCL], and acute 
myeloid leukemia [AML]). Further details regarding the clinical experience with alisertib may be 
found in the current version of the alisertib IB.
TAK-659
TAK-659 is a reversible, potent, dual inhibitor of spleen tyrosine kinase (SYK) and fms-related 
tyrosine kinase 3 (FLT-3) being developed for oncology indications, the pathogenesis of a subset 


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of tumors being driven by SYK- and/or FLT-3-mediated signaling. In cultured human tumor cells, 
TAK-659 potently inhibited the growth of hematopoietic-derived cell lines, with a concentration 
producing half-maximal response (EC50) ranging from 11 to 775 nM in sensitive cell systems. 
TAK-659 demonstrated antitumor activity in several experimental hematologic human tumor 
models. The results of drug metabolism and PK studies have shown that TAK-659 has an 
acceptable ADME profile. In nonclinical toxicology studies, target organ toxicities with TAK-659 
were similar in rats and dogs and generally consistent with inhibition of SYK activity. Detailed 
information regarding the nonclinical pharmacology and toxicology of TAK-659 may be found in 
the current version of the TAK-659 IB.
As of 22 October 2015, 30 patients have been dosed with TAK-659 in the FIH study 
(Study C34001), including 16 patients with solid tumors and 14 patients with lymphoma. 
Ten patients have been enrolled in the 60 mg cohort, 4 in the 80 mg cohort, 9 in the 100 mg cohort, 
and 7 in the 120 mg cohort. One patient in the 60 mg cohort presented with Grade 3 AST elevation 
as a DLT. Four DLTs occurred in 120 mg cohort: Grade 4 lipase elevation, Grade 3 lipase 
elevation, Grade 3 generalized edema, and Grade 3 mucositis. In the 100 mg cohort, no patient 
presented with a DLT or Grade 3/4 TEAEs. Based on these data, the MTD of TAK-659 in a 
continuous QD schedule is 100 mg, and therefore, this is the initial dose to be used for patients 
allocated to Cohort A in this trial.
Table 4.b summarizes drug-related TEAEs reported in ≥10% of patients treated with TAK-659 as 
of the 22 October 2015 cutoff date.
Table 4.b
TAK-659 Drug-Related Treatment-Emergent Adverse Events (≥10% of 
Patients) (N=30)
TEAE
All Grades, n (%)
≥Grade 3, n (%)
Fatigue
9 (30)
0
AST increased
8 (27)
1 (3)
Diarrhea 
7 (23)
2 (7)
Anemia
5 (17)
4 (13)
Hypophosphatemia
5 (17)
3 (10)
ALT increased
4 (13)
0
ALP increased
4 (13)
0
Lipase increased
3 (10)
2 (7)
Nausea
3 (10)
0
Periorbital edema
3 (10)
0
Pneumonia
3 (10)
2 (7)
Maculo-papular rash
3 (10)
0
ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
TEAE=treatment-emergent adverse event.
Other drug-related ≥Grade 3 TEAEs were generalized edema, neutropenia, pancytopenia, 
pericardial effusion, pyrexia, stomatitis, and Pneumocystis jirovecii pneumonia (1 patient each).


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Five patients discontinued study treatment due to AEs, 1 of which (pneumonia in a patient 
receiving 80 mg TAK-659) was considered related to study drug. Seven patients died during the 
study; no deaths were considered related to TAK-659.
Three of eight patients with DLBCL achieved a response of partial response (PR). In the 
3 evaluable patients with follicular lymphoma, 1 achieved a complete response (CR) and 
2 achieved PR. Further details regarding the clinical experience with TAK-659 may be found in 
the current version of the TAK-659 IB.
4.2
Rationale for the Proposed Study
4.2.1
Rationale for Combining MLN1117 with Docetaxel, Paclitaxel, or Alisertib
Tumor cells exposed to different cytotoxic agents can respond to damage and stress by activating 
various repair and survival pathways, which may lead to the emergence of drug-resistant cells. 
One of these adaptive responses involves activation of the PI3K survival pathway [17] [18-20]. It 
was reported that protein kinase B (AKT) up-regulation increases resistance to several 
chemotherapeutic agents, in particular antimicrotubule agents such as paclitaxel and colchicine 
[21]. GDC-0941, a pan-PI3K inhibitor, was reported to enhance antitumor activity of docetaxel in 
human breast cancer models in vitro and in vivo by rapid induction of proapoptotic mechanisms 
[18]. Thus it has been hypothesized that the chemopotentiation potential of PI3K pathway 
inhibition can be exploited to maximize the effectiveness of cytotoxic cancer therapy. In addition, 
understanding the order of the administration of anti-cancer drugs may help in selecting optimal 
dosing schedules, can potentially impact antitumor outcome, and minimize any overlapping 
toxicities [22,23].
The antitumor activity of MLN1117+docetaxel was evaluated in a PIK3CA-mutated NCI-H1048 
human small cell lung carcinoma (SCLC) xenograft model in female nude mice. The combination 
was well tolerated and resulted in robust increase of antitumor activity when compared to the 
vehicle treatment in mice bearing SCLC xenografts. Furthermore, MLN1117 in combination with 
docetaxel demonstrated significant and synergistic antitumor activity when MLN1117 was 
administered 24 hours after treatment with docetaxel compared with concomitant dosing of both 
compounds in an SCLC model NCI-H1048 (Report MLN1117-11258). In the PIK3CA-mutated 
gastric cancer model GA0098, the combination of docetaxel administered 24 hours before 
MLN1117 displayed an additive effect compared to either agent alone.
Combination of MLN1117 and alisertib tested on multiple dosing schedules led to enhanced 
antitumor activity in 2 human gastric cancer models (Hs 746T and NCI-N87) and resulted in 
additive effects as compared to respective single-agent therapy, prolonged tumor re-growth delay,
and had acceptable tolerability (RPT-02978).Taken together, these results support clinical 
evaluation of MLN1117 in combination with alisertib, paclitaxel, or docetaxel in patients with 
advanced gastric or gastroesophageal adenocarcinoma, and in particular, in combination dosing 
regimens in which the chemotherapeutic agents are administered 24 hours before dosing of 
MLN1117.


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4.2.2
Rationale for Combining MLN1117 with TAK-659
There is also growing evidence that SYK is a component of the cellular signaling cascade 
associated with EBV latency and transformation. EBV-positive tumors may express latent 
membrane protein 2A (LMP2A), which contains an immunoreceptor tyrosine-based activation 
motif (ITAM) domain. ITAM-mediated SYK activation has been shown to be essential to the 
LMP2A-induced tumorigenicity in EBV-driven tumor models for both EBV-associated 
lymphomas such as Burkitt’s lymphoma, and EBV-associated solid tumors such as 
nasopharyngeal carcinoma [24]. Recently, this subtype (approximately 9%) of gastric cancer has 
been identified as positive for EBV with a high frequency of PIK3CA mutations [2], suggesting a 
role of SYK and PI3Kα in the pathogenesis of EBV-positive gastric cancer. Preliminary 
nonclinical evaluation of MLN1117 in combination with TAK-659 demonstrated acceptable 
tolerability and improved tumor growth inhibition compared to either of the single agents alone in 
2 gastric cancer models (PHTXM-30Ga and PHTX-32Ga) (Report RPT-02977). Thus, this 
evidence may constitute a rationale for investigating the combination of MLN1117 and TAK-659 
in the EBV-positive subset of patients with gastric adenocarcinoma.


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5.0
STUDY OBJECTIVES
5.1
Primary Objectives
The primary objective in Part 1 is:

To determine the initial safety of MLN1117 when administered with each of the combination 
partners measured as the MTD or recommended Part 2 dose.
The primary objective in Part 2 is:

To evaluate the ORR as the primary efficacy measure of MLN1117 in combination with each 
of the combination partners in patients with gastric or gastroesophageal junction 
adenocarcinoma.
5.2
Secondary Objectives
The secondary objective in Part 1 is:

To evaluate initial activity for each combination.
The secondary objective in Part 2 is:

To evaluate additional efficacy measures, such as PFS, disease control rate, duration of 
response (DOR), time to progression (TTP), and OS of MLN1117 in combination with each of 
the combination partners in patients with gastric or gastroesophageal junction
adenocarcinoma.
The secondary objectives in Parts 1 and 2 are:

To determine the RP2D.

To evaluate the overall safety and tolerability of MLN1117 in combination with each of the 
combination partners.

To evaluate the PK of MLN1117 when dosed in combination with alisertib, TAK-659, 
docetaxel, or paclitaxel, and to evaluate the PK of alisertib and TAK-659 when these agents are 
dosed in combination with MLN1117.
5.3
Tertiary/Exploratory Objectives
The exploratory objectives are:

 
 

 


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6.0
STUDY ENDPOINTS
6.1
Primary Endpoints
The primary endpoints in Part 1 (dose escalation) are:

The number and percentage of patients who experience Cycle 1 DLT in Part 1 of the study.

Number (percentage) of patients with at least 1 TEAE in Part 1.

Number (percentage) of patients with at least 1 ≥Grade 3 TEAE in Part 1.

Number (percentage) of patients with at least 1 treatment-emergent SAE in Part 1.

Number (percentage) of patients with at least 1 dose modification due to AE in Part 1.
The primary endpoint in Part 2 (dose expansion) is:

The ORR (defined as CR+PR) in patients with gastric or gastroesophageal junction
adenocarcinoma when treated with MLN1117 in combination with TAK-659, alisertib, 
paclitaxel, or docetaxel.
6.2
Secondary Endpoints
The secondary endpoints are:

The number (percentage) of patients with AEs, including SAEs, from the first dose of study 
drug through 30 days after the last dose of study drug.

Overall drug exposure for each drug in each combination measured as the percentage of 
patients with dose delays, dose reductions, and dose interruptions due to AEs from the first 
dose of study drug through 30 days after the last dose of study drug as measured in both Part 1 
and Part 2.

Measures of disease response (including PFS, disease control rate, DOR, TTP, and OS) based 
on the investigator’s assessment using the Response Evaluation Criteria in Solid Tumors 
(RECIST) Version 1.1 [3].

Summary statistics of the maximum observed plasma concentration (Cmax), time to reach Cmax
(tmax), and AUC of MLN1117 and TAK-659 in Part 1, Cycle 1 Days 1 and 17 when MLN117 is 
administered in combination with TAK-659.

Summary statistics of Cmax, tmax, and AUC of MLN1117 and alisertib in Part 1, Cycle 1 Day 3 
when MLN1117 is administered in combination with alisertib.

Summary statistics Cmax, tmax, and AUC of MLN1117 in Part 1, Cycle 1 Day 2 when MLN1117 
is administered in combination with paclitaxel or docetaxel.


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6.3
Exploratory Endpoints
The exploratory endpoints are:

 
 

 


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7.0
STUDY DESIGN
7.1
Overview of Study Design
This is an open-label, multicenter, phase 1b study of MLN1117 in combination with TAK-659, 
alisertib, paclitaxel, or docetaxel in adult patients with locally advanced and metastatic gastric or 
gastroesophageal junction adenocarcinoma. The study consists of a dose escalation phase (Part 1) 
and a dose expansion phase (Part 2). The statistical design for the dose expansion consists of equal 
randomization and adaptive randomization phases. The study population in Part 1 (dose escalation 
phase) will consist of adult patients with advanced solid tumors (including but not limited to 
gastric or gastroesophageal junction adenocarcinoma) with no other effective therapeutic options 
available. The study population in Part 2 (dose expansion phase) will consist of patients with 
locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma (Stage IIIb or 
IV) who progress to 1 line of prior systemic chemotherapy. It is expected that approximately 
149 to 178 patients will be enrolled in the study. 
Part 1 (Dose Escalation)
During Part 1, the dose of MLN1117 will be escalated (planned dose levels of 300 mg, 600 mg, 
and 900 mg) according to a 3+3 dose escalation scheme (Section 9.3), while TAK-659, alisertib, 
paclitaxel, and docetaxel will be administered at a fixed dose and regimen until the MTD or 
recommended Part 2 dose are determined. Approximately 12 to 15 patients may be enrolled in 
each combination treatment arm, with potentially 3 to 6 patients in each dose cohort. Therefore, 
approximately 60 patients may be enrolled in the dose escalation phase. The patient allocation 
process is detailed in the Cohort Management Plan. Patients will be assigned in the optimal way to 
complete the next open dose level in each cohort. Once a dose level is open in 1 cohort, the first 
3 patients will be allocated to this cohort before another cohort is open. Exceptions to this rule can
be made based on specific rationale provided by the investigator and discussed during regular 
investigator teleconferences based on clinical, molecular, or other considerations. Serial PK 
samples will be collected at prespecified time points in Cycle 1 to characterize the PK of 
MLN1117 when given in each of the combination regimens, and the PK of alisertib and TAK-659 
when given in combination with MLN1117. The schedule of PK sampling is provided in 
Appendix Table A and described in Section 10.4.15. Toxicity will be evaluated according to 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), 
Version 4.03 [1]. DLTs are defined in Section 9.2.
At the end of the dose escalation phase in each treatment cohort, the overall safety and exposure 
will be evaluated to decide: (1) the recommended dose for Part 2 (not exceeding the MTD or 
maximally assessed dose) for each treatment cohort, and (2) if, based on the overall preliminary 
safety and exposure, any of the cohorts should not proceed into Part 2. The decision will be made 
by the Part 1 investigators and the sponsor and documented in minutes that will be distributed to
Part 2 investigators and institutional review boards (IRBs).


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Part 2 (Dose Expansion)
All patients who enter Part 2 of the study will be screened to determine whether or not their tumor 
tissue is positive for EBV (approximately 9% of patients with gastric cancer). An estimated 
28 patients who are EBV positive will be assigned to treatment with TAK-659 in combination with 
MLN1117 (Cohort A). Patients who are EBV negative initially will be randomized equally to 1 of 
the other treatment cohorts, 5 patients per group: MLN1117+alisertib (Cohort B), 
MLN1117+paclitaxel (Cohort C), or MLN1117+docetaxel (Cohort D). These patients will be 
assessed using a proportional weighted clinical utility function (allocating specific weights for CR, 
PR, stable disease [SD], and progressive disease [PD]). Patients then will be randomized to 
treatment according to an adaptive randomization algorithm, which incorporates a weighted 
clinical utility function. The resulting probability will continually be updated per accumulating 
data on the associations between the ORR and Bayesian stopping rules (defined in Section 14.1.2).
Adaptive randomization will be applied to newly enrolling patients every 2 months based on 
cumulative data. The adaptive randomization will increase the opportunity for each patient to 
receive the most effective experimental treatment possible based on posterior probabilities. Up to 
an additional 25 patients may be enrolled in each treatment regimen. Based on simulation results, 
the sample size for Part 2 (umbrella portion) of the study may be between 61 and 90 patients.
Therefore, a maximum number of 118 patients may be enrolled in the dose expansion phase.
ORR will be used as the efficacy benchmark: target 25% (0.25); undesirable 10% (0.1). Early 
stopping rules will be prespecified if there is a clear signal of efficacy or lack of efficacy. The 
stopping rules are as follows: (1) achieve maximum sample size of each arm (30 patients); (2) stop 
an arm if probability (Pr), Pr (response rate [RR]>0.25/Data) >80% and Pr (RR>0.10)/Data) 
>90%; (3) suspend accrual to an arm if Pr (RR≤0.10/Data) >80%. The treatment arm(s) is/are 
chosen in relation to the efficacy bar prespecified (target and undesirable); therefore, it is possible 
to select multiple treatment arms per this study design. 


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Figure 7.a
Study Design for Part 2 of the Study
EBV=Epstein-Barr virus, GC=gastric cancer [2].
Radiological evaluations (CT scan or magnetic resonance imaging [MRI] as clinically indicated) 
will be employed to assess the status of the patient’s underlying disease, and serial blood samples 
will be collected for tumor-specific markers. Disease response will be evaluated using the 
RECIST, Version 1.1 [3].
AEs will be assessed, and laboratory values, vital signs, and electrocardiograms (ECGs) will be 
obtained to evaluate the safety and tolerability of MLN1117 when administered in combination 
with TAK-659, alisertib, paclitaxel, or docetaxel.
Sparse PK blood samples will be collected in Part 2 for all patients in all treatment cohorts to 
contribute to future population PK analysis of MLN1117, TAK-659, and alisertib. Samples will be 
obtained at prespecified time points as described in Appendix Table B and Table C, and in 
Section 10.4.15.
 
Equal Randomization
Cohort B
(w/ Alisertib)
N=5
1
Cohort C
(w/ Paclitaxel)
N=5
Cohort D
(w/ Docetaxel)
N=5
Adaptive Randomization
(Efficacy-Based & Repeated)
Cohort B
Up to addl N=25
Cohort C
Up to addl N=25
Cohort D
Up to addl N=25
• Re-allocation of patients 
based on early efficacy signals
•Repeated adaptation based on 
cumulative and evolving data 
•Early stopping of treatment 
arm(s) based on prespecified 
stopping rules for clear signal of 
efficacy or lack of efficacy
Cohort A
(w/ TAK-659)
N=28
EBV Screening
EBV+
EBV-
9% GC


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Patients may receive study drugs until they experience PD or unacceptable toxicity. The maximum 
duration of treatment will be 1 year for MLN1117, alisertib, and TAK-659, and 6 cycles for 
paclitaxel and docetaxel. Exceptions can be made for patients with clear clinical benefit after 
discussion between the investigator and the sponsor. If it is necessary to discontinue paclitaxel or 
docetaxel due to cumulative toxicity, it would be possible to continue treatment with MLN1117 as 
single agent. If it is necessary to discontinue MLN1117 for safety reasons, the patient should be 
withdrawn from the trial. For special circumstances, in which it is recommended that the patient 
continue only on the companion drug, agreement between the investigator and sponsor is required. 
Paclitaxel and docetaxel may be administered after Cycle 6 if the investigator and sponsor 
determine that the patient would derive benefit from continued treatment.
Patients will be followed for 30 days after the last dose of any study drug or until the start of 
subsequent antineoplastic therapy to permit the detection of any delayed treatment-related AEs. 
Patients who discontinue study drug treatment for reasons other than PD will undergo CT/MRI 
scans every 12 weeks from End of Treatment (EOT) until the occurrence of PD, the start of 
subsequent antineoplastic therapy, or until 6 months after the discontinuation of study treatment, 
whichever occurs first. Patients will be followed for OS every 12 weeks until death or until 1 year 
after the last dose of study drug, whichever occurs first.
7.2
Number of Patients
Approximately 149 to 178 patients will be enrolled in this study from approximately 30 study 
centers in North America and Europe. Approximately 60 patients may be enrolled in Part 1 (dose 
escalation) and approximately 89 to 118 patients may be enrolled in Part 2 (dose expansion). 
Enrollment is defined as the time when the patient receives the first dose of any study drug. 
In Part 1, patients who are withdrawn from treatment during Cycle 1 for reasons other than DLT 
will be replaced.
In Part 2, patients who withdraw early and do not have a postbaseline response assessment will be 
replaced, unless they were withdrawn for PD.
7.3
Duration of Study
Patients will be followed for 30 days after the last dose of any study drug or until the start of 
subsequent alternative anticancer therapy to permit the detection of any delayed treatment-related 
AEs. Patients who discontinue study drug treatment for reasons other than PD will undergo 
CT/MRI scans every 12 weeks from EOT until the occurrence of PD, the start of subsequent 
antineoplastic therapy, or until 6 months after the discontinuation of study treatment, whichever 
occurs first. Patients will be followed for OS every 12 weeks until death or until 1 year after the 


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last dose of study drug, whichever occurs first. The final analyses for the clinical study report will 
be conducted after all patients enrolled in the study have had the opportunity to complete 6 cycles 
of treatment with study drug.
It is anticipated that the duration of this study will be 10 months for Part 1 (dose escalation), 
24 months for Part 2 (dose expansion), 6 months for treatment, and 6 months for OS.


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8.0
STUDY POPULATION
8.1
Inclusion Criteria
Each patient must meet all of the following inclusion criteria to be enrolled in the study.
8.1.1
Part 1 and Part 2
1. Male or female patients aged 18 years or older at the time of consent.
2. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (refer to 
Appendix C) within 14 days before enrollment. 
3. Adequate organ and hematologic function as evidenced by the following laboratory values 
within 14 days before enrollment:

Absolute neutrophil count (ANC) ≥1.5×109/L. 

Platelet count ≥100×109/L. 

Hemoglobin ≥9 g/dL (Transfusions are allowed to reach this hemoglobin level.). 

Serum creatinine ≤1.5 times the upper limit of the normal range (ULN) or creatinine 
clearance ≥50 mL/min either as estimated by the Cockcroft-Gault equation (Appendix D) 
or based on urine collection (12 or 24 hours). 

Total bilirubin ≤1.5×ULN.

AST and ALT ≤2.5×ULN.
4. Female patients who:

Are postmenopausal 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 (see 
Appendix E) and 1 additional effective (barrier) method of contraception at the same time, 
from the time of signing the informed consent form through 30 days after the last dose of 
study drug (with the exception of those subjects assigned to TAK-659, for whom the 
duration required is 180 days), or for as long as mandated by local labeling for docetaxel 
and paclitaxel, OR

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle 
of the subject, from the time of signing the informed consent form through 30 days after the 
last dose of study drug (with the exception of those subjects assigned to TAK-659, for 
whom the duration required is 180 days), or for as long as mandated by local labeling for 
docetaxel and paclitaxel. (Periodic abstinence [eg, calendar, ovulation, symptothermal, 
postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are not 


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acceptable methods of contraception. Female and male condoms should not be used 
together.)
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 (with the exception of those subjects 
assigned to TAK-659, for whom the duration required is 180 days), or for as long as 
mandated by local labeling for docetaxel and paclitaxel, OR

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle 
of the subject, during the entire study treatment period and through 120 days after the last 
dose of study drug (with the exception of those subjects assigned to TAK-659, for whom 
the duration required is 180 days) or for as long as mandated by local labeling for docetaxel 
and paclitaxel. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 
methods for the female partner] and withdrawal are not acceptable methods of 
contraception.)
5. Voluntary written consent must be given before performance of any study-related procedure 
not part of standard medical care, with the understanding that consent may be withdrawn by 
the patient at any time without prejudice to future medical care.
6. Suitable venous access for the study-required blood sampling (ie, PK sampling, circulating 
tumor DNA).
8.1.2
Part 1 Only
2.1 A histologically confirmed diagnosis of advanced solid tumor, including but not limited to 
gastric or gastroesophageal junction adenocarcinoma.
2.2 Radiographically or clinically evaluable disease. Measurable disease as defined by RECIST, 
Version 1.1 is not required.
2.3 Relapsed or refractory patients with no effective therapeutic options available.
8.1.3
Part 2 Only
3.1 A histologically confirmed diagnosis of metastatic or locally advanced adenocarcinoma of the 
stomach or gastroesophageal junction (Stage IIIb or IV according to International Union 
Against Cancer [UICC] tumor, node, metastases [TNM] classification 7th edition [25]).
3.2 At least 1 measurable lesion per RECIST, Version 1.1 [3] by radiographic techniques (CT or 
MRI).
3.3 Receipt of 1 prior systemic chemotherapy regimen for advanced or metastatic adenocarcinoma 
of the stomach or gastroesophageal junction with documented PD.
3.4 Archived or fresh tumor biopsy samples obtained during screening sufficient for EBV testing 
and genotyping.


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8.2
Exclusion Criteria
Patients meeting any of the following exclusion criteria are not to be enrolled in the study.
8.2.1
Part 1 and Part 2
1. Has received prior systemic anticancer therapies or other investigational agents within 2 weeks 
before the first administration of study drug or has failed to recover from the adverse drug 
effects of prior therapies (to ≤Grade 1 or to a level meeting inclusion criteria). For prior 
therapies with a half-life longer than 3 days, the interval must equal minimally 28 days before 
the first administration of study drug and the subject must have documented PD.
2. Radiotherapy within 14 days before enrollment.
3. Fasting glucose ≥130 mg/dL. Poorly controlled diabetes mellitus (glycosylated hemoglobin 
[HbA1c] >7.0%). Patients with a history of transient glucose intolerance due to corticosteroid 
administration are allowed.
4. Has received strong cytochrome P-450 (CYP) 3A4 inducers/inhibitors (Appendix F) within 
7 days before the first administration of study drug or has conditions that require the 
concomitant use of CYP3A4 inducers/inhibitors during the course of the study.
5. For TAK-659 (Cohort A) only: Receiving treatment with medications that are known to be 
inhibitors or inducers of P-glycoprotein (P-gp; Appendix G). Baseline lipase >ULN. Patients 
not fulfilling these exclusion criteria can be enrolled in other cohorts (Part 1 only).
6. Has taken proton pump inhibitors within 7 days before the first administration of study drug or 
has conditions that require the concomitant use of proton pump inhibitors during the course of 
the study.
7. Signs of peripheral neuropathy ≥NCI CTCAE Grade 2.
8. Symptomatic brain metastases or brain metastases with a stable neurologic status for <2 weeks 
after completion of the definitive therapy and steroids.
9. Systemic infection requiring intravenous (IV) antibiotic therapy or other serious infection 
within 14 days before the first dose of study drug. 
10. Known or suspected human immunodeficiency virus (HIV) positive or hepatitis B surface 
antigen-positive status, or known or suspected active hepatitis C infection. Testing for these 
agents is not required in the absence of clinical findings or suspicion.
11. Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral 
absorption or tolerability of orally administered study drug, including difficulty swallowing 
tablets; diarrhea >Grade 1 despite supportive therapy; or prior total gastrectomy.
12. Previous exclusion criterion #12 deleted in Amendment 1.


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13. Clinically significant comorbidities, such as uncontrolled pulmonary disease, known impaired 
cardiac function or clinically significant cardiac disease, active central nervous system disease, 
or any other condition that could compromise the subject’s participation in the study.

Known impaired cardiac function or clinically significant cardiac disease includes: 
evidence of currently uncontrolled cardiovascular conditions (including arrhythmias, 
angina, pulmonary hypertension, acute ischemia or active conduction system 
abnormalities); current history of New York Heart Association Class III or IV heart failure; 
acute myocardial infarction within 6 months before starting study drug; baseline QT 
interval corrected for heart rate (QTc) ≥Grade 1 according to NCI CTCAE Version 4.03 
criteria; or abnormalities on baseline 12-lead ECG that are considered clinically significant 
per the investigator.
14. Female patients who are lactating and breastfeeding or have a positive serum pregnancy test 
during the screening period or a positive urine pregnancy test on Day 1 before the first dose of 
study drug.
15. Patients with bilirubin >ULN, or AST and/or ALT >1.5ULN concomitant with alkaline 
phosphatase >2.5ULN cannot be allocated to Cohort D (MLN1117+docetaxel) in Part 1 and 
are not eligible for Part 2 if they are also EBV negative.
8.2.2
Part 2 Only
2.1
Prior treatment with any of the following:

An Aurora A-targeted agent (not eligible for randomization in Cohorts B, C, or D, but 
eligible for Cohort A if EBV positive).

A docetaxel- or paclitaxel-containing chemotherapy regimen (not eligible for 
randomization in Cohorts B, C, or D, but eligible for Cohort A if EBV positive).

An SYK inhibitor (MLN1117+TAK-659 [Cohort A] only).

A PI3K or AKT inhibitor.


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9.0
STUDY DRUG
9.1
Study Drug Administration
All protocol-specific criteria for administration of study drug must be met and documented prior to 
drug administration. Study drug will be administered only to eligible patients under the 
supervision of the investigator or identified subinvestigator(s).
The dosing regimen for study drugs in each of the cohorts is outlined in the following sections.
9.1.1
MLN1117+TAK-659 (Cohort A)
MLN1117 will be administered PO QD for 3 days on (ie, Days 1, 2, 3; 8, 9, 10; 15, 16, 17; 22, 23, 
and 24) and 4 days off per week in each 28-day cycle. The dose of MLN1117 when administered 
in combination with TAK-659 as determined in Part 1 will be used in Part 2. TAK-659 will be 
administered PO at the MTD of 100 mg in a continuous QD dosing schedule in each 28-day cycle 
as determined in the FIH Study C34001. Please see Table 9.a for further information on dosing 
schedule for each cycle in Cohort A.
9.1.2
MLN1117+Alisertib (Cohort B)
MLN1117 will be administered PO QD for 3 days on (ie, Days 1, 2, 3; 8, 9, 10; 15, 16, 17; 22, 23, 
and 24) and 4 days off per week in each 28-day cycle. The dose of MLN1117 when administrated 
concomitantly with alisertib will be determined in the Part 1 dose escalation phase and used in the 
Part 2 dose expansion phase. Alisertib will be administered PO at 40 mg BID for 3 days on 
(ie, Days 1, 2, 3; 8, 9, 10; 15, 16, and 17) and 4 days off per week on Weeks 1-3, and 1 week off in 
each 28-day cycle. Please see Table 9.b for further information on dosing schedule for each cycle 
in Cohort B.
9.1.3
MLN1117+Paclitaxel (Cohort C)
MLN1117 will be administered PO QD for 3 days on (ie, Days 2, 3, 4; 9, 10, 11; 16, 17, 18; 23, 24, 
and 25) and 4 days off per week in each 28-day cycle. The dose of MLN1117 when administrated 
concomitantly with paclitaxel will be determined in the Part 1 dose escalation phase and used in 
the Part 2 dose expansion phase. Paclitaxel will be administered IV at 80 mg/m2 once weekly on 
Days 1, 8, and 15, and 1 week off, in each 28-day cycle. Please refer to the paclitaxel label or 
prescribing information (US Prescribing Information [USPI] or Summary of Product 
Characteristics [SmPC]) for further details regarding administration, and Section 9.6.1 for 
paclitaxel premedications. Please see Table 9.c for further information on dosing schedule for each 
cycle in Cohort C.
9.1.4
MLN1117+Docetaxel (Cohort D)
MLN1117 will be administered PO QD for 3 days on (ie, Days 2, 3, 4; 9, 10, 11; 16, 17, and 18) 
and 4 days off per week in each 21-day cycle. The dose of MLN1117 when administrated
concomitantly with docetaxel will be determined in the Part 1 dose escalation phase and used in 


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the Part 2 dose expansion phase. Docetaxel will be administered IV at 75 mg/m2 on Day 1 once 
every 3 weeks in a 21-day cycle. Please refer to the docetaxel USPI or SmPC for further details 
regarding administration, and Section 9.6.1 for docetaxel premedications. Please refer to Table 9.d
for further information on dosing schedule for each cycle in Cohort D.


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Table 9.a
Cohort A: MLN1117+TAK-659 Dosing Schedule
Cohort A
28-Day Cycle, All Cycles
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
MLN1117
x
x
x
x
x
x
x
x
x
x
x
x
TAK-659
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Table 9.b
Cohort B: MLN1117+Alisertib Dosing Schedule
Cohort B
28-Day Cycle, All Cycles
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
MLN1117
x
x
x
x
x
x
x
x
x
x
x
x
Alisertib
xx
xx
xx
xx
xx
xx
xx
xx
xx
Table 9.c
Cohort C: MLN1117+Paclitaxel Dosing Schedule
Cohort C
28-Day Cycle, All Cycles
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
MLN1117
x
x
x
x
x
x
x
x
x
x
x
x
Paclitaxel
x
x
x
Table 9.d
Cohort D: MLN1117+Docetaxel Dosing Schedule
Cohort D
21-Day Cycle, All Cycles
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
MLN1117
x
x
x
x
x
x
x
x
x
Docetaxel
x


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The study drug that is administered orally, such as MLN1117, TAK-659, and alisertib, should be 
taken on an empty stomach, at least 1 hour before and no sooner than 2 hours after a meal. Each 
tablet should be swallowed separately with a sip of water. A total of approximately 8 ounces 
(240 mL) of water should be taken with the tablets. Patients should swallow the study medication 
whole. The study medication should not be chewed before swallowing. Administration of the 
tablets will be guided by the dosing tables included above and also in the Pharmacy Manual.
Patients should be instructed to take their study medication at approximately the same time each 
day and not take more than the prescribed dose at any time. On visit days, patients should be 
instructed to hold their dose until predose assessments are performed (unless otherwise specified 
for visits in which holding the dose is not needed, ie, in Part 2 when patients are instructed to take 
the dose of study drug at home and report to the study site according to Appendix Table B and 
Table C to enable collection of sparse PK samples). In the event that a patient fails to take study 
drug(s) on 1 day, the patient must not make dose adjustments to account for the missed dose on 
subsequent days, for example, by taking a double dose of study drug(s) on the following day. 
Patients should record any skipped doses in their dosing diary (see the Study Manual) and resume 
dosing at the next scheduled time with the prescribed dosage.
If severe emesis or stomatitis prevents the patient from taking a dose of study drug(s), that dose 
will be skipped. If emesis occurs after study medication ingestion, patients should simply adhere to 
the dosing schedule and continue dosing at the next scheduled time with the prescribed dosage. 
Patients should not take a repeat dose following emesis after study medication ingestion. Patients 
should record the time of the emesis in their dosing diary (see the Study Manual). 
In cohorts where both study drugs are administered orally (Cohort A: MLN1117+TAK-659 and 
Cohort B: MLN1117+alisertib), there is no requirement for a specific sequence of administration 
for each of the study drugs in both cohorts. For patients in Cohort B, the 2 daily doses of alisertib 
should be separated by approximately 12 hours. Patients will be advised to establish a routine 
based on their own preference and adhere to the same dosing routine as much as possible.
9.2
Definitions of Dose-Limiting Toxicity
Toxicity will be evaluated according to the NCI CTCAE, Version 4.03 [1]. These criteria are 
provided in the Study Manual. DLT will be defined as any of the following events occurring 
during Cycle 1 in Part 1 that are considered by the investigator to be at least possibly related to 
either or both of the study drugs (MLN1117, TAK-659, alisertib, paclitaxel, or docetaxel) in an 
assigned combination regimen:

Grade 4 neutropenia (ANC<500 cells/mm3) lasting more than 7 consecutive days.

≥Grade 3 neutropenia (ANC<1000 cells/mm3) with fever and/or infection, where fever is 
defined as a single temperature ≥38.3oC (101ºF) or sustained temperature of ≥38ºC (100.4ºF) 
for more than 1 hour.

Grade 4 thrombocytopenia lasting more than 7 consecutive days.

Grade 3 thrombocytopenia of any duration accompanied by clinically significant bleeding.


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
A platelet count <10,000/mm3 at any time.

Grade 3 or greater nonhematologic toxicity with the following exceptions:
–
Grade 3 arthralgia/myalgia.
–
Grade 3 fatigue that lasts less than 1 week.
–
Grade 3 nausea and/or emesis that can be controlled to ≤Grade 1 or baseline in 7 days with 
the use of optimal antiemetic prophylaxis (defined as an antiemetic regimen that employs 
both a 5-HT antagonist and a corticosteroid given in standard doses and according to 
standard schedules).
–
Grade 3 diarrhea that can be controlled to ≤Grade 1 or baseline in 7 days with optimal
supportive therapy.
–
Grade 2 fasting hyperglycemia lasting ≤14 days with optimal treatment or Grade 3 fasting 
hyperglycemia lasting ≤24 hours with optimal treatment.
–
Grade 3 rash lasting ≤7 days with optimal treatment that includes topical steroid treatment, 
PO antihistamines, and pulse PO steroids, if necessary.
–
Any other Grade 3 nonhematologic toxicity that can be controlled to ≤Grade 1 or baseline 
in 7 days with appropriate treatment. In this setting, a course of action will be determined 
jointly by the investigators and the sponsor clinician.

Delay in the initiation of the subsequent cycle of therapy by more than 7 days due to 
treatment-related hematological or nonhematologic toxicities.

Greater than or equal to Grade 2 nonhematologic toxicities that are considered by the 
investigator to be related to study drug(s) and dose-limiting. In this setting, a course of action 
will be determined jointly by the investigators and the sponsor clinician.
Although DLT may occur at any point during treatment, only DLT occurring during Cycle 1 of 
treatment in Part 1 (dose escalation) will necessarily influence decisions regarding dose escalation, 
expansion of a dose level, or evaluation of intermediate dose levels. Patients in both Parts 1 and 2 
will be monitored through all cycles of therapy for treatment-related toxicities.
Patients experiencing DLT in Cycle 1 may continue in the study provided they are deriving clinical 
benefit, but will be administered reduced doses of MLN1117 and/or the combination agent as 
appropriate.
9.3
Dose Escalation Rules (Part 1)
A standard 3+3 dose escalation scheme will be used to determine the MTD of MLN1117 when 
administered in combination with 1 of the combination partners (ie, TAK-659, alisertib, paclitaxel, 
or docetaxel), each administered at a fixed dose and schedule. The initial MLN1117 dose will be 
300 mg administered PO QD following the 3-days-on and 4-days-off weekly schedule. The next 
planned dose levels will be 600 mg and then 900 mg. However, alternative escalation in response 
to evolving safety, PK, and other relevant data is permissible, following discussion and agreement 


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between investigators and the sponsor. This includes evaluation of intermediate dose levels, 
expansion of an existing dose level, and alternative regimens/schedule of MLN1117 if 
appropriate. In the event that the initial dose of 300 mg is determined to be intolerable, 
de-escalation of the dose in 100-mg decrements may be considered, or a decision may be made 
jointly by the investigators and sponsor to discontinue the dose escalation for that cohort.
Dose escalation will be based on DLT as determined in Cycle 1. Rules for dose escalation based on 
Cycle 1 DLT include: 
1. If 0 of 3 patients experience 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 DLT, 3 more patients will be enrolled at that same dose level. 
3. Dose escalation will continue if 1 of 6 patients experiences DLT.
4. If 2 or more patients in any dose level experiences DLT, dosing will stop, and the previous 
dose level will be considered the MTD.
5. If 0 of 3 or 1 of 6 patients experience DLT at the dose level of 900 mg MLN1117, no further 
escalation will occur and 900 mg will be considered the maximum administered dose (MAD).
During the dose escalation phase, patients not receiving at least 75% of the MLN1117 dose for 
reasons other than DLT in Cycle 1 will be replaced within the cohort.
The MTD is defined as the highest dose level of MLN1117 when administered in combination 
with the combination agent at which no more than 1 of 6 patients experiences a DLT during the 
first cycle of therapy in Part 1 (dose escalation). Although toxicities determined to be related or 
possibly related to the combination agent in each cohort will not directly influence the 
determination of the MTD for MLN1117, the determination of the recommended dose for Part 2 
will take into account the frequency and severity of non-MLN1117 drug-related AEs and dose 
modification of the combination agents during Cycle 1 and beyond.
The RP2D of MLN1117 will be determined at the end of the trial (Part 1 and Part 2) on the basis of 
the totality of safety, tolerability, PK, dose modifications, and preliminary efficacy data (if 
available). The RP2D will not exceed the MTD. 
While the primary dose escalation schema (see Figure 9.a) is designed to determine a classical 
Cycle 1-based MTD, dose escalation may be halted at any time after consultation between the 
investigators and sponsor clinician if cumulative toxicity beyond Cycle 1 indicates that a given 
dose exceeds a tolerable recommended Part 2 dose.
Treatment with MLN1117 will be administered on a weekly schedule that includes 3 consecutive 
dosing days per week. During dose escalation, a reduction in the number of treatment days per 
week (eg, reducing dosing days from 3 to 2 days or further to 1 day) while maintaining the same 
dose may be considered as an alternative to reducing to a lower dose when dose de-escalation is 
indicated. This decision will be made jointly by investigators and the sponsor project clinician.


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Although dose escalation is planned for MLN1117 only when the combination agent in each 
cohort is administered with a fixed dose and schedule, in the event that the first dose level of any 
cohort is not feasible because of the occurrence of DLT in more than 1 of 6 patients or in case of 
frequent occurrences of dose modification of the combination agent in Cycle 1 and/or Cycle 2 and 
beyond, upon discussion and agreement between investigators and the sponsor project clinician (or 
designee), the fixed dose of the combination agent could be reset at a lower dose (eg, -1 dose 
according to Table 9.e) for the purpose of further evaluation and determination of the MLN1117 
MTD/recommended Part 2 dose/RP2D. For alisertib, which will be administered in a 3-days-on 
and 4-days-off schedule, reducing the number of dosing days per week instead of reducing the 
dose level could be considered.
Figure 9.a
Dose Escalation Algorithm
DLT=dose-limiting toxicity, MTD=maximum tolerated dose.
9.4
Dose Modification Guidelines
In both Part 1 (dose escalation) and Part 2 (dose expansion) of the study, patients will be evaluated 
according to the Schedule of Events (Appendix A) for each of the 4 cohorts for possible toxicities 
that may have occurred after the previous dose(s). Toxicities are to be assessed according to the 
NCI CTCAE, Version 4.03 [1]. The causal relationship of each AE should be assessed in relation 
to MLN1117 and to the combination agent in each cohort so that dose modifications can be made 
accordingly. Administration and dose adjustment of docetaxel (Cohort D) or paclitaxel (Cohort C) 
will follow applicable prescribing information, the guidance on dose modification 
(Section 9.4.4.3), and the guidance on the management of clinical events (see Section 9.8). 
Minimum requirements described in the docetaxel and paclitaxel prescribing information must be 
met before starting the next cycle or dose of docetaxel and paclitaxel treatment (see 
Enter 3
1 DLT
0 DLTs
2-3 DLTs
Escalate to 
next dose
Enter 3 at 
same dose
1 of 6 DLT
>1 of 6 DLTs
Stop
MTD=Previous dose


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Section 9.4.4.2). Dose modification guidelines for hematologic and nonhematologic toxicities are 
described below for both study drugs in each of the combination cohorts based on the type and 
severity of AEs, causality determination by investigators, and safety and tolerability profiles of 
each of the study drugs. Further clarification can be obtained in consultation with the sponsor 
clinician (or designee). 
Per dose modification guidelines, patients who have the study drug held because of 
treatment-related or possibly related AEs may resume study drug treatment after resolution of the 
AE but may either maintain the same dose level or have doses of study drug reduced (dose 
reduction) by at least 1 dose level. When a dose reduction of MLN1117 occurs, the MLN1117 
dose will be reduced to the next lower dose that has been established as a safe dose during dose 
escalation (Part 1). During Part 2, depending on the recommended Part 2 dose determined during 
Part 1, MLN1117 dose reduction will follow, in general, a decrement of 300 mg, or a decrement of 
100 mg for doses ≤300 mg. If initial dose adjustment does not provide sufficient relief, the dose of 
MLN1117 can be further reduced if the treating physician considers that the patient is benefiting 
from study treatment and may benefit at a further reduced dose of MLN1117. Up to 2 dose level 
reductions of MLN1117 due to AEs are generally recommended. If more than 2 dose reductions of 
MLN1117 (below those presented in Table 9.e) are needed to manage MLN1117-related AEs, 
discontinuation of treatment should be considered unless the treating physician, in consultation 
with the sponsor (or designee), feels the patient may benefit from continued study treatment after 
resolution of AEs to <Grade 1 or baseline.
For Cohort A, the MTD of TAK-659 was determined to be 100 mg in a continuous QD dosing 
schedule in each 28-day cycle (Study C34001, a FIH dose-escalation study of TAK-659 in patients 
with advanced solid tumor and lymphoma) (see Section 4.1.2). The dose reduction of TAK-659 
will, in general, follow a decrement of 20 mg (Table 9.e). 
For Cohorts B, C, and D, dose reduction levels for alisertib, paclitaxel, and docetaxel are described 
in Table 9.e for AEs that are attributed to each of the combination agents. Requirements for dose 
reduction below those presented in Table 9.e should prompt withdrawal of the patient from the 
study.
Table 9.e
Dose Reduction Levels for MLN1117 and Combination Partners
Dose Reduction 
Levels
MLN1117
TAK-659
Alisertib
Paclitaxel
Docetaxel
RP2D/standard dose
RP2D TBD
100 mg (a)
40 mg
80 mg/m2
75 mg/m2
(–) 1 dose level
RP2D-300 mg (b)
80 mg
30 mg
65 mg/m2
60 mg/m2
(–) 2 dose level
RP2D-600 mg (b)
60 mg
20 mg
50 mg/m2
45 mg/m2
The need for dose reductions below those stated in this table should result in withdrawal of the patient from the study.
FIH=first in human, MTD=maximum tolerated dose, RP2D=recommended phase 2 dose, TBD=to be determined.
(a) The MTD of TAK-659 determined in Study C34001, a FIH dose escalation study of TAK-659 in advanced solid 
tumor and lymphoma.
(b) MLN1117 dose reduction will follow, in general, a decrement of 300 mg, or a decrement of 100 mg for doses 
≤300 mg, depending on the MTD/recommended Part 2 dose as determined in Part 1.


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If the dose of 1 study drug in a combination regimen is delayed because of toxicity attributed to its 
use, the dose of the other study drug in the combination regimen is to be administered as 
scheduled. 
9.4.1
Intrapatient Dose Escalation (Part 1)
Once the recommended Part 2 dose of MLN1117 is determined, all patients in Part 1 who have 
received MLN1117 and another combination agent at a lower dose for a minimum of 2 cycles, in 
the absence of PD or unacceptable treatment-related toxicity per the investigator, may dose 
escalate to the recommended Part 2 dose of the assigned treatment cohort at the investigator’s 
discretion and with the sponsor’s approval. Patients in whom an increase in the dose of MLN1117 
is being considered must have treatment-related AEs resolved to ≤Grade 1 or baseline or to a level 
that is acceptable to the investigators (nonhematologic toxicity must be ≤Grade 2, and hematologic 
toxicities must be less than the minimal requirement for starting a new cycle of treatment).
9.4.2
Intrapatient Dose Reduction(Part 1, Cycle 1)
Intrapatient dose reductions of MLN1117 are not permitted during Part 1 Cycle 1 unless the patient 
experiences a DLT attributed to MLN1117. DLT is defined in Section 9.2. If a patient experiences 
a DLT during Part 1 Cycle 1, treatment should be held, and the event counted toward the 
assessment of MTD for the given cohort. Patients experiencing DLT in Part 1 Cycle 1 may 
continue in the study upon resolution of the toxicity; however, the dose of MLN1117 (in 
combination with other combination agents) will be reduced by at least 1 dose level (or reduced by 
a 100-mg decrement if the patient is receiving the first dose level). Patients who receive a reduced 
dose of MLN1117 during Cycle 1 for reasons other than DLT will be replaced for DLT evaluation 
and dose escalation. Dose delay and dose reduction of any of the combination partners, and dose 
modification are allowed in Cycle 1 during Part 1 (see Section 9.4.3 and Section 9.4.4, which 
includes paclitaxel and docetaxel retreatment criteria). Frequency of dose delay and reduction of 
other combination agents will be taken into account in determining the recommended Part 2 dose 
and the RP2D for MLN1117 when administered in combination with these agents.
9.4.3
Dose Modification Guideline for Cohort A (MLN1117+TAK-659)
Please refer to Table 9.f for dose delay and reduction recommendations for hematologic toxicities 
and Table 9.g for nonhematologic toxicities for patients treated with MLN1117+TAK-659 in 
Cohort A. When TEAEs occur, the causality in relation to the study drug(s) will be determined by 
the investigators and dose modification will be applied to 1 or both study drugs determined to be 
the cause or possibly the cause of the AEs. When the dose of MLN1117 and/or TAK-659 is 
withheld based on the following criteria (Table 9.f and Table 9.g), clinical and laboratory 
re-evaluation should be repeated at least weekly or more frequently until the toxicity resolves to 
≤Grade 1, baseline, or to a level considered acceptable by the investigator. Upon resolution of the 
toxicity, MLN1117 and/or TAK-659 may be reinitiated either at the same dose level or at a 
reduced dose level. In events where there are transient laboratory value abnormalities that, based 
on investigator assessment, are considered to be not clinically significant or related to disease and 


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not the drug, continuation of therapy without following the dose modification guideline is 
permissible upon discussion with the sponsor. 
When a TEAE is likely drug-related, but it is difficult to determine to which study drug the TEAE 
is related, relatedness or possible relatedness will be assigned to both study drugs and dose 
modification made for both study drugs per the guideline below. After dose reduction of both 
study drugs, if the same event does not reoccur, or occurs at a level considered by the investigator 
to be not clinically significant, dose re-escalation of 1 study drug (while maintaining the other 
study drug at the reduced dose) could be explored with caution and close monitoring at the 
investigator’s discretion, in consultation with the sponsor project clinician (or designee). 
There are no separate criteria for beginning or delaying the subsequent cycles for Cohort A.
Table 9.f
Dose Modification Guidelines for Hematologic Toxicities for Cohort A
(MLN1117+TAK-659)
NCI 
CTCAE 
Grade
Description
Dose Modification for MLN1117 Dose Modification for TAK-659
Neutropenia 
1 or 2
ANC <1500 to 1000/mm3; 
<1.5 to 1.0×109/L
No change. Continue MLN1117 at 
same dose and schedule. 
No change. Continue TAK-659 at same 
dose and schedule.
3
ANC <1000 to 500/mm3; 
<1.0 to 0.5×109/L
Hold MLN1117 until 
ANC ≥1500/mm3, then restart 
MLN1117. If resolved in ≤7 days, 
maintain the same dose of 
MLN1117. If resolved in >7 days, 
reduce dose by 1 level.
Hold TAK-659 until ANC ≥1500/mm3, 
then restart TAK-659. If resolved in 
≤7 days, maintain the same dose of 
TAK-659. If resolved in >7 days, reduce 
dose by 1 level.
4
ANC <500/mm3; 
<0.5×109/L
Hold MLN1117 until 
ANC ≥1500/mm3, then restart 
MLN1117 at a reduced dose by 
1 level.
Hold TAK-659 until ANC ≥1500/mm3, 
then restart TAK-659 at a reduced dose by 
1 level.
Other
Febrile Neutropenia
ANC <1000/mm3 and fever 
defined as a single 
temperature of >38.3oC 
(101oF) or a sustained 
temperature of ≥38oC 
(100.4oF) for more than 
1 hour), OR
ANC <1000/mm3 with 
systemic infection
Hold MLN1117 until 
ANC ≥1500/mm3 and fever and 
infection are resolved, then restart 
MLN1117 at a reduced dose by 
1 level.
Hold TAK-659 until ANC ≥1500/mm3
and fever and infection are resolved, then 
restart TAK-659 at a reduced dose by 
1 level.
Footnotes are on last table page.


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Table 9.f
Dose Modification Guidelines for Hematologic Toxicities for Cohort A 
(MLN1117+TAK-659) (continued)
NCI 
CTCAE 
Grade
Description
Dose Modification for MLN1117 Dose Modification for TAK-659
Thrombocytopenia 
1 or 2
PLT 50,000 to 
100,000/mm3; 
<50 to 100×109/L
No change. Continue MLN1117 at 
same dose and schedule. 
No change. Continue TAK-659 at same 
dose and schedule.
3
PLT 25,000 to 50,000/mm3; 
<25 to 50×109/L
Hold MLN1117 until 
PLT ≥100,000/mm3 or baseline; 
then restart MLN1117. If resolved 
in ≤7 days, maintain the same dose 
of MLN1117. If resolved in 
>7 days, reduce dose by 1 level. 
Hold TAK-659 until PLT ≥100,000/mm3
or baseline; then restart TAK-659. If 
resolved in ≤7 days, maintain the same 
dose of combination agent. If resolved in 
>7 days, reduce dose by 1 level. 
4
PLT <25,000/mm3; 
<25×109/L
Hold MLN1117 until 
PLT ≥100,000/mm3 ; When 
resolved, reduce dose by 1 level
(first occurrence) and by 2 levels
(repeat occurrence).
Hold TAK-659 until PLT ≥100,000/mm3. 
When resolved, reduce dose by 1 level
(first occurrence) and by 2 levels (repeat 
occurrence). 
Other
PLT <10,000 cells/mm3 or
clinically significant 
bleeding
Consider permanently withdrawing 
the patient from the study, except 
when the investigator determines 
that the patient is obtaining clinical 
benefit and has discussed this with 
the sponsor. If the patient’s study 
treatment is not discontinued, then 
the MLN1117 dose will be reduced 
to at least 1 dose level lower when 
PLT ≥100,000/mm3 and clinically 
significant bleeding is completely 
resolved. 
Consider permanently withdrawing the 
patient from the study, except when the 
investigator determines that the patient is 
obtaining clinical benefit and has 
discussed this with the sponsor. If the 
patient’s treatment is not discontinued, 
then the TAK-659 dose will be reduced to 
at least 1 dose level lower when 
PLT ≥100,000/mm3 and clinically 
significant bleeding are completely 
resolved. 
Anemia 
3
Hgb <8.0 g/dL not due to 
bleeding; transfusion 
indicated
Hold MLN1117 until 
Hgb ≥9.0 g/dL; restart MLN1117
at same dose. In case of repeat 
occurrence at a reduced dose of 
TAK-659, MLN1117 will be 
reduced by 1 level.
Hold TAK-659 until Hgb ≥9.0 g/dL. If 
resolved in ≤7 days, maintain the same 
dose of TAK-659. If resolved in >7 days, 
reduce dose by 1 level.
Footnotes are on last table page.


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Table 9.f
Dose Modification Guidelines for Hematologic Toxicities for Cohort A 
(MLN1117+TAK-659) (continued)
NCI 
CTCAE 
Grade
Description
Dose Modification for MLN1117 Dose Modification for TAK-659
Anemia (continued)
4
Hgb <6.5 g/dL not due to 
bleeding; life-threatening 
consequences; urgent 
intervention indicated
Hold MLN1117 until 
Hgb ≥9.0 g/dL. Consider 
discontinuation if anemia is 
attributable to the study drugs. If 
multifactorial, restart MLN1117 
at same dose (with a reduced dose 
of TAK-659), or restart at a dose 
reduced by at least 1 level.
Hold TAK-659 until Hgb ≥9.0 g/dL. When 
resolved, consider discontinuation or 
continue at a reduced dose by at least 
1 level.
ANC=absolute neutrophil count, Hgb=hemoglobin, NCI CTCAE=National Cancer Institute Common Terminology 
Criteria for Adverse Events, PLT=platelets.
Table 9.g
Dose Modification Guidelines for Nonhematologic Toxicity for Cohort A 
(MLN1117+TAK-659)
NCI CTCAE
Grade
MLN1117 Dose Modification
TAK-659 Dose Modification 
Hyperglycemia 
Grade 2 
(Fasting glucose value >160 to 
250 mg/dL; fasting glucose 
value >8.9 to 13.9 mmol/L)
Continue MLN1117 at same dose. Refer to 
Section 9.8.2 for guidelines on hyperglycemia 
management. 
Continue TAK-659 at same dose. 
Grade 3 
(>250 to 500 mg/dL; >13.9 to 
27.8 mmol/L; hospitalization 
indicated)
Hold MLN1117 until hyperglycemia ≤Grade 2. 
Optimize antihyperglycemic therapy and 
resume MLN1117 based on timing of recovery.

≤1 week: resume MLN1117 at same dose 
and schedule.

>1 but ≤2 weeks or recurrent with 
antihyperglycemic treatment: reduce 
MLN117 dose to the next lower dose level 
for all subsequent cycles.

>2 weeks: stop MLN1117 and discontinue 
subject from study.
Continue TAK-659 at same dose and schedule. 
Grade 4
(>500 mg/dL; >27.8 mmol/L; 
life-threatening consequences)
Hold MLN1117 until hyperglycemia ≤Grade 2. 

≤1 week: reduce MLN117 dose to the next 
lower dose level for all subsequent cycles.

>1 week: discontinue.
Hold TAK-659 until hyperglycemia improves to 
≤Grade 2; then continue at same dose and 
schedule.
Footnotes are on last table page.


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Table 9.g
Dose Modification Guidelines for Nonhematologic Toxicity for Cohort A 
(MLN1117+TAK-659) (continued)
NCI CTCAE
Grade
MLN1117 Dose Modification
TAK-659 Dose Modification 
Asymptomatic serum lipase 
increase
Grade 3 serum lipase increase 
accompanied by ≥Grade 3 
serum amylase increase; OR 
Grade 4 serum lipase increase
Maintain the same dose/regimen of MLN1117 
if determined to be unrelated.
Hold TAK-659 until resolution to ≤Grade 1, 
baseline, or a level acceptable by the 
investigator (must be ≤Grade 2), then restart 
TAK-659 at a reduced dose by 1 level.
AST/ALT
Grade 3 elevation of single 
enzyme (AST or ALT) in the 
absence of significant bilirubin 
elevation (<Grade 2)
Maintain the dose of MLN1117 with close 
monitoring.
Maintain the dose of TAK-659 with close 
monitoring.
Grade 3 elevation of both AST 
and ALT
Hold MLN1117 until AST and ALT decrease 
to Grade 1. Restart MLN1117 at the same dose 
if resolved within 7 days, or reduce by 1 level if 
resolution is >7 days. If concomitant bilirubin 
elevation >Grade 1 attributable to drug toxicity, 
discontinue treatment.
Hold TAK-659 until AST and ALT decrease to 
Grade 1. Restart TAK-659 at the same dose if 
resolved within 7 days or reduce by 1 level if 
resolution is more than 7 days.
Grade 4 elevation of AST 
and/or ALT
Hold MLN1117 until AST and ALT decrease 
to Grade 1. Restart MLN1117 at a reduced dose 
by 1 level. If concomitant bilirubin elevation 
>Grade 1 attributable to drug toxicity, 
discontinue treatment.
Hold TAK-659 until AST and ALT decrease to 
Grade 1. Restart TAK-659 at a reduced dose by 
1 level.
All other Grade 3 
nonhematologic toxicities with 
the exception of:

Grade 3 nausea, vomiting, 
and diarrhea resolved to 
≤Grade 1 or baseline 
within 1 week with 
optimal antiemetics and 
antidiarrheals following 
SOC.

Transient Grade 3 fatigue 
(lasting <1 week).

Grade 3 rash lasting 
≤7 days with optimal 
treatment. 

Any other Grade 3 
nonhematologic toxicity 
that can be controlled to 
≤Grade 1 or baseline in 
1 week with appropriate 
treatment in 7 days. 
Hold MLN117 if determined to be related to 
MLN1117 until resolution to ≤Grade 1, 
baseline, or a level acceptable by the 
investigator (must be ≤Grade 2). 

If resolved in ≤7 days, then maintain dose 
level.

If resolved in >7 days, then dose reduce by 
1 dose level.

If recurred, then dose reduce by 1 dose 
level.

For the exceptions listed, maintain the 
dose level. 
Permanent discontinuation should be 
considered if the toxicities persist as ≥Grade 3 
for more than 14 days despite temporary 
disruption of study drug.
Hold TAK-659 if determined to be related to 
TAK-659 until resolution to ≤Grade 1, 
baseline, or a level acceptable by the 
investigator (must be ≤Grade 2).

If resolved in ≤7 days, then maintain dose 
level.

If resolved in >7 days, then dose reduce by 
1 dose level.

If recurred, then dose reduce by 1 dose 
level.

For the exceptions listed, maintain the 
dose level. 
Permanent discontinuation should be 
considered if the toxicities persist as ≥Grade 3 
for more than 14 days despite temporary 
disruption of study drug.
Footnotes are on last table page.


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Table 9.g
Dose Modification Guidelines for Nonhematologic Toxicity for Cohort A 
(MLN1117+TAK-659) (continued)
NCI CTCAE
Grade
MLN1117 Dose Modification
TAK-659 Dose Modification 
AST/ALT (continued)
All other Grade 4 
nonhematologic toxicities 
Consider permanently discontinuing MLN1117 
based on causality except when the investigator 
determines that the patient is obtaining clinical 
benefit and has discussed this with the sponsor
project clinician or designee. If the patient is 
not withdrawn from the study, the MLN1117 
dose will be reduced to at least 1 dose level 
lower when toxicity resolves to ≤Grade 1, 
baseline, or a level acceptable by the 
investigator (must be ≤Grade 2).
Consider permanently discontinuing TAK-659 
based on causality except when the investigator 
determines that the patient is obtaining clinical 
benefit and has discussed this with the sponsor. 
If the patient is not withdrawn from the study, 
the TAK-659 dose will be reduced to at least 1 
dose level lower when toxicity resolves to 
≤Grade 1, baseline, or a level acceptable by the 
investigator (must be ≤Grade 2).
ALT=alanine aminotransferase, AST=aspartate aminotransferase, NCI CTCAE=National Cancer Institute Common 
Terminology Criteria for Adverse Events, SOC=system organ class, ULN=upper limit of normal range.
9.4.4
Dose Modification Guidelines for Cohorts B, C, and D 
(MLN1117+Alisertib/Paclitaxel/Docetaxel)
9.4.4.1
Criteria for Beginning or Delaying a Treatment Cycle for Cohort B
Treatment with alisertib and MLN1117 in Cohort B will be repeated every 28 days. Both alisertib 
and MLN1117 will be administered following a 3-days-on and 4-days-off schedule for the first 
3 weeks, and only MLN1117 will be administered in the fourth week of a given cycle. The patient 
must meet the following criteria before starting the next treatment cycle for Cohort B patients:

ANC ≥1500/mm3.

Platelet count ≥100,000/mm3.

All toxicity considered to be related to treatment with MLN1117 or any of the combination 
partners must have resolved to ≤Grade 1, baseline values, or to a level considered acceptable 
by the investigator.

There has been a minimal rest period of 10 days since last dose of alisertib.
If the patient fails to meet the above-cited criteria for retreatment, initiation of the next cycle of 
treatment should be delayed for 1 week. At the end of that time, the patient should be re-evaluated 
to determine whether the criteria for re-treatment have been met. If the patient continues to fail to 
meet the above-cited criteria, therapy should be delayed and re-evaluation continued. Should the 
start of the next cycle be delayed for ≥2 weeks because of incomplete recovery from 
treatment-related toxicity, the dose will be reduced by 1 dose level when therapy resumes. Should 
treatment be delayed for 3 weeks because of incomplete recovery from treatment-related toxicity, 
therapy with alisertib should be discontinued, or dose reduction by more than 1 dose level should 
be considered if, in the investigator’s opinion, therapy still has a reasonable probability of 
providing a benefit.


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9.4.4.2
Retreatment Criteria for Paclitaxel or Docetaxel (Cohort C or D)
Per the prescribing information for paclitaxel and docetaxel, the patient must meet the following 
re-treatment criteria before starting the next dose of paclitaxel (Cohort C) or docetaxel (Cohort D): 

ANC ≥1500/mm3.

Platelet count ≥100,000/mm3.

Total bilirubin <ULN, or ALT and/or AST ≤1.5×ULN concomitant with alkaline phosphatase 
(ALP) ≤2.5×ULN (for docetaxel only).
For patients treated with docetaxel in combination with MLN1117, 1 dose of 75 mg/m2 docetaxel 
is given per 21-day cycle. If a patient fails to meet the docetaxel retreatment criteria, the next cycle 
of docetaxel dosing should be delayed for 1 week while supportive care is given based on the local 
standard practice or as specified in Section 9.8.11. The patient should be re-evaluated after 1 week 
to determine whether the criteria for docetaxel retreatment have been met. If the criteria have not 
been met, further delay of the next cycle of docetaxel and re-evaluation of docetaxel retreatment 
criteria will occur at weekly intervals until all retreatment criteria are satisfied. Dose modification 
guidelines will be followed to determine whether the dose of docetaxel will be maintained or 
reduced when docetaxel dosing is resumed.
For patients treated with MLN1117+paclitaxel, 3 doses of 80 mg/m2 paclitaxel will be given on 
Day 1, Day 8, and Day 15 in 28-day treatment cycles. If the patient fails to meet retreatment 
criteria for paclitaxel before Day 1 dosing in a given cycle, the start of the cycle will be delayed. If 
the retreatment criteria are not met for the Day 8 dosing of paclitaxel, the Day 8 dose will be 
delayed to Day 15 (provided that all retreatment criteria are met on Day 15), and the third dose will 
be withheld so that the cycle will not be further expanded beyond 28 days. If further delay is 
needed, the second and third doses of paclitaxel will be withheld, and paclitaxel will be resumed in 
the next cycle. If the retreatment criteria are not met for the Day 15 dosing of paclitaxel, this third 
dose of paclitaxel within a cycle will be withheld and paclitaxel will be resumed in the next cycle.
Discontinuation of study treatment should be considered if, because of lack of adequate recovery 
of the toxicities, there is a delay of a new cycle (due to Day 1 dosing delay for Cohort C or D) for
≥21 days (≥3 weeks), or a failure to resume the next cycle due to a delay of Day 8 or Day 15 
paclitaxel dosing (for Cohort C only) for ≥21 days (≥3 weeks) after the initial delay. An exception 
may be considered in the case of investigator-determined clinical benefit and discussion with the 
sponsor project clinician (or designee). However, study treatment may be resumed only after these 
retreatment criteria are fully met. If a delay of ≥4 days (≥2 weeks) is required for resolution of 
toxicities before meeting the pretreatment criteria, dose reduction of paclitaxel and docetaxel to 
the next lower level should be considered (Table 9.e). The need for dose reductions below those 
stated in Table 9.e should result in withdrawal of the patient from the study.
If the toxicities that result in failure to meet the paclitaxel or docetaxel retreatment criteria are 
determined to be related to paclitaxel or docetaxel and not to MLN1117, patients should continue 
to receive MLN1117 according to the planned dose and regimen. If in the investigator’s opinion, 
MLN1117 contributes to the toxicities (related or possibly related) that lead to not meeting 


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paclitaxel or docetaxel retreatment criteria, dose delay or modification of MLN1117 should be 
considered per the dose modification guidelines in Section 9.4.4.3.
9.4.4.3
Dose Modification for Hematologic and Nonhematologic Toxicity: MLN1117 and Other 
Combination Agents (Alisertib/Paclitaxel/Docetaxel) 
A decision regarding which study drug requires dose modification will be dependent upon the 
toxicity, its onset, and time course. The causal relationship of any reported events (AEs or SAEs) 
should be assessed by the investigator in relation to MLN1117 and in relation to the combination 
agent (alisertib, paclitaxel, or docetaxel) in Cohort B, C, or D. If multiple toxicities are noted, the 
dose adjustments and/or delays should be made according to the most severe toxicity guidelines 
and the causal relationship to 1 or both study drugs. Guidelines for dose modifications for 
hematologic and nonhematologic toxicity are presented in Table 9.h and Table 9.i, respectively. In 
particular, since the docetaxel retreatment criteria include specific requirements pertaining to liver 
function tests, dose modification guidance for hepatotoxicity is provided specifically for Cohort D 
in Table 9.j. After discussion between the investigator and the sponsor project clinician, 
alternative dose modifications may be recommended to maximize exposure of study treatment 
while protecting patient safety. 
Table 9.h
Dose Modification Guidelines for Hematologic Toxicities for Cohort B 
(MLN1117+Alisertib), Cohort C (MLN1117+Paclitaxel), and 
Cohort D (MLN1117+Docetaxel)
NCI 
CTCAE 
Grade
Description
Dose Modification for 
MLN1117
Dose Modification for Combination 
Agent (a)
Neutropenia 
2 or 3
ANC <1500 to 500/mm3; 
<1.5 to 0.5×109/L
No change. Continue MLN1117 
at same dose and schedule. 
Hold combination agent until 
ANC ≥1500/mm3, then restart at the 
same dose.
4
ANC <500/mm3; 
<0.5×109/L
Hold MLN1117 until 
ANC ≥1500/mm3, then restart 
MLN1117 at same dose and 
schedule. In case of repeat 
occurrence at a reduced dose of 
the combination agent, MLN1117 
or both may be reduced by 1 level.
Hold combination agent until 
ANC ≥1500/mm3, then restart 
combination agent. If resolved in 
≤7 days, maintain the same dose of 
combination agent. If resolved in 
>7 days, reduce dose by 1 level. 
Footnotes are on last table page.


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Table 9.h
Dose Modification Guidelines for Hematologic Toxicities for Cohort B 
(MLN1117+Alisertib), Cohort C (MLN1117+Paclitaxel), and 
Cohort D (MLN1117+Docetaxel) (continued)
NCI 
CTCAE 
Grade
Description
Dose Modification for 
MLN1117
Dose Modification for Combination 
Agent (a)
Neutropenia (continued)
Other
Febrile Neutropenia
ANC <1000/mm3 and fever 
defined as a single 
temperature of >38.3oC 
(101oF) or a sustained 
temperature of ≥38oC 
(100.4oF) for more than 
1 hour); OR
ANC <1000/mm3 with 
systemic infection
Hold MLN1117 until 
ANC ≥1500/mm3 and both fever 
and infection are resolved, then 
restart MLN1117 at same dose 
and schedule. In case of repeat 
occurrence at a reduced dose of 
the combination agent, MLN1117 
may be reduced by 1 level.
Hold combination agent until 
ANC ≥1500/mm3 and both fever and 
infection are resolved, then restart 
combination agent at reduced dose by 
1 level. 
Thrombocytopenia 
1 or 2
PLT 50,000 to 
100,000/mm3; 
<50 to 100×109/L
No change. Continue MLN1117 
at same dose and schedule. 
Hold combination agent until 
PLT ≥100,000/mm3, then restart 
combination agent at the same dose.
3
PLT 25,000 to 
500,000/mm3; 
<25 to 50×109/L
Hold MLN1117 until 
PLT ≥100,000/mm3 or baseline; 
restart MLN1117 at same dose 
and schedule.
Hold combination agent until 
PLT ≥100,000/mm3. If resolved in 
≤7 days, maintain the same dose of 
combination agent. If resolved in 
>7 days, reduce dose by 1 level. Please 
see Table 9.e.
4
PLT <25,000/mm3; 
<25×109/L
Hold MLN1117 until 
PLT ≥100,000/mm3 or baseline; 
restart MLN1117 at same dose. In 
case of recurrence at a reduced 
dose of the combination agent, 
MLN1117 may be reduced by 
1 level.
Hold combination agent until 
PLT ≥100,000/mm3 or baseline. When 
resolved, reduce dose by 1 level.
Footnotes are on last table page.


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Table 9.h
Dose Modification Guidelines for Hematologic Toxicities for Cohort B 
(MLN1117+Alisertib), Cohort C (MLN1117+Paclitaxel), and 
Cohort D (MLN1117+Docetaxel) (continued)
NCI 
CTCAE 
Grade
Description
Dose Modification for 
MLN1117
Dose Modification for Combination 
Agent (a)
Thrombocytopenia (continued)
Other
PLT <10,000 cells/mm3;
OR
clinically significant 
bleeding
Consider permanently 
discontinuing MLN1117, except 
when the investigator determines 
that the patient is obtaining 
clinical benefit and has discussed 
this with the sponsor. If the patient 
is not withdrawn from the study, 
the MLN1117 dose will be 
reduced to at least 1 dose level 
lower when PLT ≥100,000/mm3
and/or clinically significant 
bleeding are completely resolved. 
See Table 9.e for dose 
modification guidelines.
Consider permanently discontinuing the 
combination agent, except when the 
investigator determines that the patient is 
obtaining a clinical benefit and the 
investigator has discussed this with the 
sponsor. If the combination agent is not 
discontinued, then the combination agent 
dose will be reduced to at least 1 dose 
level lower when PLT ≥100,000/mm3
and/or clinically significant bleeding are 
completely resolved. 
Anemia 
3
Hgb <8.0 g/dL not due to 
bleeding; transfusion 
indicated
Hold MLN1117 until 
Hgb ≥9.0 g/dL or baseline; restart 
MLN1117 at same dose. In case of 
repeat occurrence at a reduced 
dose of the combination agent, 
MLN1117 may be reduced by 
1 level.
Hold combination agent until Hgb 
≥9.0 g/dL. If resolved in ≤7 days, 
maintain the same dose of combination 
agent. If resolved in >7 days, reduce dose 
by 1 level.
4
Life-threatening 
consequences; urgent 
intervention indicated
Hold MLN1117 until 
Hgb ≥9.0 g/dL or baseline; restart 
MLN1117 at same dose with a 
reduced dose of combination 
agent or at a reduced dose by at 
least 1 level or consider 
discontinuation.
Hold combination agent until Hgb
≥9.0 g/dL. When resolved, reduce dose 
by at least 1 level or consider 
discontinuation. 
ANC=absolute neutrophil count, Hgb=hemoglobin, NCI CTCAE=National Cancer Institute Common Terminology 
Criteria for Adverse Events, PLT=platelets.
(a) Combination agent is alisertib (Cohort B), paclitaxel (Cohort C), or docetaxel (Cohort D).


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Table 9.i
Dose Modification Guidelines for Nonhematologic Toxicity for Cohort B 
(MLN1117+Alisertib), Cohort C (MLN1117+Paclitaxel), and Cohort D 
(MLN1117+Docetaxel)
NCI CTCAE
Grade
MLN1117 Dose Modification
Combination agent dose modification 
(a) 
Hyperglycemia
Grade 2 
(Fasting glucose value >160 to 
250 mg/dL; fasting glucose 
value >8.9 to 13.9 mmol/L)
Continue MLN1117 at same dose and 
schedule. Refer to Section 9.8.2 for 
guidelines on hyperglycemia management.
Continue combination agent at same 
dose and schedule. Refer to 
Section 9.8.2 for guidelines on 
hyperglycemia management.
Grade 3 
(>250 to 500 mg/dL; >13.9 to 
27.8 mmol/L; hospitalization 
indicated)
Hold MLN1117 until 
hyperglycemia ≤Grade 2. 
Optimize antihyperglycemic therapy and 
resume MLN1117 based on timing of 
recovery.

≤1 week: resume MLN1117 at same 
dose and schedule.

>1 but ≤2 weeks or recurrent with 
antihyperglycemic treatment: reduce 
MLN117 dose to the next lower dose 
level for all subsequent cycles.

>2 weeks: stop MLN1117 and 
withdraw subject from study.
Continue combination agent at same 
dose and schedule. 
Grade 4
(>500 mg/dL; >27.8 mmol/L; 
life-threatening consequences)
Hold MLN1117 until 
hyperglycemia ≤Grade 2. 

≤1 week: reduce MLN117 dose to the 
next lower dose level for all 
subsequent cycles.

>1 week: discontinue.
Hold combination agent until 
hyperglycemia ≤Grade 2. Continue 
combination agent at same dose and 
schedule.
Footnotes are on last table page.


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Table 9.i
Dose Modification Guidelines for Nonhematologic Toxicity for Cohort B 
(MLN1117+Alisertib), Cohort C (MLN1117+Paclitaxel), and Cohort D 
(MLN1117+Docetaxel) (continued)
NCI CTCAE
Grade
MLN1117 Dose Modification
Combination agent dose modification 
(a) 
AST/ALT (b)
Grade 3 elevation of single 
enzyme (AST or ALT) in the 
absence of significant bilirubin 
elevation (<Grade 2)
Maintain the dose of MLN1117 with close 
monitoring.
Maintain the dose of the combination 
agent with close monitoring.
Grade 3 elevation of both AST 
and ALT
Hold MLN1117 until AST and ALT return 
to Grade 1. Restart MLN1117 at the same 
dose if resolved within 7 days or reduce by 
1 level if resolution is more than 7 days. If 
concomitant bilirubin elevation >Grade 1 
is attributable to drug toxicity, discontinue 
treatment.
Hold combination agent until AST and 
ALT return to Grade 1. Restart the 
combination agent at the same dose if 
resolved within 7 days or reduce by 
1 level if resolution is more than 7 days. 
If concomitant bilirubin elevation 
>Grade 1 is attributable to drug toxicity, 
discontinue treatment.
Grade 4 elevation of AST 
and/or ALT
Hold MLN1117 until AST and ALT return 
to Grade 1. Restart MLN1117 at a reduced 
dose by 1 level. If concomitant bilirubin 
elevation >Grade 1 is attributable to drug 
toxicity, discontinue treatment.
Hold the combination agent until AST 
and ALT <2.5×ULN. Restart 
combination agent at a reduced dose by 
1 level. If concomitant bilirubin 
elevation >Grade 1 is attributable to 
drug toxicity, discontinue treatment.
Stomatitis
Grade 2
Maintain MLN1117 if tolerated by the 
patient. Hold MLN1117 if not tolerated by 
the patient until recovery to ≤Grade 1, then 
restart at same dose.
Maintain combination agent if tolerated 
by the patient. Hold combination agent 
if not tolerated by the patient until 
recovery to ≤Grade 1, then restart at 
same dose.
Grade 3
Hold MLN1117 if not tolerated by the 
patient until recovery to ≤Grade 1, then 
restart at same dose. If after dose delay of 
the combination agent and provision of 
standard care for 7 days, the stomatitis has 
not resolved, dose reduction of MLN1117 
should be considered, initially by 1 dose 
level.
Hold combination agent until recovery 
to ≤Grade 1, then restart at a dose 
reduced by 1 level.
Grade 4
Discontinue MLN1117 and withdraw 
patient from the study.
Discontinue combination agent and 
withdraw patient from the study.
Footnotes are on last table page.


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Table 9.i
Dose Modification Guidelines for Nonhematologic Toxicity for Cohort B 
(MLN1117+Alisertib), Cohort C (MLN1117+Paclitaxel), and Cohort D 
(MLN1117+Docetaxel) (continued)
NCI CTCAE
Grade
MLN1117 Dose Modification
Combination agent dose modification 
(a) 
Other Nonhematologic 
Toxicities
Peripheral neuropathy
≥Grade 3
Maintain the same dose/regimen of 
MLN1117 if determined to be unrelated.
Permanently discontinue combination 
agent.
All other ≥Grade 3 
nonhematologic toxicities with 
the exception of:

Grade 3 nausea, vomiting, 
and diarrhea resolved to 
≤Grade 1 or baseline 
within 1 week with 
optimal antiemetics and 
antidiarrheals following 
standard of care

Transient Grade 3 fatigue 
(lasting <1 week)

Grade 3 rash lasting 
≤7 days with optimal 
treatment 

Any other Grade 3 
nonhematologic toxicity 
that can be controlled to 
≤Grade 1 or baseline in 
1 week with appropriate 
treatment in 7 days 
Hold MLN117 if determined to be related 
to MLN1117 until resolution to ≤Grade 1, 
baseline, or a level acceptable by the 
investigator (must be ≤Grade 2): 

If resolved in ≤7 days, then maintain 
dose level.

If resolved in >7 days, then reduce 
dose by 1 dose level.

If recurs, then reduce dose by 1 dose 
level.

For the exceptions listed, maintain the 
dose level. 
Permanent discontinuation should be 
considered if the toxicities persist as 
≥Grade 3 for more than 14 days despite 
temporary disruption of study drug.
Hold combination agent if determined to 
be related to docetaxel until resolution to 
≤Grade 1, baseline, or a level acceptable 
by the investigator (must be ≤Grade 2): 

If resolved in ≤7 days, then 
maintain dose level.

If resolved in >7 days, then dose 
reduce by 1 dose level.

If recurs, then reduce dose by 
1 dose level.

For the exceptions listed, maintain 
the dose level. 
Permanent discontinuation should be 
considered if the toxicities persist as 
≥Grade 3 for more than 14 days despite 
temporary disruption of study drug.
Footnotes are on last table page.


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Table 9.i
Dose Modification Guidelines for Nonhematologic Toxicity for Cohort B 
(MLN1117+Alisertib), Cohort C (MLN1117+Paclitaxel), and Cohort D 
(MLN1117+Docetaxel) (continued)
NCI CTCAE
Grade
MLN1117 Dose Modification
Combination agent dose modification 
(a) 
All other Grade 4 
nonhematologic toxicities 
Consider permanently discontinuing 
MLN1117 based on causality, except when 
the investigator determines that the patient 
is obtaining clinical benefit and has 
discussed this with the sponsor. If the 
patient’s treatment is not discontinued, the 
MLN1117 dose will be reduced to at least 
1 dose level lower when toxicity resolves 
to ≤Grade 1, baseline, or a level acceptable 
by the investigator (must be ≤Grade 2).
Consider permanently discontinuing 
combination agent based on causality, 
except when the investigator determines 
that the patient is obtaining a clinical 
benefit and has discussed this with the 
project clinician or designee. If the 
patient’s treatment is not discontinued, 
the combination agent dose will be 
reduced to at least 1 dose level lower 
when toxicity resolves to ≤Grade 1, 
baseline, or a level acceptable by the 
investigator (must be ≤Grade 2).
ALT=alanine aminotransferase, AST=aspartate aminotransferase, NCI CTCAE=National Cancer Institute Common 
Terminology Criteria for Adverse Events, ULN=upper limit of normal range.
(a) Combination agent is alisertib (Cohort B), paclitaxel (Cohort C), or docetaxel (Cohort D).
(b) For Cohorts B and C only; please refer to Table 9.j for Cohort D.
Dose modification guidelines for managing abnormal liver function tests (LFTs) or hepatotoxicity 
are provided in Table 9.j for Cohort D, in concert with the docetaxel retreatment criteria per 
docetaxel label.


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Table 9.j
Dose Modification Guidelines for Abnormal Liver Function Tests or 
Hepatotoxicity for Cohort D (MLN1117+Docetaxel)
NCI 
CTCAE 
Grade
Description
Dose Modifications for MLN1117 
Dose Modifications for Docetaxel
ALT and/or 
AST >2.5 to 
5×ULN and ALP 
≤2.5×ULN, or 
AST/ALT >1.5 to 
≤5×ULN and ALP 
>2.5 to ≤5×ULN

When ALP >2.5×ULN together with 
bilirubin <ULN, hold MLN1117 
until both ALT and AST ≤1.5×ULN 

When ALP <2.5×ULN together with 
bilirubin <ULN, hold MLN1117 
until both ALT and AST <2.5×ULN.
Then resume study drug at the same dose 
and schedule.
Reduce docetaxel by 1 dose level for the 
next cycle.
ALT and/or AST 
and/or ALP >5 to 
≤20×ULN

When ALP >2.5×ULN together with 
bilirubin <ULN, hold MLN1117 
until both ALT and AST ≤1.5×ULN

When ALP <2.5×ULN together with 
bilirubin <ULN, hold MLN1117 
until both ALT and AST <2.5×ULN.
If resolved <7 days, resume study drug at 
the same dose and schedule.
If resolved >7 days, reduce study drug by 
1 dose level (first occurrence) and by 
2 dose levels (repeat occurrence). 
Discontinue if bilirubin >Grade 1.
Discontinue docetaxel permanently.
4
ALT and/or 
AST >20ULN

When ALP >2.5×ULN together with 
bilirubin <ULN, hold MLN1117 
until both ALT and AST ≤1.5×ULN; 
OR

When ALP <2.5×ULN together with 
bilirubin <ULN, hold MLN1117 
until both ALT and AST <2.5×ULN.
When resolved, reduce study drug by 
2 dose levels. Discontinue if bilirubin 
>Grade 1.
Discontinue docetaxel permanently.
ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, NCI CTCAE=National 
Cancer Institute Common Terminology Criteria for Adverse Events, ULN=upper limit of the normal range.
9.5
Excluded Concomitant Medications and Procedures
Medications and procedures in the following subsections are prohibited during the study.
9.5.1
Excluded Concomitant Medications Applicable to All Cohorts (Cohorts A-D)

Use of other investigational medicinal products or devices.


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
Other antineoplastic therapy, including chemotherapy, immunotherapy, targeted agents, and 
radiation or surgery (patients can have palliative radiation or surgery during the study for 
pre-existing lesions upon discussion with the sponsor project clinician).

Daily, chronic, or regular use of any proton pump inhibitors (such as omeprazole, 
esomeprazole, lansoprazole, pantoprazole) is prohibited in all cohorts. Patients may be given 
alternative agents to manage gastric acidity or reflux (eg, histamine-2 [H2]-receptor 
antagonists or antacids) according to the guidelines described in Section 9.6.2.

Strong inhibitors/inducers of CYP3A are prohibited in all cohorts. Examples of strong CYP3A 
inhibitors/inducers are provided in Appendix F.
9.5.2
Excluded Concomitant Medications Applicable to a Specific Cohort

Cohort A (MLN1117+TAK-659): Inhibitors/inducers of P-gp are prohibited. Examples of 
P-gp inhibitors/inducers are provided in Appendix G.

Cohort B (MLN1117+alisertib): Although not prohibited, the use of benzodiazepines for the 
prophylaxis or treatment of nausea or vomiting is discouraged because of the potential 
benzodiazepine-like effects of alisertib.

Cohort C (MLN1117+paclitaxel): Please refer to the most recent paclitaxel USPI or SmPC for 
information on medications that are prohibited in patients receiving paclitaxel. 

Cohort D (MLN1117+docetaxel): Please refer to the most recent docetaxel USPI or SmPC for 
information on medications that are prohibited in patients receiving docetaxel.
9.6
Permitted Concomitant Medications and Procedures
9.6.1
Paclitaxel or Docetaxel Premedication for Cohorts C or D
Premedication before and/or concomitant with paclitaxel or docetaxel, including corticosteroids 
and antiemetics, will be administered in accordance with the recommendations in the paclitaxel 
(Cohort C) or docetaxel (Cohort D) prescribing information. Appropriate institutional practices 
consistent with paclitaxel or docetaxel label and recommendation should be followed. 
All patients receiving docetaxel should be premedicated with corticosteroids to reduce the 
incidence and severity of fluid retention and/or hypersensitivity reaction. For example, 
dexamethasone 16 mg per day (eg, 8 mg BID) may be used for 3 days starting 1 day before 
docetaxel when docetaxel is administered every 3 weeks. When paclitaxel is administered weekly, 
premedication to prevent paclitaxel-associated hypersensitivity reactions may include 
corticosteroid (eg, high-dose dexamethasone as a 20-mg single dose administered 6 to 12 hours 
before paclitaxel treatment, which can be reduced with subsequent paclitaxel cycles), 
diphenhydramine, and an H2-receptor antagonist (eg, cimetidine or ranitidine). Only brief 
administration of a H2-receptor antagonist (eg, single dose of cimetidine or ranitidine) is allowed if 
required on the day of paclitaxel administration, but prolonged administration of a H2-receptor


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antagonist (or any other agents that can alter stomach pH or drug absorption) is to be avoided 
(see Section 9.5). 
Other premedications including, but not limited to, 5-hydroxytryptamine (5-HT3) antiemetics may 
be administered per the local standard of care on the day of paclitaxel or docetaxel administration.
9.6.2
Histamine-2 Receptor Antagonists and Neutralizing Antacids

Restricted use of H2-receptor antagonists (such as ranitidine, famotidine, cimetidine, and 
nizatidine) is permitted during the treatment cycle days listed by cohort below. However, the 
timing after the previous MLN1117 dose (6 hours) or before the next MLN1117 dose 
(24 hours) must be strictly followed.
–
Cohort A (MLN1117+TAK-659) and Cohort B (MLN1117+alisertib): Treatment with an 
H2-receptor antagonist is permitted if it is administered at least 6 hours after administration 
of MLN1117 and 24 hours before the next scheduled dose of MLN1117. Patients are thus 
allowed to take an H2-receptor antagonist on Days 4, 5, 6, 7, 11, 12, 13, 14, 18, 19, 20, 21, 
25, 26, 27, and 28 of each cycle.
–
Cohort C (MLN1117+paclitaxel): Treatment with an H2-receptor antagonist is permitted if 
it is administered at least 6 hours after administration of MLN1117 and 24 hours before the 
next scheduled dose of MLN1117. Treatment with an H2-receptor antagonist is allowed on 
Days 1, 8, and 15 if required to prevent hypersensitivity reactions associated with 
paclitaxel administration. Should treatment with an H2-receptor antagonist be warranted 
for paclitaxel premedication, the timing of MLN1117 administration must be adjusted 
accordingly on Days 2, 9, and 16. Patients are also allowed to take an H2-receptor 
antagonist on Days 5, 6, 7, 12, 13, 14, 19, 20, 21, 26, 27, and 28 of each cycle.
–
Cohort D (MLN1117+docetaxel): Treatment with an H2-receptor antagonist is permitted if 
it is administered at least 6 hours after administration of MLN1117 and 24 hours before the 
next scheduled dose of MLN1117. Treatment with an H2-receptor antagonist is allowed on 
Day 1 if required to prevent hypersensitivity reactions associated with docetaxel 
administration. Should treatment with an H2-receptor antagonist be warranted for 
docetaxel premedication, the timing of MLN1117 administration must be adjusted 
accordingly on Day 2. Patients are also allowed to take an H2-receptor antagonist on 
Days 5, 6, 7, 8, 12, 13, 14, 15, 19, 20, and 21 of each cycle.

Neutralizing antacids, such as Maalox Max (magnesium and aluminum hydroxide) and Tums 
(calcium carbonate), antigas preparations, and calcium supplements are not permitted from 
2 hours before and within 6 hours after study drug administration on MLN1117 dosing days, 
and as needed on non-dosing days.
9.6.3
Additional Concomitant Medications and Procedures

Oral contraceptive agents or any other type of hormonal contraception are permitted.


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
Additional concomitant medications and procedures are permitted during the course of the 
study (please refer to Section 9.6) to prevent and/or actively manage AEs related or not related 
to the study drug(s) unless prohibited (Section 9.5) as specified in the protocol.
9.7
Precautions and Restrictions
Patients who show evidence of hyperglycemia during the study should be encouraged to follow a 
low carbohydrate diet, limit alcohol intake, and increase physical activity and exercise. No dietary 
restriction is required other than avoiding food or beverages containing grapefruit or juice from the 
grapefruit within 7 days before the first dose of study drug treatment and throughout the study 
(see Section 9.5).
It is not known what effects MLN1117 has on human pregnancy, mother’s milk, or development 
of the embryo or fetus when administered in combination with TAK-659, alisertib, paclitaxel, or 
docetaxel. Therefore, female patients participating in this study should avoid becoming pregnant, 
breastfeeding a baby, or donating eggs (ova) while on this study and for 30 days (180 days for 
TAK-659), or longer for docetaxel and paclitaxel as mandated by local labeling, after receiving 
their last dose of study drug. Male patients should avoid impregnating a female partner or donating 
sperm while on this study and for 120 days (180 days for TAK-659), or longer for docetaxel and 
paclitaxel as mandated by local labeling, after receiving their last dose of study drug. Nonsterilized 
female patients of reproductive age and male patients should use effective methods of 
contraception through defined periods during and after study treatment as specified below.
Female patients must meet 1 of the following:

Postmenopausal for at least 1 year before the screening visit, OR

Surgically sterile, OR

If they are of childbearing potential, agree to practice 1 highly effective method (see 
Appendix E) and 1 additional effective (barrier) method of contraception at the same time, 
from the time of signing of the informed consent form through 30 days after the last dose of 
study drug (with the exception of those subjects assigned to TAK-659, for whom the duration 
required is 180 days), or for as long as mandated by local labeling for docetaxel and paclitaxel, 
OR

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of 
the subject, from the time of signing the informed consent form through 30 days after the last 
dose of study drug (with the exception of those subjects assigned to TAK-659, for whom the 
duration required is 180 days), or for as long as mandated by local labeling for docetaxel and 
paclitaxel. (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.)


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Male patients, even if surgically sterilized (ie, status postvasectomy) must agree to 1 of the 
following:

Practice effective barrier contraception during the entire study treatment period and through 
120 days after the last dose of study drug (with the exception of those subjects assigned to 
TAK-659, for whom the duration required is 180 days), or for as long as mandated by local 
labeling for docetaxel and paclitaxel, OR

Practice true abstinence, when this is in line with the preferred and usual lifestyle of the 
subject, during the entire study treatment period and through 120 days after the last dose of 
study drug (with the exception of those subjects assigned to TAK-659, for whom the duration 
required is 180 days), or for as long as mandated by local labeling for docetaxel and paclitaxel. 
(Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods for the 
female partner] and withdrawal are not acceptable methods of contraception.)
9.8
Management of Clinical Events
Therapies that are required to manage AEs and control cancer symptoms are allowed based on 
standard clinical practice, unless specifically excluded.
Supportive care agents, such as blood products, antiemetics, and pain medications are permitted as 
needed per American Society of Oncology (ASCO) guidelines or local institutional practices. 
However, these agents should not be used in this study in a manner that would either help establish 
eligibility for the study or support escalation of study drug dose during dose escalation.
9.8.1
Hematologic Events
A complete blood count (CBC) should be monitored regularly as outlined in the Schedules of 
Events (SOEs) (Appendix A) for each cohort with additional testing obtained according to 
standard clinical practice. Transfusion of blood products (such as packed red blood cell [RBC] and 
platelets) and use of myeloid growth factors (eg, granulocyte colony stimulating factor [G-CSF] or
granulocyte macrophage colony stimulating factor [GM-CSF]) are permitted as necessary and per 
local institutional practice or ASCO guidelines. In general, RBC transfusion is recommended for 
all symptomatic patients with anemia or any asymptomatic patients with a hemoglobin <8 g/dL 
with the purpose of maintaining the hemoglobin between 8 and 10 g/dL. Platelet transfusion 
should be given prophylactically to patients with platelet counts <10,000 cells/mm3 or to any 
patients with signs of overt bleeding, such as oral purpura. Each transfusion episode, including the 
type of transfusion (RBC and/or platelet), should be recorded.
9.8.2
Hyperglycemia
Hyperglycemia or elevated fasting blood glucose levels have been observed following MLN1117 
administration. It may be noted that patients in Cohorts C and D will be more prone to developing 
hyperglycemia due to premedication with corticosteroids in order to prevent hypersensitivity 
and/or other reactions associated with paclitaxel or docetaxel administration.


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All patients developing hyperglycemia during the study should have their glucose closely 
monitored by study staff. It is not necessary to treat patients with transient Grade 1 or 2 
hyperglycemia. It is important to check if blood glucose levels return to normal values during the 
off-drug days in patients with hyperglycemia on days of MLN1117 administration. Metformin is 
the first-line drug of choice for sustained Grade 1, Grade 2, and asymptomatic Grade 3 
hyperglycemia. Metformin does not cause hypoglycemia which is important to take into account 
as MLN1117 is administered with a 3-day-on 4-day-off schedule, and there is potential for 
variations in glycemic values between on-treatment and off-treatment days. The investigator may 
choose to continue close monitoring of patients who develop Grade 1 hyperglycemia (fasting 
glucose level above the ULN but ≤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. Metformin is contraindicated in patients with risk factors for lactic
acidosis (glomerular filtration rate <60 mL/minute, liver impairment, sepsis). Patients can be 
initially treated with metformin at 500 mg PO QD and titration up to a maximum of 1000 mg PO 
BID as needed. Concurrent DPP-4 inhibitors (eg, sitagliptin or vildagliptin) and/or insulin should 
also be considered in addition to metformin. Oral sulfonylureas (eg, glipizide or glyburide) should 
be used with caution due to the higher risk of inducing hypoglycemia in patients. The investigator 
should consult an endocrinologist, if needed, to aid in optimizing the patient’s hyperglycemia 
treatment plan.
All patients developing hyperglycemia during the study should be encouraged to adopt lifestyle 
modifications, such as balanced diet including limited consumption of carbohydrates and alcohol, 
and increased physical activity and exercise. Table 9.k summarizes the guidance for management 
of and study drug dose modification for patients with hyperglycemia.


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Table 9.k
Management of Hyperglycemia
Grade
Description
Treatment
MLN1117 Dose Modifications (a)
1
Fasting blood sugar 
>ULN to 160 mg/dL

Start once-per-day home glucose 
monitoring.

Therapeutic lifestyle changes 
(TLC).

Consider initiation of oral 
hypoglycemic agent.
None
2
>160 to 250 mg/dL

Start twice-per-day home glucose 
monitoring.

TLC

Initiate metformin and/or insulin if 
not well controlled on oral agent. 
Add basal insulin if not controlled 
after 1 week.
None
≥3
>250 mg/dL

Start home glucose monitoring 
before breakfast and dinner.

TLC

Initiate metformin with rapid 
titration and/or insulin.

If symptomatic and/or 
hypovolemic, consider hospital 
admission for intravenous fluids, 
diabetic consultation, and 
4-injection basal bolus insulin 
injection.
Hold MLN1117 until ≤Grade 2. Resume 
study drug based on timing of recovery 
after maximal treatment:

≤1 week: resume study drug at same 
dose and schedule.

>1 but ≤2 weeks: reduce study drug 
by 1 dose level

>2 but ≤3 weeks: reduce study drug 
by 2 dose levels.

>3 weeks: withdraw patient from 
the study.

Please see Table 9.e for dose 
modification guidelines.
Prevention/Prophylaxis:

Follow fasting glucose levels during clinic visits.

Monitor home glucometer test results.

Check HbA1c levels every 3 months during therapy.

Fasting blood glucose levels ≥160 mg/dL by glucometer should be followed by closer monitoring of serum 
glucose and possible intervention.

Most episodes of Grade 1 to 2 hyperglycemia respond quickly to oral metformin. Early initiation of therapy at the 
lowest therapeutic dose is recommended to prevent higher grade hyperglycemia.

Therapeutic lifestyle changes: a low carbohydrate diet, limited alcohol consumption, increased physical activity.
HbA1c=glycosylated hemoglobin, ULN=upper limit of the normal range.
(a) For additional details, please refer to Table 9.e.


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9.8.3
Nausea and Vomiting
This study allows prophylactic use of antiemetic and antinausea medications as clinically 
indicated according to the institutional standard of care. These may be administered before each 
dose of the study drugs as needed throughout the study, except before Cycle 1 Day 1 of Part 1 
(dose escalation) when prophylactic antiemetics can be used only after nausea and vomiting have 
been observed. In addition, a patient who develops nausea and/or vomiting will be actively 
managed by employing optimal antiemetic treatment based on local standard practice. An optimal 
antiemetic regimen is defined as one that employs both a 5-HT3 antagonist and a corticosteroid 
given in standard doses and according to standard schedules.
9.8.4
Diarrhea
Prophylactic antidiarrheals will not be used in this study; however, patients should be instructed to 
take loperamide or comparable antidiarrheal medication according to institutional or local 
practice, once infectious causes are ruled out. Adequate fluid intake should be maintained to avoid 
dehydration, and any fluid deficit should be corrected before initiation of treatment with study 
drugs and during treatment.
9.8.5
Stomatitis/Oral Mucositis
Pooled data across the alisertib single-agent studies reported stomatitis (31%) as 1 of the most 
common TEAEs. Oral mucositis is also 1 of the common AEs observed in patients treated with 
paclitaxel or docetaxel. Please refer to the most recent paclitaxel or docetaxel USPI or SmPC for 
more information for the management of oral mucositis. Guidance for the management of patients 
who develop oral mucositis is provided in Table 9.i. Prevention or prophylaxis of oral mucositis 
may include initiation of a nonalcoholic mouthwash or 0.9% salt water rinses 4 to 6 times daily 
with start of therapy before signs of mucositis develop. Mouth washes or rinses may be used to 
treat patients with Grade 1 oral mucositis, and topical steroids may be considered with observation 
of the earliest signs of mucositis. Patients with ≥Grade 2 oral mucositis may be treated with topical 
analgesic mouth treatments, topical corticosteroids, and antiviral or antifungal therapy if indicated. 
Intralesional corticosteroids may be considered for Grades 3 and 4 lesions. Agents containing 
hydrogen peroxide, iodine, and thyme derivatives should be avoided in the management of 
patients with oral mucositis as these agents may worsen mouth ulcers.
9.8.6
Rash
Prophylactic measures should be considered if a patient develops a rash (eg, using a thick, 
alcohol-free emollient cream on dry areas of the body). In the case of ≤Grade 2 rash, treatment 
with a topical steroid cream/ointment and/or oral antihistamines or antibiotics may be considered. 
Patients with rash ≥Grade 3 should be managed aggressively (topical steroid cream/ointment, oral 
antihistamines, oral antibiotics, and/or pulsed corticosteroids). The investigator should consider 
consulting a dermatologist or other specialist if needed. A skin biopsy at the site of the rash is 
highly recommended to ascertain the etiology and histology of the rash. Refer to Table 9.g and 
Table 9.i for dose modification guidelines.


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9.8.7
Asthenia, Weakness, and Fatigue
The management of patients with asthenia, weakness, and fatigue includes initiation of appropriate 
medical therapy and monitoring. If Grade 1 or Grade 2 toxicity is tolerated by the patient, then no 
adjustment of study drugs (MLN1117 in combination with TAK-659, alisertib, paclitaxel, or 
docetaxel) is required. If study drugs are to be held, then both agents should be held for the patient 
in that combination drug cohort. If Grade 2 toxicity is not tolerated by the patient, hold study drugs
until recovery to ≤Grade 1, then reinitiate at same dose. For ≥Grade 3 toxicity, hold study drugs
until recovery to ≤Grade 1. Reinitiate study drug(s) at a reduced dose by 1 level (first occurrence) 
and by 2 levels (repeat occurrence). Please refer to Table 9.e for dose level guidelines.
9.8.8
Elevated Serum Lipase (Cohort A)
Elevated levels of serum lipase, without any clinical symptoms, have been reported in patients 
treated with TAK-659. Dose modification will not be required for any Grade 1 or 2 elevation of
serum lipase (≤2.0×ULN). Dose modifications will be considered in accordance with Table 9.g
and in consultation with the investigator and sponsor clinician (or designee), if there is Grade 3 or 
4 elevation of serum lipase (>2.0×ULN) or if any elevated serum lipase is also presented with 
related clinical symptoms.
9.8.9
Central Nervous System Effects (Cohort B)
Alisertib-treated patients may experience excessive sedation. If sedation is believed to be related 
to alisertib, treatment with alisertib should be interrupted. Patients whose sedation is not 
considered immediately life-threatening should be carefully monitored and given appropriate 
supportive care. Dose modifications will also be considered in accordance with Table 9.i and in 
consultation with the investigator and sponsor project clinician (or designee).
9.8.10 Paclitaxel-Related Clinical Events (Cohort C)
Please refer to the most recent paclitaxel USPI or SmPC for more information on paclitaxel-related 
clinical events, such as conduction abnormalities, hypertension, peripheral neuropathy, etc; and 
for the management of clinical events in patients receiving paclitaxel.
9.8.11 Docetaxel-Related Clinical Events (Cohort D)
Please refer to the most recent docetaxel USPI or SmPC for more information on docetaxel-related 
clinical events, such as fluid retention, cystoid macular edema, peripheral neuropathy, etc; and for 
the management of clinical events in patients receiving docetaxel.
9.9
Blinding and Unblinding
This is an open-label study.


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9.10
Description of Investigational Agents
9.10.1 MLN1117
MLN1117 will be supplied as tablets for PO administration, and will be available in the following 
2 dose strengths:

MLN1117 100 mg tablets.

MLN1117 300 mg tablets.
MLN1117 tablets have been developed as an immediate-release formulation for PO 
administration. The drug product formulation consists of a mixture of MLN1117, microcrystalline 
cellulose, low substituted hydroxypropyl cellulose, sodium croscarmellose, colloidal silicon 
dioxide, and magnesium stearate.
9.10.2 TAK-659
TAK-659 has been formulated into immediate-release film-coated tablets for use in clinical 
studies via a common granulation process. Three different tablet dosage strengths, 20, 60, and 
100 mg, were formulated. The formulation contains compendial excipients that include mannitol, 
microcrystalline cellulose, hydroxypropyl cellulose, sodium starch glycolate, and magnesium 
stearate. Tablets were coated with Opadry film coat.
9.10.3 Alisertib
An enteric-coated tablet (ECT) dosage form of alisertib has been developed for use in clinical 
studies. One ECT dosage strength, 10 mg, expressed as alisertib free acid, has been formulated. 
The key formulation excipients that aid in the in vivo absorption of the drug are the buffer (sodium 
bicarbonate), the surfactant (sodium lauryl sulfate), and the enteric coating. The other formulation 
excipients such as binder (povidone), filler (microcrystalline cellulose), disintegrant 
(croscarmellose sodium), and lubricant (sodium stearyl fumarate) serve as manufacturing aids. 
Refer to the IB for full details.
9.10.4 Paclitaxel and Docetaxel
Docetaxel and paclitaxel both are commercially available drugs administered IV.
Please refer to the current version of the MLN1117, TAK-659, and alisertib IBs, and the USPI or 
SmPC for docetaxel and paclitaxel for full details.
9.11
Preparation, Reconstitution, and Dispensation
MLN1117, TAK-659, alisertib, paclitaxel, and docetaxel are anticancer drugs, and as with other 
potentially toxic compounds, caution should be exercised when handling these drugs.


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9.11.1 MLN1117
MLN117 will be provided in 14-count 30-cc high-density polypropylene (HDPE), with 
child-resistant caps and induction seals. MLN1117 bottles are to be dispensed according to the site 
procedures, and according to instruction and guidelines provided in the study Pharmacy Manual, 
including the requirement that tablets are stored in their original containers. Materials provided by 
the sponsor should be dispensed to patients with clear administration instructions from the 
investigator.
9.11.2 TAK-659
Detailed instructions for the dispensing of TAK-659 immediate-release film-coated tablets are 
provided in the Pharmacy Manual. TAK-659 is an anticancer drug, and as with other potentially 
toxic compounds, caution should be exercised when handling TAK-659.
9.11.3 Alisertib
The study drug alisertib will be provided by Takeda. Alisertib ECTs are packaged (10 tablets per 
bottle) in a 60-cc, HDPE bottle with a rayon coil, induction seal, desiccant packs, and a 
polypropylene child-resistant cap. Alisertib is an anticancer drug, and as with other potentially 
toxic compounds, caution should be exercised when handling alisertib.
9.11.4 Paclitaxel and Docetaxel
Parenteral drug products should be inspected visually for particulate matter and discoloration prior 
to administration, whenever solution and container permit.
9.12
Packaging and Labeling
9.12.1 MLN1117
MLN1117 will be handled at the investigative site as open-label material. MLN1117 tablets will
be provided in 14-count, 30-cc HDPE bottles, with child-resistant caps and induction seal. For 
both dose strengths, each bottle contains 14 tablets and will have a label containing pertinent study 
information, country-specific requirements, and a caution statement.
9.12.2 TAK-659
TAK-659 in 20-, 60- and 100-mg tablets will be packaged into round, white, HDPE bottles with 
induction seal, desiccant pack, and polypropylene child-resistant caps. Each bottle of TAK-659 
will be labeled with either a single-panel or multilanguage label containing pertinent study 
information, country-specific requirements, and a caution statement.
9.12.3 Alisertib
The packaged and labeled study drug, alisertib, will be provided by the sponsor and will be 
handled at the investigative site as open-label material. The labels on the study drug will fulfill all 


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requirements specified by governing regulations. Ten alisertib ECTs are packaged into each 60-cc, 
HDPE bottle. Alisertib will be supplied as ECTs in 10-mg strength. The bottles will have a 
child-resistant cap and be labeled for take-home use. Patients will receive instructions for home 
use of alisertib, including the requirement that alisertib be administered as intact tablets.
As required by local regulations, any modifications to the plan for drug supply or storage will be 
communicated to the investigator and detailed in the Study Manual.
9.12.4 Paclitaxel and Docetaxel
Docetaxel and/or paclitaxel may be supplied either by the study site from commercial sources (US 
sites) or provided by the sponsor (ex-US sites). When provided by the sponsor, docetaxel and 
paclitaxel will be appropriately labeled in compliance with local and regional regulations.
9.13
Storage, Handling, and Accountability
9.13.1 MLN1117
Upon receipt at the investigative site, MLN1117 study drug should be stored in the original bottles 
at room temperature from 15°C to 30°C (59°F to 86°F) until use. 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 MLN1117 should be used before the retest date.
A drug dispensing log, including records of drug received from the sponsor and drug dispensed to 
the subjects, will be provided and kept at the study site. Storage area temperature conditions must 
be monitored and recorded daily. A daily temperature log will also be kept at the study site.
Because MLN1117 is an investigational agent, it should be handled with due care. Patients will 
receive instructions for home storage and administration of MLN1117. Patients will receive diary 
cards to record dosing compliance of MLN1117. 
Patients will be instructed to return any unused study drug in the original packaging along with 
their completed diary cards at the appropriate visits.
9.13.2 TAK-659
TAK-659 tablets should be stored in the original dispensing bottles. The container should be stored 
at the investigative site at controlled room temperature (20C to 25C; 68F to 77F; excursions 
permitted from 15C to 30C; 59F to 86F) and used before the retest date indicated on the label 
or accompanying documentation. Drug supply must be kept in an appropriate, limited access, 
secure place until it is dispensed to the enrolled patients, returned to sponsor, or forwarded to the 
sponsor’s designee for destruction. Drug supplies received at the clinical sites will be counted and 
reconciled before being returned to the sponsor.


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9.13.3 Alisertib
Tablets should remain in the bottle provided until use. The container should be stored at the 
investigative site at controlled room temperature (20C to 25C; 68F to 77F; excursions 
permitted from 15C to 30C; 59F to 86F) and used before the retest date indicated on the label 
or accompanying documentation. The stability of the drug product will be monitored for the 
duration of the clinical trials. Tablets are not intended to be broken or manipulated in any way. 
Containers should be kept closed during storage.
Because this is an investigational agent, it should be handled with due care. In case of contact with 
broken tablets, raising dust should be avoided during the clean-up operation.
The product may be harmful by inhalation, ingestion, or skin absorption. 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 tablet), 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. Patients are to be instructed on proper 
storage, accountability, and administration of alisertib, including that alisertib is to be taken as 
intact tablets.
9.13.4 Paclitaxel and Docetaxel
Docetaxel and paclitaxel should be stored according to the label and the instructions provided in 
the manufacturer’s most recent USPI or SmPC. 
Please refer to the site Pharmacy Manual for additional instructions regarding study drugs.
9.14
Other Protocol-Specified Materials
Not applicable.


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10.0
STUDY CONDUCT
This trial will be conducted in compliance with the protocol, Good Clinical Practice (GCP), 
applicable regulatory requirements, and International Conference on Harmonisation (ICH) 
guidelines.
10.1
Study Personnel and Organizations
The contact information for the project clinician for this study, the central and secondary 
laboratories, the coordinating investigator for each member state/country, the interactive web 
response system (IWRS) provider, and the Quintiles team may be found in the Study Manual. A 
full list of investigators is available in the sponsor’s investigator database.
10.2
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 IRB/independent ethics committee (IEC). 
10.3
Treatment Group Assignments
In Part 1 (dose escalation) of the study, patients will be assigned to a current, open cohort. Refer to 
the Cohort Management Plan for detailed information on slot allocation in Part 1. Refer to 
Section 14.1.2 for a description of assignment to study drug treatment in Part 2 (see also
Figure 7.a).
10.4
Study Procedures
Refer to the SOEs (Appendix A) for timing of assessments. Additional details are provided as 
necessary in the sections that follow.
10.4.1 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.
10.4.2
Enrollment
A patient is considered to be enrolled in the study when the patient receives the first dose of any 
study drug.
Procedures for completion of the enrollment information are described in the Study Manual. 
10.4.3 Patient Demographics
The date of birth, race, ethnicity, and sex of the patient are to be recorded during Screening.


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10.4.4 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 10.4.10.
10.4.5 Physical Examination
A physical examination will be completed per standard of care at the times specified in the 
Schedule of Events (Appendix A).
10.4.6 Patient Height
Height will be measured only during screening (within 28 days before the first dose of any study 
drug).
10.4.7 Vital Signs
Vital signs include blood pressure, heart rate, and temperature, to be determined at the times 
specified in the Schedule of Events (Appendix A).
10.4.8 Eastern Cooperative Oncology Group Performance Status
ECOG performance status will be assessed at the times specified in the Schedule of Events 
(Appendix A).
10.4.9
Electrocardiogram
A 12-lead ECG will be administered at the time points specified in the SOEs (Appendix A).
10.4.10
Concomitant Medications and Procedures
Medications used by the patient and therapeutic procedures completed by the patient will be 
recorded in the electronic case report form (eCRF) from the date of the first dose of study drug 
through 30 days after the last dose of study drug. See Section 9.5 and Section 9.6 for a list of 
medications and therapies that are prohibited and/or allowed during the study.
10.4.11
Adverse Events
Monitoring of AEs, serious and nonserious, will be conducted throughout the study as specified in 
the SOEs (Appendix A). Refer to Section 11.0 for details regarding definitions, documentation, 
and reporting of pretreatment events (PTEs), AEs, and SAEs.
10.4.12
Pregnancy Test
A serum pregnancy test will be performed for women of childbearing potential at screening. A 
urine pregnancy test must be performed predose on Cycle 1 Day 1 with negative results available 


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before the first dose may be administered. A serum pregnancy test may also be performed within 
3 days of dosing in place of the Cycle 1 Day 1 urine test.
10.4.13
Clinical Laboratory Evaluations
All scheduled clinical laboratory evaluations will be performed centrally. Additionally, the 
following safety laboratory tests should be performed locally for dosing decisions: standard 
hematology (with white blood cell differential count), AST, ALT, total bilirubin, ALP, creatinine, 
and fasting serum glucose. For patients allocated to Cohort A (TAK-659), serum lipase and 
amylase are part of the compulsory safety laboratory tests. Additionally, any other chemistry value 
that was considered before as abnormal and clinically meaningful can be performed locally for 
dosing decisions. Unscheduled or repeat laboratory evaluations may be performed locally but also 
should be collected for central analysis. Clinical laboratory evaluations to be performed are 
outlined in the tables below.
Handling of clinical laboratory samples will be outlined in the Study Manual.
10.4.13.1
Clinical Chemistry, Hematology, and Urinalysis
Blood samples for analysis of the clinical chemistry and hematological parameters shown in 
Table 10.a, blood samples for analysis of the coagulation parameters shown in Table 10.b, and 
urine samples for analysis of the parameters shown in Table 10.c will be obtained as specified in 
the SOEs (Appendix A).
Table 10.a
Hematology and Clinical Chemistry Tests
Hematology
Serum Chemistry
Hematocrit
Hemoglobin
Leukocytes with differential
Neutrophils (ANC)
Platelet (count)
Albumin
Alkaline phosphatase (ALP)
ALT
Amylase (Screening only, except in Cohort 
A, which is at each scheduled clinical 
chemistry)
AST
Bilirubin (total)
Blood urea nitrogen (BUN)
Calcium
Carbon dioxide (CO2)
Creatinine
Chloride
γ-glutamyl transferase (GGT)
Glucose
Lactate dehydrogenase (LDH)
Lipase (Screening only, except in 
Cohort A, which is at each scheduled 
clinical chemistry)
Magnesium
Phosphate
Potassium
Sodium
Urate


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Table 10.b
Clinical Coagulation Tests
Coagulation
Activated partial thromboplastin time (aPTT)
Prothrombin time/international normalized ratio (PT/INR)
Table 10.c
Clinical Urinalysis Tests
Urinalysis
Bilirubin
Glucose
Ketones
Leukocytes
Nitrite
Occult blood
pH
Protein
Specific gravity
Turbidity and color
Urobilinogen
10.4.13.2
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).
The fasting lipid profile includes the following:

Total cholesterol.

Triglycerides.

High-density lipoprotein 
cholesterol (HDL-C).

Low-density lipoprotein 
cholesterol (LDL-C).
Sampling for the fasting lipid profile will be obtained at the times specified in the Schedule of 
Events (Appendix A).
10.4.13.3
Fasting Serum Glucose
Fasting serum glucose will be measured at the time points specified in the Schedule of Events
(Appendix A) before administration of study drugs.

Patients are required to fast overnight (nothing except water and/or medications after 
midnight) or for 8 hours minimum.

On Cycle 1 Day 1 (Cohorts A and B only) and Cycle 1 Day 2 (Cohorts C and D only), patients 
will be required to fast for 2 hours after dosing, until the completion of the 2-hour postdose 
fasting glucose sample. On all other dosing days, the patient is only required to fast for 1 hour 
postdose.

Samples for fasting glucose will be obtained at the times specified in the Schedule of Events 
(Appendix A).


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10.4.14 In-Home Daily Fasting Glucose Monitoring
Patients who experience on-study hyperglycemia will be given a glucometer to monitor their daily 
predose fasting blood glucose (FBG) levels at home and will be instructed to notify the 
investigator when the FBG is abnormal (ie, ≥140 mg/dL). 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. See Section 9.8.2 for further instruction.
10.4.15 Pharmacokinetic Measurements
Serial PK samples will be collected at various time points during Part 1 of the study (as specified in 
Appendix Table A) to characterize the PK of MLN1117, alisertib, and TAK-659 only.
As permitted by the data, PK parameters, including Cmax; tmax; area under the plasma 
concentration-time curve from time 0 to time of the last quantifiable concentration (AUCt); area 
under the plasma concentration-time curve from time 0 to infinity (AUC∞), calculated as 
AUC∞=AUCt+Clast/λz (AUC); terminal elimination half-life (t1/2); and apparent clearance after 
extravascular administration, calculated as dose/AUC∞after a single dose and as dose/AUCτ after 
multiple dosing (at steady state) (CL/F), will be generated using noncompartmental methods.
The primary purpose of PK assessments in this study is to characterize the PK of MLN1117, 
TAK-659, and alisertib. However, if considered necessary to confirm treatment assignments or to 
further understand the disposition of the study drugs being evaluated in the patient population 
enrolled in this study, a subset of the PK samples may be used additionally, pending technical 
feasibility, to measure concentrations of paclitaxel, docetaxel, and/or metabolites of MLN1117, 
TAK-659, or alisertib.
Additionally, sparse PK samples will be collected during Part 2 of the study to characterize the PK 
of MLN1117, alisertib, and TAK-659 (Appendix Table B and Table C). The sparse PK data 
collected in this study may be pooled with similar data collected in other studies for future 
population PK analysis (to understand the effect of intrinsic and extrinsic factors on PK and to 
contribute to analyses of exposure-response relationships for safety and/or efficacy). The results of 
such population analyses will not be presented in the clinical study report but will be reported 
separately.
10.4.16
DNA Measurements
Plasma samples will be collected at the time points specified in the SOEs (Appendix A). 
 
 
 
 
 


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In addition, blood samples will be collected for extracting germline DNA to be used as a 
comparator for mutations detected in tumor samples.
10.4.17
Banked Tumor Specimen Measurements
An archival tumor tissue sample needs to be available for enrollment in Part 2. Archival tumor 
tissue will be collected from Part 1 patients whenever possible. 
 
 
 
 
 
10.4.18 Tumor Biopsies
For Part 2, access to a tumor tissue sample is required. If a patient does not have archived tumor 
tissue for evaluation of the EBV status and analysis of biomarkers, a new fresh pretreatment 
biopsy is required. Patients undergoing tumor biopsy procedures must have a platelet count 
>75,000/mm3 and an activated partial thromboplastin time (aPTT) and prothrombin time (PT) 
within the normal range; must not have an ECOG performance status >1; must not be receiving 
any anticoagulant therapy or antiplatelet agents; and must not have any other known coagulation 
abnormalities that would contraindicate the tumor biopsy procedure. The tumor biopsy procedure 
will be performed by core needle, under radiological guidance if indicated, or surgically if the site 
of disease is superficial and palpable or visible.
10.4.19 Disease Assessment
Patients will undergo CT scan, with contrast as appropriate, or MRI scan to monitor and assess 
disease progression, using RECIST, Version 1.1 [3] as outlined in the Schedule of Events 
(Appendix A).
Determination of disease status will be based on local investigator assessment. The collection and 
central storage of scans are planned in the event that more detailed analysis of imaging data, as 
determined by the sponsor, is needed. To support the potential exploratory
 
 as described in Section 14.1.6.2, prestudy scans, if available, may be collected at the 
sponsor’s discretion.
10.4.20 Pharmacodynamic Measurements
Pharmacodynamic measurements will not be performed in this study.
10.5
Completion of Treatment
Patients will be considered to have completed treatment if they discontinue study drug for any of 
the reasons outlined in Section 10.7.


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10.6
Completion of Study
Patients will be considered to have completed the study if they complete a minimum of 6 cycles of 
treatment with MLN1117 and any of the combination partners and complete follow-up for PFS or 
OS as described in Section 10.10. Patients will be considered to have completed the study if they 
withdraw from the study for any of the reasons outlined in Section 10.8.
10.7
Discontinuation of Treatment With Study Drug and Patient Replacement
Study drug may be permanently discontinued for patients meeting any of the following criteria:

Adverse event.

Protocol violation.

Progressive disease. 

Symptomatic deterioration. 

Unsatisfactory therapeutic response.

Study terminated by sponsor.

Withdrawal by patient.

Lost to follow-up.

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 are withdrawn from treatment during Cycle 1 for reasons other than DLT will be 
replaced.
Note that some patients may discontinue study drug for reasons other than PD before completing 
the full treatment course; these will remain in the study for posttreatment assessments as outlined 
in the Schedule of Events until disease progression occurs.
10.8
Withdrawal of Patients From Study
A patient may be withdrawn from the study for any of the following reasons:

Lost to follow-up.

Study terminated by sponsor.

Withdrawal by patient.

Death.

Other.


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The consequence of study withdrawal is that no new information will be collected from the 
withdrawn patient and added to the existing data or any database.
10.9
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 study drug for each treatment cycle and a diary in 
which to record their dosing. The study center staff will check the patient’s diary versus the 
patient’s supply of remaining study drug 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.
10.10 Posttreatment Follow-up Assessments (Progression-Free Survival and Overall 
Survival)
Patients who stop treatment for any reason other than PD will continue to have PFS follow-up 
visits. The PFS follow-up visit should be conducted at the site every 12 weeks from the EOT visit 
until the occurrence of PD, the start of subsequent antineoplastic therapy, or until 6 months after 
the patient discontinued treatment, whichever occurs first.
After the occurrence of PD or the start of subsequent anticancer therapy, patients will continue to 
have OS follow-up visits. The OS visits should be conducted every 12 weeks after documented PD 
until death or until 1 year after the last dose of study drug, whichever occurs first.
Survivor information may be collected by methods that include, but are not limited to, telephone, 
e-mail, mail, or retrieved from online or other databases (eg, social security indexes). In addition, 
information on the start of another anticancer therapy will be collected.
The EOS visit is to be completed at the time the patient withdraws from the study during the 
follow-up period. See the Schedule of Events (Appendix A) for appropriate assessments during 
follow-up.
NOTE: Related SAEs must be reported to the sponsor’s Department of Pharmacovigilance or 
designee. This includes deaths that the investigator considers related to study drugs and that occur 
during the posttreatment follow-up period. Refer to Section 11.0 for details regarding definitions, 
documentation, and reporting of SAEs.


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11.0
ADVERSE EVENTS
11.1
Definitions
11.1.1 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.
11.1.2 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.
11.1.3 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 11.2 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 laboratory abnormality, will be determined 
using the NCI CTCAE, Version 4.03 [1]. Clarification should be made between an SAE and an AE 
that is considered severe in intensity (Grade 3 or 4), because the terms serious and severe are NOT 
synonymous. The general term severe is often used to describe the intensity (severity) of a specific 
event; the event itself, however, may be of relatively minor medical significance (such as a Grade 
3 headache). This is NOT the same as serious, which is based on patient/event outcome or action 
criteria described above, and is usually associated with events that pose a threat to a patient’s life 
or ability to function. A severe AE (Grade 3 or 4) does not necessarily need to be considered 
serious. For example, a white blood cell count of 1000/mm3 to less than 2000 is considered Grade 
3 (severe) but may not be considered serious. Seriousness (not intensity) serves as a guide for 
defining regulatory reporting obligations.
PD per se is not considered to be an SAE. However, symptoms or diagnoses likely caused by 
tumor progression that meet seriousness criteria should be reported as SAEs (eg, pulmonary 
embolism in the context of PD).
11.2
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 11.3 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 11.1) must be 
reported (see Section 11.3 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.


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SAE Reporting Contact Information
Cognizant
US and Canada
Toll-Free Fax #: 
E-mail: 
All Other Countries (Rest of World)
Fax #: 
E-mail: 
Planned hospital admissions or surgical procedures for an illness or disease that existed before the 
patient was enrolled in the trial or before study drug was given are not to be considered AEs unless
the condition deteriorated in an unexpected manner during the trial (eg, surgery was performed 
earlier or later than planned).
For both serious and nonserious AEs, the investigator must determine both the intensity of the 
event and the relationship of the event to study drug administration. For serious pretreatment 
events, the investigator must determine both the intensity of the event and the relationship of the 
event to study procedures.
Intensity for each AE, including any lab abnormality, will be determined using the NCI CTCAE, 
Version 4.03 [1]. The criteria are provided in the Study Manual.
Relationship to study drug administration will be determined by the investigator responding yes 
or no to this question: Is there a reasonable possibility that the AE is associated with the study 
drug?
11.3
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 first dose of study drug through 30 days after administration of the
last dose of study drug and recorded in the eCRFs. 

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, 
but will not be recorded in the eCRF.

Related and unrelated 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, stabilized with sequelae, or are clearly determined 
to be due to a patient’s stable or chronic condition or intercurrent illness(es).
PPD
PPD
PPD
PPD


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11.4
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 11.2). The pregnancy must be followed 
for the final pregnancy outcome.
If a female partner of a male patient becomes pregnant during the male patient’s participation in 
this study, the sponsor must also be contacted immediately by faxing a completed Pregnancy Form 
to the Takeda Global Pharmacovigilance department or designee (see Section 11.2). Every effort 
should be made to follow the pregnancy for the final pregnancy outcome.
11.5
Procedures for Reporting Product Complaints
A product complaint is a verbal, written, or electronic expression that implies dissatisfaction 
regarding the identity, strength, purity, quality, or stability of a drug product. Individuals who 
identify a potential product complaint situation should immediately report this via the phone 
numbers or email addresses below:
Call center
Phone number
E-mail
Fax
Hours
Dohmen Life 
Science Services
Mon-Fri
9AM-7PM, 
ET
Product complaints in and of themselves are not AEs. If a product complaint results in an SAE, an 
SAE form should be completed and sent to Cognizant (refer to Section 11.2).
PPD
PPD
PPD


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12.0
STUDY-SPECIFIC COMMITTEES
For Part 1, patient information will be discussed in regularly scheduled meetings with 
investigators, other site personnel, and sponsor representatives. The main outcomes of these 
meetings are DLT evaluation, dose escalation decisions, patient allocation, and determination of 
the MTD or recommended dose for Part 2. Meetings will be documented in minutes that require 
approval by the voting members. For more details, refer to the Cohort Management Plan.
For Part 2 a Steering Committee (SC) will be formed. The sponsor will select up to 5 investigators 
for periodic review of enrollment and ongoing clinical data with special focus on safety. These 
meetings will be documented in minutes that require approval by the voting members and will be 
distributed to all participating investigators. The SC can issue recommendations about the conduct 
of the study and the need for changes in the protocol and/or ICF.


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13.0
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the Data Management Plan. 
If selected for coding, AEs, PTEs, medical history, and concurrent conditions will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA). Drugs will be coded using the 
World Health Organization (WHO) Drug Dictionary.
13.1
eCRFs 
Completed eCRFs are required for each subject who receives study drug.
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.
13.2
Record Retention
The investigator agrees to keep the records stipulated in Section 13.1 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 informed consent forms, subject authorization forms 
regarding the use of personal health information (if separate from the informed consent forms), 
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 


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and filed with the original in the subject’s chart to ensure long term legibility. Furthermore, 
International Conference on Harmonisation (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.


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14.0
STATISTICAL METHODS
14.1
Statistical and Analytical Plans
In general, summary tabulations will be presented by treatment arm and will display the number of 
observations, mean, standard deviation, median, minimum, and maximum for continuous 
variables, and the number and percentage per category for categorical data. The Kaplan-Meier 
survival curves and 25th, 50th (median), and 75th percentiles will be provided along with their 
2-sided 95% confidence intervals (CIs) for time-to-event data.
Details for the statistical analysis will be provided in the statistical analysis plan (SAP). The SAP 
will be written by Takeda and finalized before database lock for the final analysis.
Deviations from the statistical analyses outlined in this protocol will be indicated in the SAP; any 
further modifications will be noted in the final clinical study report.
14.1.1 Analysis Sets
The populations used for analysis will include the following:

Safety population: The Safety population is defined as all patients who receive at least 1 dose 
of MLN1117+TAK-659 or 1 dose of MLN1117+alisertib or 1 dose of MLN1117+paclitaxel or 
1 dose of MLN1117+docetaxel. Patients will be analyzed according to the treatment actually 
received.

Intent-to-Treat (ITT) population: In Part 2, the ITT population is defined as all patients who 
are randomized and receive at least 1 dose of any study drug. For the TAK-659 cohort, the ITT 
population is defined as all patients who receive at least 1 dose of any of the study drugs. The 
ITT population will be used for the analysis of PFS, TTP, and OS. Patients will be analyzed 
according to the treatment they were randomized to receive, regardless of any errors of dosing. 

Response-Evaluable population: The Response-Evaluable population is defined as all 
patients with gastric cancer, with measurable disease at baseline, who receive at least 1 dose of 
MLN1117 plus 1 of the combination partners and have at least 1 postbaseline response 
assessment. The Response-Evaluable population will be used for the analysis of RR (CR+PR), 
disease control rate (CR+PR+SD), and DOR.

DLT-Evaluable population: The DLT-Evaluable population, defined as all patients in Part 1 
(dose escalation) of the study who either experience DLT during Cycle 1 or complete 
treatment with at least 75% of the planned doses of MLN1117 and the combination partner, 
and have sufficient follow-up data to allow the investigators and sponsor to determine whether 
DLT occurred, will be used for the analysis of DLT. 

PK-Evaluable population: The population of patients evaluable for the determination of the 
PK of MLN1117 is defined as all patients in Part 1 (dose escalation of the study for whom there 
are sufficient dosing and MLN1117 concentration-time data to permit noncompartmental PK 
analysis.


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14.1.2 Randomization and Stratification
In the dose escalation phase (Part 1), there is no randomization; all patients will receive 
MLN1117+TAK-659 (Cohort A) or MLN1117+alisertib (Cohort B) or MLN1117+paclitaxel 
(Cohort C) or MLN1117+docetaxel (Cohort D). Details regarding patient allocation are provided 
in the Cohort Management Plan document.
In the dose expansion phase (Part 2), patients who are EBV positive will be assigned to treatment 
with TAK-659 in combination with MLN1117 (Cohort A). For patients who are EBV negative, 
there will be 2 parts to the randomization phase. Patients initially will be randomized equally to 
1 of the other treatment cohorts, 5 patients per group: MLN1117+alisertib (Cohort B), 
MLN1117+paclitaxel (Cohort C), or MLN1117+docetaxel (Cohort D). These patients will be 
assessed using a proportional weighted clinical utility function (allocating specific weights for CR, 
PR, SD, and PD. Initially, the clinical utility function will assign weights for CR=5, PR=2, SD=1, 
and PD=0; after 6 months of having CR, PR, and SD, weights will increase to CR=6, PR=4, SD=2, 
and PD weighting will remain the same. Patients then will be randomized to treatment according to 
an adaptive randomization algorithm, which incorporates weighted clinical utility function. The 
resulting probability will continually be updated per accumulating data. Adaptive randomization 
will be applied to newly enrolling patients every 2 months based on cumulative data. 
The randomization scheme will be generated by an independent statistician at Takeda who is not 
on the study team. Before dosing, a randomization number will be assigned to each patient. The 
randomization assignment will be implemented by an IWRS. The proportional weighted utility 
function based on response assessment will be calculated by the study statistician at Takeda and 
the assignment of treatment group ratios will be implemented through IWRS.
Stratification will not be used in this study.
14.1.3 Analysis of Demographics and Other Baseline Characteristics
The demographic and baseline characteristics will be summarized in a descriptive fashion. Data to 
be evaluated will include age, gender, race, weight, baseline disease characteristics, histology, and 
genotype status.
14.1.4 Efficacy Analysis
14.1.4.1 Analysis of Primary Efficacy Endpoints
Dose Escalation Phase (Part 1)
There is no primary efficacy endpoint in the dose escalation portion of the study.
Dose Expansion Phase (Part 2)
The primary efficacy endpoint for the dose expansion portion is ORR, defined as CR+PR. The 
estimate of the RR will be presented with 2-sided 95% exact binomial CIs for each treatment arm. 
The number and percentage of patients in each response category will be tabulated for each 
treatment arm based on RECIST, Version 1.1 [3]. Fisher’s exact tests will be performed for the 


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comparison of RR between the treatment arms. RR will be analyzed based on the 
Response-Evaluable population.
14.1.4.2 Analysis of Secondary Efficacy Endpoints
Dose Escalation Phase (Part 1)
The secondary efficacy endpoint in the dose escalation portion of the study is the ORR, defined as 
CR+PR, which will be presented in a listing.
Dose Expansion Phase (Part 2)
The secondary endpoints in the phase 2 portion of the study include PFS, disease control rate 
(CR+PR+SD), DOR, TTP, and OS. PFS is defined as the time from the date of randomization to 
the date of first documentation of PD or death due to any cause, whichever occurs first. The 
censoring method will be described in the SAP. PFS will be tested based on the ITT population. 
An unstratified log-rank test will be used to compare the treatment arms with respect to PFS. In 
addition, a Cox regression model will be used to estimate the hazard ratio and its 95% CI for the 
treatment effect. The Kaplan-Meier survival curves, 25th, 50th (median), and 75th percentiles (if 
estimable), along with their 2-sided 95% CIs, will also be provided for each treatment arm.
Disease control rate is defined as CR+PR+SD. The estimate of the disease control rate will be 
presented with 2-sided 95% exact binomial CIs for each treatment arm. The number and 
percentage of patients in each response category will be tabulated for each treatment arm based on 
RECIST, Version 1.1 [3]. Fisher’s exact tests will be performed for the comparison of disease 
control rate between the treatment arms. Disease control rate will be analyzed based on the 
Response-Evaluable population. 
DOR is defined as the time from the date of first documentation of a response to the date of first 
documentation of PD. Patients without documentation of PD at the time of analysis will be 
censored at the date of their last response assessment that is SD or better. 
TTP is defined as the time from the date of randomization to the date of first documentation of PD. 
Patients without documentation of PD at the time of analysis will be censored at the date of their 
last response assessment that is SD or better. 
OS is defined as the time from the date of randomization to the date of death from any cause.
DOR, TTP, and OS will be analyzed using the Kaplan-Meier method. Unstratified long-rank tests 
will be performed for the comparisons between the 2 treatment arms. DOR will be analyzed based 
on the responders in the Response-Evaluable population. TTP and OS will be analyzed using the 
ITT population.


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14.1.5 Pharmacokinetic Analysis
Individual and mean plasma concentration data collected during Part 1 (dose escalation) will be 
plotted over time as follows:
MLN1117+TAK-659
Individual and mean MLN1117 and TAK-659 plasma concentration data collected during Part 1 
(dose escalation) will be plotted over time for Cycle 1 Day 1 and Cycle 1 Day 17. 
Noncompartmental PK analysis will be performed on individual concentration-time data to 
calculate plasma PK parameters, including Cmax, AUClast, AUCinf, and t½ for MLN1117 and 
TAK-659 as permitted by the data. Descriptive statistics will be presented for plasma PK 
parameters of MLN1117 and TAK-659 by day and by time.
MLN1117+alisertib
Individual and mean MLN1117 and alisertib plasma concentration data collected during Part 1 
(dose escalation) will be plotted over time for Cycle 1 Day 3. 
Noncompartmental PK analysis will be performed on individual concentration-time data to 
calculate plasma PK parameters, including Cmax, AUClast, AUCinf, and t½ for MLN1117 and 
alisertib as permitted by the data. Descriptive statistics will be presented for plasma PK parameters 
of MLN1117 and alisertib by day and by time.
MLN1117+docetaxel and MLN1117+paclitaxel
Individual and mean MLN1117 plasma concentration data collected during Part 1 (dose 
escalation) will be plotted over time for Cycle 1 Day 2. 
Noncompartmental PK analysis will be performed on individual concentration-time data to 
calculate plasma PK parameters, including Cmax, AUClast, AUCinf, and t½ for MLN1117 as 
permitted by the data. Descriptive statistics will be presented for plasma PK parameters of 
MLN1117 by day and by time. The serial PK of paclitaxel or docetaxel is not being collected in 
this study and will not be reported.
Sparse PK data during Part 2 (dose expansion) of the study will be collected for all patients at the 
prespecified time points outlined in Appendix Table B and Table C. Plasma concentration data for 
individual patients will be provided in listings. The sparse PK data collected during Part 2 of the 
study may be combined with similar data in other studies for the purposes of future population PK 
analysis.
14.1.6 Exploratory Analysis
14.1.6.1 Exploratory Endpoints
 


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14.1.6.2
 
14.1.7 Biomarker Analysis
Descriptive statistics, graphical methods, and statistical modeling as appropriate will be used to 
explore the relationship between response and the levels of various biomarkers.
14.1.8 Safety Analysis
The incidence of DLT will be tabulated for each dose group. In addition, to assess the relationship 
between toxicities and MLN1117 dose, the preferred term of individual toxicities will be 
summarized by their frequency and intensity for each dose group. The DLT-evaluable population 
will be used for the analysis of DLT.
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 
population. Exposure to study treatment 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. 
AEs will be tabulated according to the MedDRA and will include the following categories:

TEAEs.

Drug-related TEAEs.

Grade 3 or higher TEAEs.

Grade 3 or higher, drug-related, TEAEs.

The most commonly reported TEAEs (ie, those events reported by ≥10% of all patients). 

SAEs


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
Drug-related SAEs.
A listing of TEAEs resulting in study drug discontinuation will be provided. 
Descriptive statistics for actual values of clinical laboratory parameters (and/or change from 
baseline) will be presented for all scheduled measurements over time. Central laboratory test 
values will be used for the safety analysis. Mean laboratory values over time will be plotted for key 
laboratory parameters. Creatinine clearance, will be derived by the sponsor using Cockcroft-Gault 
equation (see Appendix D), will also be assessed as a laboratory parameter. 
Descriptive statistics for the actual values (and/or the changes from baseline) of vital signs and 
weight over time will be tabulated by scheduled time point. Shift tables for laboratory parameters 
will be generated on the basis of changes in NCI CTCAE grade from baseline to the worst 
postbaseline value. Graphical displays of key safety parameters, such as scatter plots of baseline 
versus worst postbaseline values and/or e-dish plots, may be used to understand the safety profile 
of the combinations.
All concomitant medications collected from the first dose throughout the study period will be 
summarized by preferred term according to the WHO drug dictionary.
Descriptive statistics for the actual values and changes from baseline in ECGs will be tabulated by 
time point including any unscheduled measurements.
ECOG performance status and change from baseline will be summarized. Shifts from baseline to 
the worst postbaseline score will be tabulated by treatment arm. 
Additional safety analyses may be determined at any time without prejudice to most clearly 
enumerate rates of toxicities and to further define the safety profile of study drugs.
14.1.9 Procedures for Handling Missing, Unused, and Spurious Data
All available efficacy and safety data will be included in data listings and tabulations. No 
imputation of values for missing data will be performed, unless specified otherwise. The relevance 
of missing sample data will be assessed. Data that are potentially spurious or erroneous will be 
examined according to standard data management operating procedures.
14.2
Interim Analysis and Criteria for Early Termination
No formal interim analysis is planned for this study.
14.3
Determination of Sample Size
14.3.1 Dose Escalation Phase (Part 1)
The number of patients enrolled in this study will be driven initially by the dose escalation part and 
by the dose expansion part. In Part 1 (dose escalation), approximately 15 patients may be enrolled
in each combination treatment group, with potentially 3 to 6 patients in each dose cohort. 
Therefore, approximately 60 patients may be enrolled in the dose escalation phase.


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14.3.2 Dose Expansion Phase (Part 2)
All patients who enter Part 2 of the study will be screened to determine whether or not their tumor 
tissue is positive for EBV (approximately 9% of patients with gastric cancer). An estimated 
28 patients who are EBV positive will be assigned to treatment with TAK-659 in combination with 
MLN1117 (Cohort A). The sample size is estimated based on the following parameters: a 1-sided 
test at the significance level of alpha=0.05, power of 75%, a null hypothesis of RR=10%, and an 
alternative hypothesis of RR=25%. Based on a single proportion test, 28 evaluable patients need to 
be enrolled in Cohort A. For patients who are EBV negative, there will be 2 parts to the 
randomization phase. Patients initially will be randomized equally to 1 of the other treatment 
cohorts, 5 patients per group: MLN1117+alisertib (Cohort B), MLN1117+paclitaxel (Cohort C), 
or MLN1117+docetaxel (Cohort D). These patients will be assessed using a proportional weighted 
clinical utility function (allocating specific weights for CR, PR, SD, and PD. Initially the clinical 
utility function will assign weights for CR=5, PR=2, SD=1 and PD=0; after 6 months of having 
CR, PR, or SD, weights will increase to CR=6, PR=4, SD=2, and PD weighting will remain the 
same. Patients then will be randomized to treatment according to an adaptive randomization 
algorithm, which incorporates weighted clinical utility function. The resulting probability will 
continually be updated per accumulating data on the associations between the ORR and Bayesian 
stopping rules (defined below). Adaptive randomization will be applied to newly enrolling patients
every 2 months based on cumulative data. The adaptive randomization will increase the 
opportunity for each patient to receive the most effective experimental treatment possible based on 
posterior probabilities. Simulations results for adaptive randomization using clinical utility 
function and Bayesian stopping rules will be described in the SAP. Up to an additional 25 patients 
may be enrolled in each treatment regimen. Based on simulation results, the sample size for Part 2 
(the umbrella portion) may be between 61 and 90 patients. Therefore, a maximum number of 
118 patients may be enrolled in the dose expansion phase.
ORR will be used as the efficacy benchmark: target 25% (0.25); undesirable 10% (0.1). Early 
stopping rules will be prespecified if there is a clear signal of efficacy or lack of efficacy. The 
stopping rules are as follows:
1. Achieve maximum sample size of each arm (30 patients).
2. Select an arm if probability (Pr), Pr (RR>0.25/Data) >80% and Pr (RR>0.10)/Data) >90%.
3. Suspend accrual to an arm if Pr (RR≤0.10/Data) >80%.
The treatment arm(s) is/are chosen in relation to the efficacy bar prespecified (target and 
undesirable); therefore, it is possible to select multiple treatment arms per this study design.


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15.0
QUALITY CONTROL AND QUALITY ASSURANCE
15.1
Study-Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and institution guarantee access to source documents by the sponsor or its 
designee (CRO) and by the IRB or IEC.
All aspects of the study and its documentation will be subject to review by the sponsor or designee 
(as long as blinding is not jeopardized), including but not limited to the Investigator’s Binder, 
study medication, subject medical records, informed consent documentation, documentation of 
subject authorization to use personal health information (if separate from the informed consent 
forms), 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.
15.2
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 EC, as 
required). Significant deviations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the subject, or confound interpretation of primary study 
assessment. A Protocol Deviation Form should be completed by the site and signed by the sponsor 
or designee for any significant deviation from the protocol.
15.3
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 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 15.1.


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16.0
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.
16.1
IRB and/or IEC Approval
IRBs and IECs must be constituted according to the applicable state and federal/local requirements 
of each participating region. The sponsor or designee will require documentation noting all names 
and titles of members who make up the respective IRB or IEC. If any member of the IRB or IEC 
has direct participation in this study, written notification regarding his or her abstinence from 
voting must also be obtained. Those American sites unwilling to provide names and titles of all 
members due to privacy and conflict of interest concerns should instead provide a Federal Wide 
Assurance Number or comparable number assigned by the Department of Health and Human 
Services.
The sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the Investigator’s Brochure, a copy of 
the informed consent form, 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, informed consent form) 
reviewed; and state the approval date. The sponsor will notify the 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 informed consent 
form, 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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16.2
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 informed consent form, 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 informed consent form 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 informed consent form 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 
informed consent form and if applicable, the subject authorization form. The informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) must 
be approved by both the IRB or IEC and the sponsor prior to use.
The informed consent form, 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 informed consent 
form, 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 informed consent form 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 prior to 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 informed consent 
form and subject authorization (if applicable) at the time of consent and prior to subject entering 
into the study; however, the sponsor may allow a designee of the investigator to sign to the extent 
permitted by applicable law.
Once signed, the original informed consent form, subject authorization form (if applicable), and 
subject information sheet (if applicable) will be stored in the investigator’s site file. The 
investigator must document the date the subject signs the informed consent in the subject’s 
medical record. Copies of the signed informed consent form, the signed subject authorization form 
(if applicable), and subject information sheet (if applicable) shall be given to the subject.


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All revised informed consent forms must be reviewed and signed by relevant subjects or the 
relevant subject’s legally acceptable representative in the same manner as the original informed 
consent. The date the revised consent was obtained should be recorded in the subject’s medical 
record, and the subject should receive a copy of the revised informed consent form.
16.3
Subject Confidentiality
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or date 
of birth, and subject initials may be used to verify the subject and accuracy of the subject’s unique 
identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the sponsor 
requires the investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (eg, 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 16.2).
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 [e]CRF).
16.4
Publication, Disclosure, and Clinical Trial Registration Policy
16.4.1 Publication and Disclosure
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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16.4.2 Clinical Trial Registration
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations and guidance, Takeda will, at a minimum register 
interventional clinical trials it sponsors anywhere in the world on ClinicalTrials.gov or other 
publicly accessible websites before start of study, as defined in Takeda Policy/Standard. Takeda 
contact information, along with investigator’s city, state (for Americas investigators), country, and 
recruiting status will be registered and available for public viewing. 
For some registries, Takeda will assist callers in locating trial sites closest to their homes by 
providing the investigator name, address, and phone number to the 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. 
16.4.3 Clinical Trial Results Disclosure
Takeda will post the results of clinical trials on ClinicalTrials.gov or other publicly accessible 
websites, as required by Takeda Policy/Standard, applicable laws and/or regulations.
16.5
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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17.0
REFERENCES
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4. Yao Z, Guo H, Yuan Y, Zhao Y, Yao S, Xu Y, et al. Retrospective analysis of docetaxel, 
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oxaliplatin, and capecitabine with or without panitumumab for patients with previously 
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12. Hironaka S, Zenda S, Boku N, Fukutomi A, Yoshino T, Onozawa Y. Weekly paclitaxel as 
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24. Dawson CW, Port RJ, Young LS. The role of the EBV-encoded latent membrane proteins 
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2012;22(2):144-53.
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26. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
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Appendix A
Schedules of Events


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Schedule of Events for MLN1117+TAK-659 (Cohort A) Treatment Arm (28-Day Cycle)
Screening (a)
Cycle 1
(Part 1, Escalation Only)
Cycle 1 (Part 2, 
Expansion Only)
Cycles 2-4
Cycles 5 and 
Beyond
EOT
PFSFU/ 
OSFU
Day 1 
Predose
Day
Day 1 
Predose
Day
Day
Day 1
2 (PK 
only)
8
17
8
15
1
15
Informed consent (b)
X
Inclusion/exclusion criteria
X
Demographics
X
Medical history
X
Physical examination (c)
X
X
X
X
X
X
X
X
X
X
X
Height
X
Weight
X
X
X
X
X
X
Vital signs (d)
X
X
X
X
X
X
X
X
X
X
X
ECOG performance status
X
X
X
X
X
X
12-lead ECG (e)
X
X
X
X
X
X
Monitoring of concomitant 
medications and procedures (f)
Recorded from first dose of study drug through 30 days after the last dose of study drug.
Adverse event reporting
Recorded from first dose of study drug through 30 days after the last dose of study drug.
Serious adverse event reporting (g)
Serious adverse events will be reported from signing of the informed consent form through 30 days after the last dose of study drug.
Study drug administration
TAK-659 (Dose TBD) PO continuous daily dosing in combination with MLN1117 (starting dose of 
300 mg) PO 3 days on (Days 1-3) and 4 days off per week in a 28-day cycle.
Patient diary review(h)
X
X
X
X
X
X
X
X
X
X
Samples/Laboratory Assessments
Pregnancy test(i)
X
X
X
Hematology (j)
X
X
X
X
X
X
X
X
X
X
X
Chemistry (j)
X
X
X
X
X
X
X
X
X
X
X
Coagulation (j)
X
X
X
X
X
Urinalysis
X
X
X
X
X
X


TAK-117 (MLN1117)
Study No. C032-6001 (also known as MLN1117-1003)
Page 109 of 138
Protocol Incorporating Amendment No. 2
25 January 2016
Schedule of Events for MLN1117+TAK-659 (Cohort A) Treatment Arm (28-Day Cycle)
Screening (a)
Cycle 1
(Part 1, Escalation Only)
Cycle 1 (Part 2, 
Expansion Only)
Cycles 2-4
Cycles 5 and 
Beyond
EOT
PFSFU/ 
OSFU
Day 1 
Predose
Day
Day 1 
Predose
Day
Day
Day 1
2 (PK 
only)
8
17
8
15
1
15
Fasting serum glucose (j,k)
X
X 
X
X
X
X
X
X
X (l)
X 
X
Fasting lipid profile
X
Day 1 of Cycle 3 and every 3 cycles 
thereafter.
HbA1c
X
Day 1 of Cycle 3 and every 3 cycles 
thereafter.
In-home daily fasting glucose 
monitoring (m)
See footnote m.
Blood sample for PK (n, o)
X (n)
X (n)
X (n)
X (o)
Plasma ctDNA (p)
X
Plasma will be collected on Day 1 of 
Cycle 3 and every 2 cycles thereafter.
Blood sample germline DNA (t)
X
Banked tumor tissue or fresh biopsy 
sample (q)
X
Disease Assessment
Disease evaluation by RECIST, 
Version 1.1 (CT/MRI) (r)
X
Disease assessment to be conducted 
during Days 25-28 at the end of 
Cycles 2, 4, 6, and every other cycle 
thereafter.
X
q 12 wk
OS follow-up (OS and subsequent 
anticancer therapy) (s)
X
q 12 wk
CxDx=Cycle x Day x, CT=computed tomography, ctDNA=circulating tumor deoxyribonucleic acid, DNA=deoxyribonucleic acid, ECG=electrocardiogram, ECOG=Eastern 
Cooperative Oncology Group, EOT=End of Treatment, HbA1c=glycosylated hemoglobin, MRI=magnetic resonance imaging, OS=overall survival, OSFU=overall survival 
follow-up, PD=progressive disease, PFS=progression-free survival, PFSFU=progression-free survival follow-up, PK=pharmacokinetic(s), PO=orally, RECIST=Response 
Evaluation Criteria in Solid Tumors.
(a) The Screening visit must occur within 28 days before the day of the first dose of study drug (C1D1). Screening assessments performed no more than 3 days before Day 1 will 
qualify as baseline assessments and need not be repeated, unless otherwise specified.
(b) The informed consent form (ICF) may be signed more than 28 days prior to C1D1, but has to be signed before any study-required procedures are conducted, unless those 


TAK-117 (MLN1117)
Study No. C032-6001 (also known as MLN1117-1003)
Page 110 of 138
Protocol Incorporating Amendment No. 2
25 January 2016
procedures are performed as part of the patient’s standard care
(c) A complete physical examination should be performed at screening and EOT. A symptom-directed physical examination should be performed on all other days as specified above.
(d) Vital signs measurements should be obtained at screening and on all other days as specified above. Vital signs include blood pressure, heart rate, and temperature.
(e) Single 12-lead ECGs will be obtained. When the timing of a PK or safety laboratory blood sample coincides with the timing of ECG measurements, then the ECG will be 
completed before the collection of the blood sample.
(f) See Section 9.5 for medications and procedures that are prohibited during the study, and Section 9.6 for medications that should be used cautiously during the study.
(g) Only those serious adverse events (SAEs) that occur after the first dose of study drug will be collected in the electronic case report form; however, all SAEs occurring after consent 
will be reported. See Section 10.4.11.
(h) The study center staff will check the patient diary versus the patient’s supply of MLN1117 and TAK-659 tablets to assess compliance.
(i) A serum pregnancy test will be performed for women of childbearing potential at screening. A urine pregnancy test must be performed predose on C1D1 with negative results 
available before the first dose of the study drug may be administered. A serum pregnancy test may also be performed within 3 days of dosing in place of the C1D1 urine test.
(j) Samples may be collected up to 3 days before the scheduled visit except for Cycle 1 Day 1. See Section 10.4.13.1 for the full hematology, coagulation, and clinical chemistry 
panels.
(k) Fasting serum glucose collected prior to MLN1117 dosing in every cycle, and at 2 hours post dosing only on Cycle 1 Day 1.
(l) The only exception to (k) is in Part 2, Cycle 2 Day 15, when patients will take the study drugs at home before coming to the clinic for sparse PK sample collection.
(m) Patients who experience on-study hyperglycemia will be given a glucometer to monitor their daily predose fasting blood glucose (FBG) levels at home and will be instructed to 
notify the investigator when the FBG is abnormal (ie, ≥140 mg/dL). 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. See Section 9.8.2 for further instruction.
(n) Patients in Part 1 (dose escalation) of the study will return to the clinic to have their PK samples collected as specified in Appendix Table A.
(o) Patients in Part 2 (dose expansion) of the study will return to the clinic to have their sparse PK samples collected as specified in Appendix Table B.
(p) A blood sample for plasma will be obtained at screening and as specified above for evaluation of circulating tumor DNA.
(q) Collection of tumor tissue (banked) will be requested (Part 1) and required (Part 2) at screening as specified in Section 10.4.17. For banked tissue, the sample can be from either 
paraffin-embedded tumor block or unstained slides. If a paraffin-embedded tumor block or unstained slides are not available, the patient will be required to undergo a fresh tumor 
biopsy as specified in Section 10.4.18 (Part 2 only). The sample must be collected during screening before the first dose of study drug. Epstein-Barr virus (EBV) testing must be 
performed on all Part 2 (dose expansion) patients prior to randomization. In addition, tumor tissue will be analyzed and will be tested retrospectively for genetic mutations and
amplifications.
(r) Response assessments will be performed on Days 25-28 at the end of treatment of Cycles 2, 4, 6, and then every 2 cycles thereafter until the patient discontinues study drug due to 
disease progression, unacceptable toxicity, or death. A CT scan with intravenous contrast of the chest, abdomen, and pelvis will be performed during screening (MRI of disease sites 
poorly imaged by CT is permitted; however, imaging modalities used for each disease site must be consistent throughout the study). If the patient has had an appropriate CT or MRI 
scan performed within 28 days of Cycle 1 Day 1, the results of that scan may be used for tumor lesion measurements at screening. Patients who discontinue study drug treatment for 
reasons other than PD will undergo CT/MRI scans every 12 weeks from EOT until the occurrence of PD, the start of subsequent antineoplastic therapy, or until 6 months after 
discontinuation of study drug treatment, whichever occurs first.
(s) OS is to be assessed every 12 weeks until patient death or 1 year after the patient’s last dose of study drug, whichever occurs first.
(t) Blood samples will be collected at screening for extracting germline DNA to be used as a comparator for mutations in tumor samples.
Note: Tests and procedures should be performed on schedule, but occasional changes are allowable (±2 days) with permission of the project clinician for holidays, vacations, and 
other administrative reasons. If extenuating circumstances prevent a patient from beginning treatment or completing a scheduled procedure or assessment within this time, 
the patient may continue the study only with the written permission of the project clinician.


TAK-117 (MLN1117)
Study No. C032-6001 (also known as MLN1117-1003)
Page 111 of 138
Protocol Incorporating Amendment No. 2
25 January 2016
Schedule of Events for MLN1117+Alisertib (Cohort B) Treatment Arm (28-Day Cycle)
Screening (a)
Cycle 1
(Part 1, Escalation Only)
Cycle 1 (Part 2, Expansion 
Only)
Cycles 2 and 
Beyond
EOT
PFSFU/ 
OSFU
Day 1 
Predose
Day
Day
Day 
3 (PK
only)
4 (PK 
only)
8
15
22
1
8
15
1
15
Informed consent (b)
X
Inclusion/exclusion criteria
X
Demographics
X
Medical history
X
Physical examination (c)
X
X
X
X
X
X
X
X
X
X
X
Height
X
Weight
X
X
X
X
X
Vital signs (d)
X
X
X
X
X
X
X
X
X
X
X
ECOG performance status
X
X
X
X
X
12-lead ECG (e)
X
X
X
X
X
Monitoring of concomitant 
medications and procedures (f)
Recorded from first dose of study drug through 30 days after the last dose of study drug.
Adverse event reporting
Recorded from first dose of study drug through 30 days after the last dose of study drug.
Serious adverse event reporting (g) Serious adverse events will be reported from signing of the informed consent form through 30 days after the last dose of study drug.
Study drug administration
Alisertib (40 mg PO BID) 3 days on (Days 1-3) and 4 days off per week (during Weeks 1, 2, and 3), 1 week off 
in a 28-day cycle in combination with MLN1117 (starting dose 300 mg) PO 3 days on (Days 1-3) and 4 days 
off per week in a 28-day cycle.
Patient diary review(h)
X
X
X
X
X
X
X
X
X
X
Samples/Laboratory Assessments
Pregnancy test(i)
X
X
X
Hematology(j)
X
X
X
X
X
X
X
X
X
X
X
Chemistry (j)
X
X
X
X
X
X
X
X
X
X
X
Coagulation (j)
X
X
X
X
Urinalysis
X
X
X
X
X


TAK-117 (MLN1117)
Study No. C032-6001 (also known as MLN1117-1003)
Page 112 of 138
Protocol Incorporating Amendment No. 2
25 January 2016
Schedule of Events for MLN1117+Alisertib (Cohort B) Treatment Arm (28-Day Cycle)
Screening (a)
Cycle 1
(Part 1, Escalation Only)
Cycle 1 (Part 2, Expansion 
Only)
Cycles 2 and 
Beyond
EOT
PFSFU/ 
OSFU
Day 1 
Predose
Day
Day
Day 
3 (PK
only)
4 (PK 
only)
8
15
22
1
8
15
1
15
Fasting serum glucose (j, k)
X
X
X
X
X
X
X
X
X
X (l)
X
Fasting lipid profile
X
Day 1 of Cycle 3 
and every 3 cycles 
thereafter.
HbA1c
X
Day 1 of Cycle 3 
and every 3 cycles 
thereafter.
In-home daily fasting glucose 
monitoring (m)
See footnote m.
Blood samples for PK (n, o)
X (n)
X (n)
X (o)
Plasma ctDNA (p)
X
Plasma will be 
collected on Day 1 
of Cycle 3 and every 
2 cycles thereafter.
Blood sample germline DNA (t)
X
Banked tumor tissue or fresh 
biopsy sample (q)
X
Disease Assessment
Disease evaluation by RECIST, 
Version 1.1 (CT/MRI) (r)
X
Disease assessment 
to be conducted 
during Days 25-28 
at the end of 
Cycles 2, 4, 6 and 
every other cycle 
thereafter.
X
q 12 wk
OS follow-up (OS and subsequent 
anticancer therapy) (s)
X
q 12 wk


TAK-117 (MLN1117)
Study No. C032-6001 (also known as MLN1117-1003)
Page 113 of 138
Protocol Incorporating Amendment No. 2
25 January 2016
BID=twice daily, CxDx=Cycle x Day x, CT=computed tomography, ctDNA=circulating tumor deoxyribonucleic acid, ECG=electrocardiogram, ECOG=Eastern Cooperative 
Oncology Group, EOT=End of Treatment, HbA1c=glycosylated hemoglobin, MRI=magnetic resonance imaging, OS=overall survival, OSFU=overall survival follow-up, 
PD=progressive disease, PFS=progression-free survival, PFSFU=progression-free survival follow-up, PK=pharmacokinetic(s), PO=orally, RECIST=Response Evaluation Criteria in 
Solid Tumors.
(a) The Screening visit must occur within 28 days before the day of the first dose of study drug (C1D1). Screening assessments performed no more than 3 days before Day 1 will 
qualify as baseline assessments and need not be repeated, unless otherwise specified.
(b) The informed consent form (ICF) may be signed more than 28 days prior to C1D1, but has to be signed before any study-required procedures are conducted, unless those 
procedures are performed as part of the patient’s standard care.
(c) A complete physical examination should be performed at screening and EOT. A symptom-directed physical examination should be performed on all other days as specified above.
(d) Vital signs measurements should be obtained at screening and on all other days as specified above. Vital signs include blood pressure, heart rate, and temperature.
(e) Single 12-lead ECGs will be obtained. When the timing of a PK or safety laboratory blood sample coincides with the timing of ECG measurements, then the ECG will be 
completed before the collection of the blood sample.
(f) See Section 9.5 for medications and procedures that are prohibited during the study and Section 9.6 for medications that should be used cautiously during the study.
(g) Only those serious adverse events (SAEs) that occur after the first dose of study drug will be collected in the electronic case report form; however, all SAEs occurring after consent 
will be reported. See Section 10.4.11.
(h) The study center staff will check the patient diary versus the patient’s supply of MLN1117 tablets and alisertib tablets to assess compliance.
(i) A serum pregnancy test will be performed for women of childbearing potential at screening. A urine pregnancy test must be performed predose on C1D1 with negative results 
available before the first dose of the study drug may be administered. A serum pregnancy test may also be performed within 3 days of dosing in place of the C1D1 urine test.
(j) Samples may be collected up to 3 days before the scheduled visit except for Cycle 1 Day 1. See Section 10.4.13.1 for the full hematology, coagulation, and clinical chemistry 
panels.
(k) Fasting serum glucose collected prior to MLN1117 dosing in every cycle, and at 2 hours post dosing only on Cycle 1 Day 1.
(l) The only exception to (k) is Part 2, Cycle 2 Day 15, when patients will take the study drugs at home before coming to the clinic for sparse PK sample collection.
(m) Patients who experience on-study hyperglycemia will be given a glucometer to monitor their daily predose fasting blood glucose (FBG) levels at home and will be instructed to 
notify the investigator when the FBG is abnormal (ie, ≥140 mg/dL). 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. See Section 9.8.2 for further instruction.
(n) Patients in Part 1 (dose escalation) of the study will return to the clinic to have their PK samples collected as specified in Table A.
(o) Patients in Part 2 (dose expansion) of the study will return to the clinic to have their sparse PK samples collected as specified in Table B.
(p) A blood sample for plasma will be obtained at screening and as specified above for evaluation of circulating tumor DNA.
(q) Collection of tumor tissue (banked) will be requested (Part 1) and required (Part 2) at screening as specified in Section 10.4.17. For banked tissue, the sample can be from either 
paraffin-embedded tumor block or unstained slides. If a paraffin-embedded tumor block or unstained slides are not available, the patient will be required to undergo a fresh tumor 
biopsy as specified in Section 10.4.18 (Part 2 only). The sample must be collected during screening before the first dose of study drug. Epstein-Barr virus (EBV) testing must be 
performed on all Part 2 (dose expansion) patients prior to randomization. In addition, tumor tissue will be analyzed and will be tested retrospectively for genetic mutations and 
amplifications.
(r) Response assessments will be performed on Days 25-28 at the end of treatment of Cycles 2, 4, 6, and then every 2 cycles thereafter until the patient discontinues study drug due to
disease progression, unacceptable toxicity, or death. A CT scan with intravenous contrast of the chest, abdomen, and pelvis will be performed during screening (MRI of disease sites 
poorly imaged by CT is permitted; however, imaging modalities used for each disease site must be consistent throughout the study). If the patient has had an appropriate CT or MRI 
scan performed within 28 days of Cycle 1 Day 1, the results of that scan may be used for tumor lesion measurements at screening. Patients who discontinue study drug treatment for 
reasons other than PD will undergo CT/MRI scans every 12 weeks from EOT until the occurrence of PD, the start of subsequent antineoplastic therapy, or until 6 months after 
discontinuation of study drug treatment, whichever occurs first.


TAK-117 (MLN1117)
Study No. C032-6001 (also known as MLN1117-1003)
Page 114 of 138
Protocol Incorporating Amendment No. 2
25 January 2016
(s) OS is to be assessed every 12 weeks until patient death or until 1 year after the last dose of study drug, whichever occurs first.
(t) Blood samples will be collected at screening for extracting germline DNA to be used as a comparator for mutations in tumor samples.
Note: Tests and procedures should be performed on schedule, but occasional changes are allowable (±2 days) with permission of the project clinician for holidays, vacations, and 
other administrative reasons. If extenuating circumstances prevent a patient from beginning treatment or completing a scheduled procedure or assessment within this time, 
the patient may continue the study only with the written permission of the project clinician.


TAK-117 (MLN1117)
Study No. C032-6001 (also known as MLN1117-1003)
Page 115 of 138
Protocol Incorporating Amendment No. 2
25 January 2016
Schedule of Events for MLN1117+Paclitaxel (Cohort C) Treatment Arm (28-Day Cycle)
Screening (a)
Cycle 1 (Part 1+Part 2)
Cycles 2-6
Cycles 7 and 
Beyond
EOT
PFSFU/ 
OSFU
Day 1 
Predose
Day
Day
Day 2 (first dose 
of MLN1117)
2
3 (Part 1 
PK only)
8
9 (Part 2 
PK only)
15
1
8
15
Informed consent (b)
X
Inclusion/exclusion criteria
X
Demographics
X
Medical history
X
Physical examination (c)
X
X
X
X
X
X
X
X
X
X
Height
X
Weight
X
X
X
X
X
Vital signs (d)
X
X
X
X
X
X
X
X
X
X
ECOG performance status
X
X
X
X
X
12-lead ECG (e)
X
X
X
X
X
Monitoring of concomitant 
medications and procedures (f)
Recorded from first dose of study drug through 30 days after the last dose of study drug.
Adverse event reporting
Recorded from first dose of study drug through 30 days after the last dose of study drug.
Serious adverse event reporting (g)
Serious adverse events will be reported from signing of the informed consent form through 30 days after the last dose of 
study drug.
Study drug administration (r)
Paclitaxel (80 mg/m2) IV once weekly on Days 1, 8, and 15, and 1 week off, in a 28-day cycle, in 
combination with MLN1117 (starting dose 300 mg) PO 3 days on (Days 2-4, 9-11, 16-18, 23-25) and 4 
days off per week, in a 28-day cycle.
At Cycle 7 and beyond, only MLN1117 will be administered (see footnote r).
Patient diary review(h)
X
X
X
X
X
X
X
X
Samples/Laboratory Assessments
Pregnancy test(i)
X
X
Hematology(j)
X
X
X
X
X
X
X
X
X
X
Chemistry (j)
X
X
X
X
X
X
X
X
X
X


TAK-117 (MLN1117)
Study No. C032-6001 (also known as MLN1117-1003)
Page 116 of 138
Protocol Incorporating Amendment No. 2
25 January 2016
Schedule of Events for MLN1117+Paclitaxel (Cohort C) Treatment Arm (28-Day Cycle)
Screening (a)
Cycle 1 (Part 1+Part 2)
Cycles 2-6
Cycles 7 and 
Beyond
EOT
PFSFU/ 
OSFU
Day 1 
Predose
Day
Day
Day 2 (first dose 
of MLN1117)
2
3 (Part 1 
PK only)
8
9 (Part 2 
PK only)
15
1
8
15
Coagulation (j)
X
X
X
X
Urinalysis
X
X
X
X
X
Fasting serum glucose (j, k)
X
X
X 
X
X
X
X
X
X
X
Fasting lipid profile
X
Day 1 of Cycles 3 and 6; Day 2 of Cycle 
9 and every 3 cycles thereafter.
HbA1c
X
Day 1 of Cycles 3 and 6; Day 2 of Cycle 
9 and every 3 cycles thereafter.
In-home daily fasting glucose 
monitoring (l)
See footnote l.
Blood samples for PK (m)
X
X
X
Plasma ctDNA (n)
X
Plasma will be collected on Day 1 of 
Cycles 3 and 5, and on Day 2 of Cycle 7 
and every 2 cycles thereafter.
Blood sample germline DNA (s)
X
Banked tumor tissue or fresh biopsy 
sample (o)
X
Disease Assessment
Disease evaluation by RECIST, 
Version 1.1 (CT/MRI) (p)
X
Disease assessment to be conducted 
during Days 25-28 at the end of Cycles 
2, 4, 6, and every other cycle thereafter.
X
q 12 wk
OS follow-up (OS and subsequent 
anticancer therapy) (q)
X
q 12 wk
CxDx=Cycle x Day x, CT=computed tomography, ctDNA=circulating tumor deoxyribonucleic acid, ECG=electrocardiogram, ECOG=Eastern Cooperative Oncology Group, 
EOT=End of Treatment, HbA1c=glycosylated hemoglobin, IV=intravenous, MRI=magnetic resonance imaging, OS=overall survival, OSFU=overall survival follow-up, 
PD=progressive disease, PFS=progression-free survival, PFSFU=progression-free survival follow-up, PK=pharmacokinetic(s), PO=orally, RECIST=Response Evaluation Criteria in 
Solid Tumors.
(a) The Screening visit must occur within 28 days before the day of the first dose of study drug (C1D1). Screening assessments performed no more than 3 days before Day 1 will 


TAK-117 (MLN1117)
Study No. C032-6001 (also known as MLN1117-1003)
Page 117 of 138
Protocol Incorporating Amendment No. 2
25 January 2016
qualify as baseline assessments and need not be repeated, unless otherwise specified.
(b) The informed consent form (ICF) may be signed more than 28 days prior to C1D1, but has to be signed before any study-required procedures are conducted, unless those 
procedures are performed as part of the patient’s standard care.
(c) A complete physical examination should be performed at screening and EOT. A symptom-directed physical examination should be performed on all other days as specified above. 
(d) Vital signs should be obtained at screening and on all other days as specified above. Vital signs include blood pressure, heart rate, and temperature.
(e) Single 12-lead ECGs will be obtained. When the timing of a PK or safety laboratory blood sample coincides with the timing of ECG measurements, then the ECG will be 
completed before the collection of the blood sample.
(f) See Section 9.5for medications and procedures that are prohibited during the study, and Section 9.6 for medications that should be used cautiously during the study.
(g) Only those serious adverse events (SAEs) that occur after the first dose of study drug will be collected in the electronic case report form; however, all SAEs occurring after consent 
will be reported. See Section 10.4.11.
(h) The study center staff will check the patient diary versus the patient’s supply of MLN1117 tablets to assess compliance.
(i) A serum pregnancy test will be performed for women of childbearing potential at screening. A urine pregnancy test must be performed predose on C1D1 with negative results 
available before the first dose of the study drug may be administered. A serum pregnancy test may also be performed within 3 days of dosing in place of the C1D1 urine test.
(j) Samples may be collected up to 3 days before the scheduled visit except for Cycle 1 Day 2. See Section 10.4.13.1 for the full hematology, coagulation, and clinical chemistry 
panels.
(k) Fasting serum glucose collected prior to MLN1117 dosing in every cycle, and at 2 hours post dosing only on Cycle 1 Day 2.
(l) Patients who experience on-study hyperglycemia will be given a glucometer to monitor their daily predose fasting blood glucose (FBG) levels at home and will be instructed to 
notify the investigator when the FBG is abnormal (ie, ≥140 mg/dL). 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. See Section 9.8.2 for further instruction.
(m) Patients in Part 1 (dose escalation) of the study will return to the clinic to have their 24-hour PK samples collected as specified in Appendix Table A.
Patients in Part 2 (dose expansion) of the study will return to the clinic to have their sparse PK samples collected as specified in Appendix Table C.
(n) A blood sample for plasma will be obtained at screening and every 2 cycles thereafter for evaluation of circulating tumor DNA.
(o) Collection of tumor tissue (banked) will be requested (Part 1) and required (Part 2) at screening as specified in Section 10.4.17. For banked tissue, the sample can be from either 
paraffin-embedded tumor block or unstained slides. If a paraffin-embedded tumor block or unstained slides are not available, the patient will be required to undergo a fresh tumor 
biopsy as specified in Section 10.4.18 (Part 2 only). The sample must be collected during screening before the first dose of study drug. Epstein-Barr virus (EBV) testing must be 
performed on all Part 2 (dose expansion) patients prior to randomization. In addition, tumor tissue will be analyzed and will be tested retrospectively for genetic mutations and 
amplifications.
(p) Response assessments will be performed on Days 25-28 at the end of treatment of Cycles 2, 4, 6, and then every 2 cycles thereafter until the patient discontinues study drug due to 
disease progression, unacceptable toxicity, or death. A CT scan with IV contrast of the chest, abdomen, and pelvis will be performed during screening (MRI of disease sites poorly 
imaged by CT is permitted; however, imaging modalities used for each disease site must be consistent throughout the study). If the patient has had an appropriate CT or MRI scan 
performed within 28 days of Cycle 1 Day 1, the results of that scan may be used for tumor lesion measurements at screening. Patients who discontinue study drug treatment for reasons 
other than PD will undergo CT/MRI scans every 12 weeks from EOT until the occurrence of PD, the start of subsequent antineoplastic therapy, or until 6 months after discontinuation 
of study treatment, whichever occurs first.
(q) OS is to be assessed every 12 weeks until patient death or until 1 year after the last dose of study drug, whichever occurs first.
(r) Paclitaxel may be administered after Cycle 6 if the investigator and sponsor determine that the patient would derive benefit from continued treatment.
(s) Blood samples will be collected at screening for extracting germline DNA to be used as a comparator for mutations in tumor samples.
Note: Tests and procedures should be performed on schedule, but occasional changes are allowable (±2 days) with permission of the project clinician for holidays, vacations, and 
other administrative reasons. If extenuating circumstances prevent a patient from beginning treatment or completing a scheduled procedure or assessment within this time, 
the patient may continue the study only with the written permission of the project clinician.


TAK-117 (MLN1117)
Study No. C032-6001 (also known as MLN1117-1003)
Page 118 of 138
Protocol Incorporating Amendment No. 2
25 January 2016
Schedule of Events for MLN1117+Docetaxel (Cohort D) Treatment Arm (21-Day Cycle)
Screening (a)
Cycle 1 (Part 1+Part 2)
Cycles 2-4
Cycles 5-6
Cycles 7 and 
Beyond
EOT
PFSFU/ 
OSFU
Day 1
Predose
Day
Day
Day 1
Day 2 (first dose of 
MLN1117)
2
3 (Part 1 
PK only)
9
16
1
9
Informed consent (b)
X
Inclusion/exclusion criteria
X
Demographics
X
Medical history
X
Physical examination (c)
X
X
X
X
X
X
X
X
X
X
Height
X
Weight
X
X
X
X
X
X
Vital signs (d)
X
X
X
X
X
X
X
X
X
X
ECOG performance status
X
X
X
X
X
X
12-lead ECG (e)
X
X
X
X
X
X
Monitoring of concomitant 
medications and procedures (f)
Recorded from first dose of study drug through 30 days after the last dose of study drug.
Adverse event reporting
Recorded from first dose of study drug through 30 days after the last dose of study drug.
Serious adverse event reporting (g) Serious adverse events will be reported from signing of the informed consent form through 30 days after the last dose of study drug.
Study drug administration (r)
Docetaxel (75 mg/m2) IV once every 3 weeks, in a 21-day cycle, in combination with MLN1117 PO 
3 days on (Days 2-4, 9-11, 16-18) and 4 days off, in a 21-day cycle.
At Cycle 7 and beyond, only MLN1117 will be administered (see footnote r).
Patient diary review(h)
X
X
X
X
X
X
X
X
X
Samples/Laboratory Assessments
Pregnancy test(i)
X
X
Hematology (j)
X
X
X
X
X
X
X
X
X
X
Chemistry (j)
X
X
X
X
X
X
X
X
X
X
Coagulation (j)
X
X
X
X
X
Urinalysis
X
X
X
X
X
X


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Schedule of Events for MLN1117+Docetaxel (Cohort D) Treatment Arm (21-Day Cycle)
Screening (a)
Cycle 1 (Part 1+Part 2)
Cycles 2-4
Cycles 5-6
Cycles 7 and 
Beyond
EOT
PFSFU/ 
OSFU
Day 1
Predose
Day
Day
Day 1
Day 2 (first dose of 
MLN1117)
2
3 (Part 1 
PK only)
9
16
1
9
Fasting serum glucose (j, k)
X
X
X
X
X
X
X
X
X
X
Fasting lipid profile
X
Day 1 of Cycle 4; Day 2 of Cycle 8 and every 4 cycles 
thereafter.
HbA1c
X
Day 1 of Cycle 4; Day 2 of Cycle 8 and every 4 cycles 
thereafter.
In-home daily fasting glucose 
monitoring (l)
See footnote l.
Blood samples for PK (m)
X
X
X
Plasma ctDNA (n)
X
Plasma will be collected on Day 1 of Cycles 3 and 5, and 
on Day 2 of Cycle 7 and every 2 cycles thereafter.
Blood sample germline DNA (s)
X
Banked tumor tissue or fresh biopsy 
sample (o)
X
Disease Assessment
Disease evaluation by RECIST, 
Version 1.1 (CT/MRI) (p)
X
Disease assessment to be conducted during Days 18-21 
at the end of Cycles 2, 4, 6, and then every other cycle 
thereafter.
X
q 12 wk
OS follow-up (OS and subsequent 
anticancer therapy) (q)
X
q 12 wk
CxDx=Cycle x, Day x, CT=computed tomography, ctDNA=circulating tumor deoxyribonucleic acid, ECG=electrocardiogram, ECOG=Eastern Cooperative Oncology Group, 
EOT=End of Treatment, HbA1c=glycosylated hemoglobin, IV=intravenous, MRI=magnetic resonance imaging, OS=overall survival, OSFU=overall survival follow-up, 
PD=progressive disease, PFS=progression-free survival, PFSFU=progression-free survival follow-up, PK=pharmacokinetic(s), PO=orally, RECIST=Response Evaluation Criteria in 
Solid Tumors.
(a) The Screening visit must occur within 28 days before the day of the first dose of study drug (C1D1). Screening assessments performed no more than 3 days before Day 1 will 
qualify as baseline assessments and need not be repeated, unless otherwise specified.
(b) The informed consent form (ICF) may be signed more than 28 days prior to C1D1, but has to be signed before any study-required procedures are conducted, unless those 
procedures are performed as part of the patient’s standard care.
(c) A complete physical examination should be performed at screening and EOT. A symptom-directed physical examination should be performed on all other days as specified above.


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(d) Vital signs measurements should be obtained at screening and on all other days as specified above. Vital signs include blood pressure, heart rate, and temperature.
(e) Single 12-lead ECGs will be obtained. When the timing of a PK or safety laboratory blood sample coincides with the timing of ECG measurements, then the ECG will be 
completed before the collection of the blood sample.
(f) See Section 9.5 for medications and procedures that are prohibited during the study and Section 9.6 for medications that should be used cautiously during the study.
(g) Only those serious adverse events (SAEs) that occur after the first dose of study drug will be collected in the electronic case report form; however, all SAEs occurring after consent 
will be reported. See Section 10.4.11.
(h) The study center staff will check the patient diary versus the patient’s supply of MLN1117 tablets to assess compliance.
(i) A serum pregnancy test will be performed for women of childbearing potential at screening. A urine pregnancy test must be performed predose on C1D1 with negative results 
available before the first dose of the study drug may be administered. A serum pregnancy test may also be performed within 3 days of dosing in place of the C1D1 urine test. 
(j) Samples may be collected up to 3 days before the scheduled visit except for Cycle 1 Day 2. See Section 10.4.13.1 for the full hematology, coagulation, and clinical chemistry 
panels.
(k) Fasting serum glucose collected prior to MLN1117 dosing on every cycle, and at 2 hours post dosing only on Cycle 1 Day 2.
(l) Patients who experience on-study hyperglycemia will be given a glucometer to monitor their daily predose fasting blood glucose (FBG) levels at home and will be instructed to 
notify the investigator when the FBG is abnormal (ie, ≥140 mg/dL). 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. See Section 9.8.2 for further instruction.
(m) Patients in Part 1 (dose escalation) of the study will return to the clinic to have their 24-hour PK samples collected as specified in Table A.
Patients in Part 2 (dose expansion) of the study will return to the clinic to have their sparse PK samples collected as specified in Appendix Table C.
(n) A blood sample for plasma will be obtained at screening and every 2 cycles thereafter for evaluation of circulating tumor DNA.
(o) Collection of tumor tissue (banked) will be requested (Part 1) and required (Part 2) at screening as specified in Section 10.4.17. For banked tissue, the sample can be from either 
paraffin-embedded tumor block or unstained slides. If a paraffin-embedded tumor block or unstained slides are not available, the patient will be required to undergo a fresh tumor 
biopsy as specified in Section 10.4.18 (Part 2 only). The sample must be collected during screening before the first dose of study drug. Epstein-Barr virus (EBV) testing must be 
performed on all Part 2 (dose expansion) patients prior to randomization. In addition, tumor tissue will be analyzed and will be tested retrospectively for genetic mutations and 
amplifications.
(p) Response assessments will be performed on Days 18-21 at the end of treatment of Cycles 2, 4, 6, and then every 2 cycles thereafter until the patient discontinues study drug due to 
disease progression, unacceptable toxicity, or death. A CT scan with IV contrast of the chest, abdomen, and pelvis will be performed during screening (MRI of disease sites poorly 
imaged by CT is permitted; however, imaging modalities used for each disease site must be consistent throughout the study). If the patient has had an appropriate CT or MRI scan 
performed within 28 days of Cycle 1 Day 1, the results of that scan may be used for tumor lesion measurements at screening. Patients who discontinue study drug treatment for 
reasons other than PD will undergo CT/MRI scans every 12 weeks from EOT until the occurrence of PD, the start of subsequent antineoplastic therapy, or until 6 months after 
discontinuation of study drug treatment, whichever occurs first.
(q) OS is to be assessed every 12 weeks until patient death or until 1 year after the last dose of study drug, whichever occurs first.
(r) Docetaxel may be administered after Cycle 6 if the investigator and sponsor determine that the patient would derive benefit from continued treatment.
(s) Blood samples will be collected at screening for extracting germline DNA to be used as a comparator for mutations in tumor samples.
Note: Tests and procedures should be performed on schedule, but occasional changes are allowable (±2 days) with permission of the project clinician for holidays, vacations, and
other administrative reasons. If extenuating circumstances prevent a patient from beginning treatment or completing a scheduled procedure or assessment within this time, 
the patient may continue the study only with the written permission of the project clinician.


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Table A
Serial Pharmacokinetic Sampling Schedule (Part 1)
Time Points
MLN1117+TAK-659 (a)
MLN1117+Alisertib (a)
MLN1117+Paclitaxel (b)
MLN1117+Docetaxel (b)
Cycle 1
Cycle 1 Day 3
Cycle 1 Day 2
Cycle 1 Day 2
Day 1
Day 17
Predose (within 30 minutes before 
dosing)
X
X
X
X
X
0.5 hour (5 min)
X
X
X
X
X
1 hour (15 min)
X
X
X
X
X
2 hours (15 min)
X
X
X
X
X
3 hours (30 min)
X
X
X
X
X
4 hours (45 min)
X
X
X
X
X
6 hours (45 min)
X
X
X
X
X
8 hours (1 hour)
X
X
X
X
X
24 hours (1 hour)
X
X
X
X
Total samples
9
8
9
9
9
(a) Measure both MLN1117 and the combination agent.
(b) Measure MLN1117 only.


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Table B
Sparse Pharmacokinetic Sampling Schedule for MLN1117+TAK-659 and MLN1117+Alisertib Arms (Part 2)
(a) The exact date and time of the previous dose of MLN1117, TAK-659, or alisertib will be recorded by the patient in the patient diary.
(b) To enable collection of a distribution of samples within the windows as defined in the table, patients are instructed to take their dose of study drug at home, early 
in the morning (before reporting for the scheduled study site visit) and to record the exact date/time of the dose in their patient diary.
Time points
MLN1117+TAK-659
MLN1117+Alisertib
Cycle 1 Day 8
Cycle 2 Day 15
Cycle 1 Day 8
Cycle 2 Day 15
Predose
X (a)
X (a)
Approximately 1 to 2 hours postdose
X
X
At time of clinic visit
X (b)
X (b)
Approximately 1 hour after last sample collection
X (b)
X (b)
Total samples
2
2
2
2


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Table C
Sparse Pharmacokinetic Sampling Schedule for MLN1117+Paclitaxel and MLN1117+Docetaxel Arms (Part 2)
Time points
MLN1117+Paclitaxel
MLN1117+Docetaxel
Cycle 1 Day 2
Cycle 1 Day 9
Cycle 1 Day 2
Cycle 1 Day 9
Predose
X (a)
X (a)
Approximately 1 to 2 hours postdose
X
X
X
X
Total samples
2
1
2
1
(a) The exact date/time of the previous dose of MLN1117 will be recorded by the patient in the patient diary.


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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 responsibilities imposed on investigators by the FDA are 
summarized in the “Statement of Investigator” (Form FDA 1572), which must be completed and 
signed before the investigator may participate in this study.
The investigator agrees to assume the following responsibilities by signing a Form FDA 1572:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff who will assist in the protocol.
3. Ensure that study-related procedures, including study-specific (non routine/non standard 
panel) screening assessments are NOT performed on potential subjects, prior to the receipt of 
written approval from relevant governing bodies/authorities.
4. Ensure that all colleagues and employees assisting in the conduct of the study are informed of 
these obligations.
5. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform to 
21 CFR Part 56, ICH, and local regulatory requirements.
6. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and approval 
of the protocol. Promptly report to the IRB/IEC all changes in research activity and all 
anticipated risks to subjects. Make at least yearly reports on the progress of the study to the 
IRB/IEC, and issue a final report within 3 months of study completion.
7. Ensure that requirements for informed consent, as outlined in 21 CFR Part 50, ICH, and local 
regulations, are met.
8. Obtain valid informed consent from each subject who participates in the study, and document 
the date of consent in the subject’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each informed consent form 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 informed consent form does not include such a subject authorization, then the 
investigator must obtain a separate subject authorization form from each subject or the 
subject’s legally acceptable representative.
9. Prepare and maintain adequate case histories of all persons entered into the study, including 
eCRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
2 years following notification by the sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
contact and receive written approval from the sponsor before disposing of any such 
documents.
10. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.


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11. Maintain current records of the receipt, administration, and disposition of sponsor-supplied
drugs, and return all unused sponsor-supplied drugs to the sponsor.
12. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours.


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Appendix C
Eastern Cooperative Oncology Group (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 D
Cockcroft-Gault Equation
Creatinine Clearance =
(140 - age [years]) weight [kg] F
72 (serum creatinine [mg/dL])
OR
(140 - age [years]) weight [kg] F
0.81 (serum creatinine [µmol/L])
Source: Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
1976;16(1):31-41.[26]
F=1 for male patients.
F=0.85 for female patients.


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Appendix E
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 (IUD) (b).

intrauterine hormone-releasing system (IUS) (b).

bilateral tubal occlusion (b).

vasectomised 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
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-About_HMA/Working_Groups/CT
FG/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.


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(b) Contraception methods that in the context of this guidance are considered to have low user 
dependency.
(c) Vasectomised 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 
vasectomised 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 F
Examples of Strong CYP3A Inhibitors and Inducers Prohibited During the 
Study
Drug / Agent Class
Examples (a)
Brand Name Example(s) (b)
Antifungal
Itraconazole
Sporanox, Onmel
Ketoconazole
Nizoral, Xolegel, Extina
Posaconazole
Noxafil
Voriconazole
Vfend
Antibiotic
Clarithromycin
Biaxin
Telithromycin
Ketek
Antimycobacterial
Rifabutin
Mycobutin
Rifampin
Rifadin
Rifapentine
Priftin
Antiepileptic
Carbamazepine
Tegretol, Equetro
Phenobarbital
Luminal, Solfoton
Phenytoin
Dilantin, Phenytek, Dilantin-125
Primidone 
Mysoline
Antidepressant
Nefazodone
Serzone
Calcium channel blocker
Mibefradil 
Posicor
Antilipid
Avasimibe
Not available in the US
Vasopressin Antagonist
Conivaptan 
Vaprisol
Herbal / Supplements / Food
Grapefruit
n/a
Grapefruit juice
n/a
St. John’s wort
n/a
Antiviral
Boceprevir
Victrelis
Telaprevir
Incivek, Incivo
HIV=human immunodeficiency virus, n/a=not applicable.
(a) Source: FDA website: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm08
0499.htm (Anti-HIV drugs are not listed here because HIV+ patients are not eligible for enrollment in this study).
(b) Examples only; other brands may contain these active ingredients.


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Appendix G
Examples of P-Glycoprotein Inhibitors and Inducers Prohibited During the 
Study
Drug / Agent Class
Examples (a)
Brand Name Example(s) (b)
Antifungal
Itraconazole
Sporanox, Onmel
Ketoconazole
Nizoral, Xolegel, Extina
Antibiotic
Azithromycin
Zithromax, Zmax, Z-Pak
Clarithromycin
Biaxin
Erythromycin
Eryc, Ery-Tab, E.E.S, Eryped, PCE
Antimycobacterial
Rifabutin
Mycobutin
Rifampin
Rifadin
Rifapentine
Priftin
Antiepileptic
Carbamazepine
Tegretol, Equetro
Phenytoin
Dilantin, Phenytek, Dilantin-125
Immunosuppressant
Cyclosporine 
Restasis, Neoral, Sandimmune
Cardiovascular medications 
(antiarrhymic, antiangina, 
antihypertensives, etc)
Amiodarone
Pacerone, Cordarone, Nexterone
Captopril
Capoten
Carvedilol
Coreg
Diltiazem 
Cardizem
Dronedarone
Multaq
Felodipine 
Plendil
Quinidine
Cardioquin, Quinidex Extentabs
Ranolazine
Ranexa
Verapamil 
Calan, Verelan, Covera-HS
Antilipid
Avasimibe
Not available in the US
Vasopressin Antagonist
Conivaptan 
Vaprisol
Antiplatelet
Ticagrelor
Brilinta
Herbal / Supplements
Quercetin 
n/a
St. John’s Wort
n/a
Antiviral
Telaprevir
Incivek, Incivo
HIV=human immunodeficiency virus.
(a) Source: FDA website: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm09
3664.htm#PgpTransport (Anti-HIV drugs are not listed here because HIV+ patients are not eligible for enrollment in 
this study).
(b) Examples only; other brands may contain these active ingredients.


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Appendix H
Detailed Description of Amendments to Text
AMENDMENT 1 RATIONALE AND PURPOSE 
The primary purposes of Amendment 1 were to update the protocol to include the TAK-659 dose 
as determined in Study C34001 and to change the protocol number. Contraception language was 
updated to align with the risk language in the updated consent form and to align with local labeling 
for paclitaxel and docetaxel. Other changes to certain procedures were incorporated, including 
changes to the Schedules of Events and some dose modification guidelines. In addition, 
administrative updates include incorporation of a development code alias for MLN1117 
(TAK-117) and an update to the list of sponsor signatories. Grammatical and editorial changes 
were included for purposes of clarification and correction of inconsistencies. The following is a 
summary of the changes made in Amendment 1.
1. The TAK-659 dose as determined in Study C34001 was included.
Justification: TAK-659 is a combination partner in 1 of the 4 cohorts in this study and the dose 
determination is for Cohort A (MLN1117+TAK-659).
2. The protocol number was changed from MLN1117-1003 to C032-6001.
Justification: The label on bottles of study drug contain the protocol number. The original 
protocol number was MLN1117-1003. In this study with novel:novel drug combinations (ie, 
MLN1117 [also known as TAK-117] in combination with TAK-659 or alisertib), the 
appearance of Study MLN1117-1003 on the label may cause confusion for patients who have 
bottles containing TAK-659 or alisertib.
3. The development code TAK-117 as a synonym for MLN1117 was incorporated.
Justification: Administrative update.
4. Sponsor signatories were updated.
Justification: Administrative update.
5. Abbreviations introduced with Protocol Amendment 1, including the use of TAK-117 as a 
synonym for MLN1117, were updated.
Justification: To define all abbreviations.
6. The Introduction and Background were updated.
Justification: To include additional information on gastric cancer, updates based on recently 
available MLN1117 data, and updates based on recently available alisertib and TAK-659 
safety data.
7. The rationale for the study was updated.
Justification: To include additional information in the rationale for combining MLN1117 with 
the combinations partners (paclitaxel, docetaxel, alisertib, or TAK-659).


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8. Objectives and endpoints were updated.
Justification: Edits for purposes of clarification and alignment between objectives and 
endpoints.
9. Contraception language was updated, and language relating to donation of eggs and sperm has 
been added; an extended list of effective methods of contraception was added as an appendix.
Justification: To align with updated risk language in the informed consent form, to align with 
paclitaxel and docetaxel labeling, and to provide an extended list of contraception methods that 
are considered to be effective.
10. Numbering of inclusion/exclusion criteria was updated to align with the EDC system.
Justification: In the original protocol, numbering in each subsection of the inclusion and 
exclusion criteria restarted with numeral 1. The EDC system requires a unique number for each 
criterion within a section.
11. Exclusion criterion #12 regarding corticosteroid use was deleted.
Justification: Oral corticosteroids used for approved conditions are not expected to interfere 
with the evaluation of safety or efficacy in patients with solid tumors.
12. Exclusion criteria relating to liver enzymes and serum lipase were updated.
Justification: To include liver enzyme criteria consistent with the docetaxel label and to limit 
enrollment of patients with elevated lipase levels to the TAK-659 cohort.
13. The inclusion criterion relating to hemoglobin and the exclusion criterion relating to fasting 
serum glucose were updated.
Justification: To provide clarification and more specific information relating to patient 
eligibility criteria.
14. Study drug administration was updated.
Justification: To provide clarification of dosing for alisertib, approximately every 12 hours.
15. Definitions of dose-limiting toxicity were updated.
Justification: To provide more specific definitions and further clarification with regard to
dose-limiting toxicity to align DLT definitions with National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.03.
16. Dose escalation rules regarding adjustment of the fixed dose of the combination agent to a 
lower dose were updated.
Justification: This update allows for adjustment to Dose Level -1 of the combination agent in 
the event that Dose Level 1 is above the MTD.
17. Dose escalation of MLN1117 above 900 mg will not be allowed.
Justification: 900 mg MLN1117 is considered the MTD of MLN1117 as a single agent.


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18. The dose-reduction levels table was updated.
Justification: Based on known TAK-659 dose, inclusion of dose reduction levels for TAK-659.
19. Dose modification guidelines for toxicities, including tables, were updated.
Justification: To provide additional guidance, including clarification and simplification, on 
dose modification guidelines for toxicities.
20. Management of hyperglycemia was updated.
Justification: To provide clarification and additional guidance.
21. The timing of antacid ingestion after study drug dosing was updated.
Justification: For consistency with timing of histamine-2 antagonist ingestion after study drug 
dosing.
22. Study drug storage information for TAK-659 was updated.
Justification: To provide additional guidance.
23. Additional laboratory evaluations (coagulation, serum lipase, serum amylase) were included.
Justification: Patient safety.
24. Study-specific committees and reference to a Cohort Management Plan document were added.
Justification: Patient safety oversight and to provide further guidance on the process to drive 
allocation of patients in Part 1.
25. A blood sample for germline DNA was added.
Justification: Comparator for mutations detected in tumor samples.
26. Crossover to a different treatment arm in Part 2 was deleted.
Justification: Crossover to a different treatment arm will not be allowed.
27. Recommended phase 2 dose (RP2D) was revised to recommended Part 2 dose in sections of 
the protocol relating to Part 1.
Justification: In sections of the protocol relating to Part 1, the determined recommended dose is 
referred to as the recommended Part 2 dose rather than the RP2D; the RP2D will be determined 
at the end of the study.
28. The duration of treatment was updated.
Justification: To clarify the maximum duration of treatment and exceptions to the maximum 
duration of treatment with MLN1117 or the combination partners.
29. The Duration of Study section was updated.
Justification: To remove redundancy with other sections and better align with the section 
heading.


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30. Disease assessment with regard to collection of electronic images of scans was updated.
Justification: To clarify the central collection of scans; all scans are collected centrally 
regardless of antitumor response.
31. The Randomization and Stratification section was updated with additional information.
Justification: To provide further details.
32. Serious adverse event definition and analysis sections were updated.
Justification: To provide additional information and updates.
33. The statement regarding the requirement for completed electronic case report forms was 
corrected.
Justification: To correct an erroneous statement.
34. The Schedule of Events for Cohort C (MLN1117+paclitaxel) was revised to remove scheduled 
procedures on Cycle 1 Day 9 (except for PK sampling) and to remove the Cycle 1 Day 16 visit.
Justification: There are clinic visits scheduled on Cycle 1 Day 8 and Cycle 1 Day 15; by 
removing the procedures as stated, this relieves the patient from clinic procedures on 
2 consecutive days.
35. Revisions, updates, and edits were made for purposes of clarification and consistency.
36. Typographical errors, punctuation, grammar, and formatting were corrected.


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AMENDMENT 2 SUMMARY OF CHANGES
This summary describes the changes made in reference to Protocol Incorporating Amendment 
No. 2.
Page 45, Section 9.2, Definitions of Dose-Limiting Toxicity
Existing Text: Toxicity will be evaluated according to the NCI CTCAE, Version 4.03. These 
criteria are provided in the Study Manual. DLT will be defined as any of the following events 
occurring during Cycle 1 in Part 1 that are considered by the investigator to be at least possibly 
related to therapy with MLN1117 when administered in combination with TAK-659, alisertib, 
paclitaxel, or docetaxel.
Revised Text: Toxicity will be evaluated according to the NCI CTCAE, Version 4.03. These 
criteria are provided in the Study Manual. DLT will be defined as any of the following events 
occurring during Cycle 1 in Part 1 that are considered by the investigator to be at least possibly 
related to either or both of the study drugs (MLN1117, TAK-659, alisertib, paclitaxel, or 
docetaxel) in an assigned combination regimen:
Rationale for Amendment: To ensure that the DLT assessments reflect the toxicity of the 
administered combination regimens and not exclusively a single agent within the combination.
Page 45, Section 9.2, Definitions of Dose-Limiting Toxicity

Existing Text: Grade 3 or greater nonhematologic toxicity with the following exceptions:
–
Grade 3 arthralgia/myalgia.
–
Grade 3 fatigue that lasts less than 1 week.
–
≥Grade 3 nausea and/or emesis that can be controlled to ≤Grade 1 or baseline in 7 days 
with the use of optimal antiemetic prophylaxis (defined as an antiemetic regimen that 
employs both a 5-HT antagonist and a corticosteroid given in standard doses and according 
to standard schedules).
–
≥Grade 3 diarrhea that can be controlled to ≤Grade 1 or baseline in 7 days with optimal 
supportive therapy.

Revised Text: Grade 3 or greater nonhematologic toxicity with the following exceptions:
–
Grade 3 arthralgia/myalgia.
–
Grade 3 fatigue that lasts less than 1 week.
–
Grade 3 nausea and/or emesis that can be controlled to ≤Grade 1 or baseline in 7 days with 
the use of optimal antiemetic prophylaxis (defined as an antiemetic regimen that employs 
both a 5-HT antagonist and a corticosteroid given in standard doses and according to 
standard schedules).
–
Grade 3 diarrhea that can be controlled to ≤Grade 1 or baseline in 7 days with optimal 
supportive therapy.


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Rationale for Amendment: Grade 4 events are life-threatening per the National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.03 and, therefore, are 
always DLTs.
Page 82, Section 10.4.17, Banked Tumor Specimen Measurements
Existing Text: An archival or fresh tumor biopsy sample needs to be available for enrollment in 
Part 2. Archival tumor tissue will be collected from Part 1 patients whenever possible. 
 
 
 
 
 
Revised Text: An archival tumor tissue sample needs to be available for enrollment in Part 2. 
Archival tumor tissue will be collected from Part 1 patients whenever possible. 
 
 
 
 
 
Rationale for Amendment: To provide clarification.
Page 82, Section 10.4.18, Tumor Biopsies
Existing Text: For Part 2, access to a tumor biopsy is required. If a patient does not have archived 
tumor tissue for evaluation of the EBV status and analysis of biomarkers, a new fresh pretreatment 
biopsy is required. This new biopsy must be obtained at least 2 days after the last dose of any prior 
anticancer therapy and within 14 days before the first dose of study drug treatment. Patients 
undergoing tumor biopsy procedures must have a platelet count >75,000/mm3 and an activated 
partial thromboplastin time (aPTT) and prothrombin time (PT) within the normal range; must not 
have an ECOG performance status >1; must not be receiving any anticoagulant therapy or 
antiplatelet agents; and must not have any other known coagulation abnormalities that would 
contraindicate the tumor biopsy procedure. The tumor biopsy procedure will be performed by core 
needle, under radiological guidance if indicated, or surgically if the site of disease is superficial 
and palpable or visible.
Revised Text: For Part 2, access to a tumor biopsy is required. If a patient does not have archived 
tumor tissue for evaluation of the EBV status and analysis of biomarkers, a new fresh pretreatment 
biopsy is required. Patients undergoing tumor biopsy procedures must have a platelet count 
>75,000/mm3 and an activated partial thromboplastin time (aPTT) and prothrombin time (PT) 
within the normal range; must not have an ECOG performance status >1; must not be receiving 
any anticoagulant therapy or antiplatelet agents; and must not have any other known coagulation 
abnormalities that would contraindicate the tumor biopsy procedure. The tumor biopsy procedure 


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will be performed by core needle, under radiological guidance if indicated, or surgically if the site 
of disease is superficial and palpable or visible.
Rationale for Amendment: To allow for flexibility in obtaining fresh pretreatment biopsies.
Page 82, Section 10.4.18, Tumor Biopsies
Existing Text: For Part 2, access to a tumor biopsy is required. If a patient does not have archived 
tumor tissue for evaluation of the EBV status and analysis of biomarkers, a new fresh pretreatment 
biopsy is required. This new biopsy must be obtained at least 2 days after the last dose of any prior 
anticancer therapy and within 14 days before the first dose of study drug treatment. Patients 
undergoing tumor biopsy procedures must have a platelet count >75,000/mm3 and an activated 
partial thromboplastin time (aPTT) and prothrombin time (PT) within the normal range; must not 
have an ECOG performance status >1; must not be receiving any anticoagulant therapy or 
antiplatelet agents; and must not have any other known coagulation abnormalities that would 
contraindicate the tumor biopsy procedure. The tumor biopsy procedure will be performed by core 
needle, under radiological guidance if indicated, or surgically if the site of disease is superficial 
and palpable or visible.
Revised Text: For Part 2, access to a tumor tissue sample is required. If a patient does not have 
archived tumor tissue for evaluation of the EBV status and analysis of biomarkers, a new fresh 
pretreatment biopsy is required. Patients undergoing tumor biopsy procedures must have a platelet 
count >75,000/mm3 and an activated partial thromboplastin time (aPTT) and prothrombin time 
(PT) within the normal range; must not have an ECOG performance status >1; must not be 
receiving any anticoagulant therapy or antiplatelet agents; and must not have any other known 
coagulation abnormalities that would contraindicate the tumor biopsy procedure. The tumor 
biopsy procedure will be performed by core needle, under radiological guidance if indicated, or 
surgically if the site of disease is superficial and palpable or visible.
Rationale for Amendment: To provide clarification.
Page: Various, Section: Various
Existing Text: Existing text is not listed individually.
Revised Text: These changes are not listed individually.
Rationale for Amendment: Correct typographical errors, punctuation, grammar, and formatting.


 
 
 
 
 
 
 
 
ELECTRONIC SIGNATURES 
 
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Amendment 2 - An Umbrella Study to Evaluate MLN1117 in Combination with Taxanes
(Docetaxel or Paclitaxel) and Other Investigational Anticancer Agents for the Treatment of
Patients with Previously Treated Advanced and Metastatic Gastric and Gastroesophageal
Adenocarcinoma
Clinical Approval
30-Jan-2016 08:47
Clinical Pharmacology Approval
01-Feb-2016 13:53
Biostatistics Approval
01-Feb-2016 14:47
Clinical Approval
01-Feb-2016 17:45
PPD
PPD
PPD
PPD